Conformational analysis of p-tert-butylcalix[4]arene derivatives with trans-alkyl substituents on opposite methylene bridges: destabilization of the cone form by axial alkyl substituents

The stereochemistry of calix[4]arenes substituted by a pair of identical alkyl substituents in a trans fashion at two distal bridges is analyzed. MM3 calculations suggest that increasing the bulk of the alkyl group at the bridges destabilizes those conformations possessing an axial disposition of the substituent. In contrast to the 1,3-dimethyl ether of p-tert-butylcalix[4]arene, which adopts a cone conformation, solution NMR data indicate that the 1,2-alternate conformation is preferred in the dimethyl ether derivatives 5b (alkyl = i-Pr) and 5c (alkyl = t-Bu). In the derivative substituted by the less bulky methyl substituent (5a), both the cone and 1,2-alternate forms coexist in CDCl3. Increasing the polarity of the solvent increases the relative population of the cone form of 5a and 5b. The steric destabilization ensuing from the presence of the axial substituent is so large in the cone conformation of 5c that the 1,2-alternate conformer is the major form even in polar solvents. The cone --> 1,2-alternate interconversion barrier of 5a is 18.2 kcal mol(-1), indicating that the presence of an axial methyl group both destabilizes the cone conformation and decreases its rigidity.     

Impact of multiple cation-pi interactions upon calix[4]arene substrate binding and specificity

The cation-pi interaction influence on the conformation and binding of calix[4]arenes to alkali-metal cations has been studied using a dehydroxylated model. The model allows for the separation of cooperative cation-pi and electrostatic forces commonly found in the binding motifs found in calixarene complexes. Starting from the four well-known calix[4]arene conformations, six conformers for this dehydroxylated model (cone, partial cone, flattened cone, chair, 1,2-alternate, and 1,3-alternate) have been characterized by geometry optimization and frequency analysis using the Becke three-parameter exchange functional with the nonlocal correlation functional of Lee, Yang, and Parr and the 6-31G(d) basis set. Without the stabilization provided by the hydroxyl hydrogen bonds in calix[4]arene, neither the cone nor the 1,2-alternate conformation is computed to be a ground-state structure. The partial cone, flattened cone, chair, and 1,3-alternate conformers have been identified as ground-state structures in a vacuum, with the partial cone and the 1,3-alternate as the lowest energy minima in the aromatic model. The C(4)(v)() cone conformation is found to be a transition structure separating the flattened cone (C(2)(v)()) conformers. The energetic and structural preferences of the calix[4]arene model change dramatically when it is bound to Li(+), Na(+), and K(+). The number of pi-faces, the positioning of these pi-faces with respect to the cations, and the nature of the cation were studied as factors in the binding strength. A detailed study of the distances and angles between the aromatic ring centroids and the cations reveals the energetic advantages of multiple weak cation-pi interactions. The geometries are often far from the optimal cation-pi interaction in which the cation approaches in a perpendicular path the aromatic ring center, where the quadrupole moment is strongest. The results reveal that multiple weaker nonoptimal cation-pi interactions contribute significantly to the overall binding strength. This theoretical analysis underscores the importance of neighboring aromatic faces and provides new insight into the significance of cation-pi binding, not only for calix[4]arenes, but also for other supramolecular and biological systems.     

Synthesis and conformational evaluation of p-tert-butylthiacalix[4]arene-crowns

Bridging of p-tert-butylthiacalix[4]arene afforded 1,3-dihydroxythiacalix[4]arene-monocrown-5 (3b), 1,2-alternate thiacalix[4]arene-biscrown-4 and -5 (4a,b), and 1,3-alternate thiacalix[4]arene-biscrown-5 and -6 (5a,b), depending on the metal carbonates and oligoethylene glycol ditosylates used. Starting from 1,3-dialkylated thiacalix[4]arenes, the corresponding bridging reaction gave 1,3-alternate, partial-cone, and cone conformers 10-19, depending on the substituents present. Temperature-dependent studies revealed that the conformationally flexible 1,3-dimethoxythiacalix[4]arene-crowns 10a-c exclusively occupy the 1,3-alternate conformation. Demethylation exclusively gave the cone 1,3-dihydroxythiacalix[4]arene-crowns (3a,c), which could not be obtained by direct bridging of thiacalix[4]arene. The different structures were assigned on the basis of several X-ray crystal structures and extensive 2-D (1)H NMR studies.     

Preparation and conformation of dioxocalix[4]arene derivatives

CrO(3) oxidation experiments conducted on atropisomeric forms of 2 (2(paco), 2(1,3)(-)(alt), and 2(1,2)(-)(alt)) indicate that under the reaction conditions only methylene groups located between pairs of geminal rings oriented in an anti disposition are oxidized to carbonyls. NMR data suggest that the tