Ipso-chlorosulfonylation of calixarenes: a powerful tool for the selective functionalization of the large rim

In our quest for the elaboration of supramolecular models of metallo-enzyme active sites, we became interested in developing new methodologies for the selective functionalization of the large rim of calix[6]arenes. Here, we describe a novel reaction, i.e. the ipso-chlorosulfonylation of calixarene derivatives. The process has been found to be highly efficient, selective and versatile. The regioselectivity is controlled by the nature of the O-substituents at the small rim. Indeed, when O-alkylated by a protonable imidazole group, the aromatic rings are deactivated toward an electrophilic attack and the anisol units can be selectively ipso-chlorosulfonylated under mild conditions (rt). Performing the reaction at a higher temperature allowed the per-chlorosulfonylation to take place. Hence, the synthesis of various sulfonate and sulfonamide derivatives is reported. Finally, a combination of ipso-nitration and chlorosulfonylation allows the per-functionalization of the aromatic units at the large rim in selective alternate positions. Overall, this novel methodology opens new routes to a variety of calixarenes, allowing the tuning of their physical properties without drastically altering their hydrophobic conic cavities.     

Calixarenes with nitrogen or phosphorus substituents on the lower rim

Calix[n]arenes (n=4,6) with diphenylphosphinite groups appended to their lower rim have been synthesized by reaction first with base, followed by chlorodiphenylphosphine. The reaction has also been carried out with the partially methoxylated calix[n]arenes. Calix[6]arenes with phosphate groups selectively bridging adjacent pairs of oxygens have been synthesized by reaction first with base, followed by ethyl dichlorophosphate. Calix[n]arenes (n=4,6) with 2-aminoethyloxy groups appended to the lower rim have been synthesized both by the reduction of an amide or nitrile group. Calixarenes with 2-hydroxyethyloxy and 2-bromoxyethyloxy groups appended to the lower rim have also been prepared. A route to preparing calixarene-functionalized polymers by the alkylation of polyethyleneimine is also described.This paper is dedicated to the commemorative issue on the 50th anniversary of calixarenes.     

Selective hetero-trisfunctionalization of the large rim of a biomimetic calix[6]arene using host-guest chemistry as a synthetic tool

A calix[6]arene has been selectively functionalized by three different groups at the large rim. The strategy relies on the hostguest recognition chemistry of a biomimetic metal complex at the small rim (so-called "funnel complex") and the Huisgen cycloaddition. The intramolecular thermal reaction proceeds with a high efficiency, chemio- and regioselectivity, allowing the monofunctionalization of one aromatic unit among three. Thanks to the high yield and selectivity of the reaction, it can be applied successively twice on the same compound, which opens the route for inherently chiral calix[6]arenes. This methodology not only is of wide potential for obtaining and exploiting calix[6]arenes that are dissymmetrized at the large rim, but also stands as an exemplary strategy for the selective appending of a functional group on a host platform.     

Solvent-driven dewetting and rim instability

An experimental method suitable for reproducible results has been used to investigate dewetting behavior of thin films of solvent-laden polymer. This solvent-driven dewetting enables one to change spreading coefficient by an order of magnitude that is not readily realizable in thermal dewetting and to study polar interactions that have not been fully exploited experimentally. While the film instability is similar to that found in thermal dewetting, the rim instability is quite different. Two different types of the rim instability have been found. With a polar solvent, the rim instability changes from one type to another with increasing film thickness whereas the unstable rim becomes stable for an apolar solvent.     

Photoswitchable ionophores based on 1,3-alternate calix[4]arenes bearing acridane units at the wide rim and bridged at the narrow rim by glycol chains

The complexation with alkali metal ions by calix[4]arenes with 1,3-alternate conformation bearing acridinium and acridane substituents at one rim and a glycol chain at the other rim has been studied by isothermal calorimetry. The thermodynamic parameters and the stoichiometry of the complexes are strongly influenced by the nature of the substituent (acridane or acridinium), by the solvent and by the length of the glycol chain. Both 9-methoxyacridane substituents are involved in the photoheterolysis leading to the corresponding acridinium calixcrowns. The nucleophilic attack of the methoxide leaving group reverses the reaction thermally. Therefore, the different complexation properties of acridane and acridinium calixcrowns can be switched on and off.     

Selectively formylated and bridged calix[6]arene derivatives at the upper rim

The strategy of bridging the anisole units at the upper rim of calix[6]arene has been applied to strain the conformations of calix[6]arene. Based on the selective formylation of the 1,3,5-tri-p-tert-butylcalix[6]arene, several new calix[6]arene derivatives with different 1,3-bridged chains or a 1,3,5-tripod bridge at the upper rim have been prepared with moderate yields. The ¹H NMR spectra indicate that these calix[6]arene derivatives adopt a cone conformation, which has also been confirmed by the theoretical calculation at AM1 level. X-ray crystal structure of 1,3,5-tripod bridged compound 5 discloses that the calix[6]arene host stands in a cone conformation with approximate C_3v symmetry, and that a methanol molecule is enclosed in its hydrophobic cavity and stabilized by multi hydrogen bonds.     

Synthesis of upper rim calix[4]arene divalent glycoclusters via amide bond conjugation

Synthetic routes for linking two sugar units at the upper rim of cone calix[4]arenes, through the formation of amide bonds, have been explored. Steric effects prevent the coupling of calix[4]arene dicarboxylic acid with simple aminoglycosides, whereas the corresponding reaction with carbohydrates bearing a two or three carbon atoms spacer, terminating with a primary amino group, allows the synthesis of several difunctionalized calix[4]arene neoglycoconjugates, attractive in chemical glycobiology and supramolecular chemistry.     

Preparation and evaluation of a chiral HPLC stationary phase based on cone calix[4]arene functionalized at the upper rim with l‐alanine units

Here we report a new chiral stationary phase (CSP) immobilized on silica gel based on cone calix[4]arene functionalized at the upper rim with two l ‐alanine units as new chiral selector that has been used in high‐performance liquid chromatography. The CSP was prepared by covalently bonding the allyl groups at the lower rim of calix[4]arene to silica gel by thiol‐ene click chemistry reaction. Elemental analysis of the CSP showed that 120 μmol of chiral selector bonded per gram of silica gel. 1‐Hexene was used for end‐capping of unreacted mercapto groups on silica gel. Since the CSP is chemically bonded to the silica, it can be used in the normal‐phase and reversed‐phase mode and with halogenated solvents as mobile phases, if desired. The chromatographic performance of the CSP was evaluated in the enantioseparation of the 3,5‐dinitrobenzoyl derivatives of some amino acids, diclofop‐methyl and dl ‐mandelic acid.     

Enantioselective recognition of phenylalanine by a chiral amphiphilic macrocycle at the air-water interface: a copper-mediated mechanism

The synthesis of a new chiral amphiphilic calix[4]resorcinarene, tetrakis(N-methylprolyl)tetraundecylcalix[4]resorcinarene (L-RA-Pro), bearing four L-prolyl moieties at the macrocyclic upper rim and four undecyl chains at the lower rim is described. This synthesis has been carried out via a Mannich-type reaction of L-proline and formaldehyde. It has been shown by means of Langmuir balance technique that L-RA-Pro self-assemble as well-defined monomolecular layers at the air-water interface. The effect of various cations on the stability of these monolayers has been studied. The experiments reveal that while there is a slight stabilization effect of K+, Cd2+, Co2+, Mg2+, and Ni2+, there is a high decrease in the collapse pressure in the presence of Cu(II) cation, showing that monolayers of L-RA-Pro, formed at the air-water interface, have a certain selectivity for copper(II) ions with regard to other cations tested. This supramolecular complex exhibits enantioselective recognition properties vs phenylalanine; the mechanism of this interaction is discussed.     

Synthesis and capsule formation of upper rim substituted tetra-acrylamido calix[4]arenes

Upper rim substituted tetraiodo calix[4]arenes are coupled to a variety of acrylamides using the palladium catalysed Heck reaction. Tetra-acrylamido upper rim substituted calix[4]arenes are obtained in good yields with exceptionally high stereoselectivity, to produce the all-trans isomers. Tetra-acrylamido calix[4]arenes derived from secondary acrylamides are shown to dimerise via eight hydrogen bonds to form dimeric capsules, which are able to include small organic molecules.     

Introduction of glyco, peptido, carboxy, and alkyno substituents at the calixarene exo rim via the p-bromodienone route

The conceptually novel "p-bromodienone route", which allows the direct introduction of nucleophiles at the calixarene exo rim, has been extended to anionic C-nucleophiles (acetylides) to give chiral meta-substituted alkynocalix[4]arenes and to appropriate O-nucleophiles to obtain para-substituted glyco, peptido, and carboxy derivatives.     

Synthesis and structure of lower rim C-linked N-tosyl peptidocalix[4]arenes

Chiral p-tert-butylcalix[4]arenes functionalized at the lower rim with amino acid residues have been prepared. The (1)H and (13)C NMR spectra indicate that the macrocycles preferably adopt a cone conformation. Calix[4]arenes bearing amino acid moieties were prepared as a class of receptors selective for anions that are bound through hydrogen bonding with the NH group. The association constants are dependent on the nature of the substituents at the lower rim. Derivative 9 shows the strongest complexation and the largest selectivity for N-tosyl-(L)-alaninate. Finally, a preliminary X-ray crystal study of the difunctionalized receptor 6f shows the "flattened cone" conformation in the solid state.     

Dynamic contact angle in rim instability of dewetting holes

The effects of dynamic contact angle (thetad), between a substrate and the melt of a dewetting polymer thin film, on the evolution of rim instabilities of dewetting holes were reported. Various thetad's were achieved by covering SiOx surfaces with different coverage of octadecyltrichlorosilane. On each surface, the morphology of the dewetting holes was examined in detail as the hole grew to a certain size. Rim instabilities, in terms of undulations in both r and z directions, became more pronounced as thetad increased, under which condition, narrower and higher rims were also observed. Experimentally, atomic force microscopic scans of the rim were used to obtain the rim profile, which was predicted using thetad. The predicted rim profile was used, in combination with the analysis of Rayleigh instability of a cylindrical fluid, to interpret the rim instability. The model captures the basic trend of the rim instability dependency on thetad. The study demonstrates the importance of the substrate properties on the rim instability and the destabilization of polymer thin films during hole growth.     

Monosubstituted lower rim thiacalix[4]arene derivatives

A clean and partially green route to monoalkyled thiacalix[4]arenes has been demonstrated. We have discovered that tetraalkylammonium halide can cleave selectively one of the two aryl alkyl ethers of dialkylated para-tert-butylthiacalix[4]arenes. Thus, p-tert-butyl thiacalix[4]arenes differently monoalkyled at the lower rim with acetyl, propyl, and benzyl group were synthesized in good yield.     

Lower rim mono-functionalization of resorcinarenes

A versatile, scaleable, one step synthesis of a lower rim mono-functionalized resorcinarene is described.     

1,3-Dipolar reactions involving corannulene: how does its rim and spoke addition vary?

[reaction: see text] Corannulene undergoes 1,3-dipolar reactions with the dipoles, diazomethane, nitrile oxide, and nitrone through its rim and spoke pi bonds; the rim addition yields "one possible" adduct whereas two "regioselective" adducts are formed by spoke addition. Mechanisms of these reactions have been investigated at the B3LYP/6-31G(d) level. Computations show that both rim and spoke additions prefer concerted pathways that lie 2-5 kcal/mol lower in energy than stepwise paths. Stepwise additions can take place in two ways and the activation energies of these two modes differ by 1-2 kcal/mol. A close inspection of the energy profiles reveals that rim addition is more favorable kinetically and thermodynamically than spoke addition in view of lower activation energy and higher exothermicity observed for rim addition. The rim bond of corannulene is more flexible for distortion and also has a stronger double bond (i.e. pi-character) than the spoke bond and this facilitates rim addition over spoke addition. Deformation energy analysis also confirms the above through higher deformation in corannulene from the spoke addition when compared to rim addition. In the spoke addition, regio1 reaction is kinetically more favored than regio2 reaction. Attempts to react corannulene in an endohedral fashion have led to the exohedral adduct. Computed activation energies suggest that corannulene acts as a deactivated dipolarophile compared to ethylene. Even more striking is the observation that rim and spoke double bonds in corannulene are part of the local aromatic system but it shows remarkable reactivity compared to benzene despite the loss of aromaticity during the reaction. This is well indicated by computed NICS values. Inclusion of acetonitrile as solvent through the PCM model increases the reaction rate and exothermicity.     

Diastereoselective lower rim (1S)-camphorsulfonylation as the shortest way to the inherently chiral calix[4]arene

[structure: see text]. A diastereomeric mixture of chiral 25-(1S)-camphorsulfonyloxy-26-isopropoxycalix[4]arene 2a (de 15%) and 25-isopropoxy-26-((1S)-10-camphorsulfonyl)calix[4]arene 2b has been obtained by asymmetrical lower rim (1S)-camphorsulfonylation of the monoisopropoxycalix[4]arene. Pure diastereomer 2a has been obtained by simple crystallization, and its absolute configuration has been determinated by X-ray analysis. Enantiomerically pure inherently chiral 5,11-dibromo-26-isopropoxycalix[4]arene 4 has been synthesized by the upper rim dibromination of the diastereomer 2a followed by hydrolytical removal of the auxiliary camphorsulfonyl group.     

Synthesis and characterization of upper and lower rim functionalized [6]cavitands

A [6]cavitand has been selectively derivatized on both the lower and upper rims. On the lower rim, two out of six potential sites were oxidized to produce a 1,4 substituted [6]cavitand bisketone, which was converted to a corresponding diol as well as a bisacetate [6]cavitand. The crystal structures of the bisketone and the diol were solved. On the upper rim, all six ArCH(3) groups were selectively brominated to ArCH(2)Br groups to produce the hexabromomethyl [6]cavitand, which was converted to the corresponding hexabenzylthiol and hexabenzylthioacetate [6]cavitands. The conformational properties of all compounds are discussed.     

A novel method for the upper rim alkoxy-substitution of calix[4]arene via a bis(spirodienone) route

A mild and efficient one-step procedure for the upper rim modification of calix[4]arene via a bis(spirodienone) is described. The bis(spirodienone) on reaction with alcohols in the presence of p-TSA affords mono- and 1,3-disubstituted alkoxy derivatives in moderate to good yields.     

Aminomethylated calix[4]resorcinolarenes with NH groups on the upper rim of the molecule

The reaction of calix[4]resorcinolarenes with N,N-dimethylethylenediamine and aqueous CH₂O in a molar ratio of 1 : 5 : 5 affords calixarenes containing secondary amino groups arranged on the upper rim of the molecule. When the double amount (with respect to primary amine) of formalin is used (ratio of reactants 1 : 5 : 10), cavitands with four oxazinyl fragments are synthesized.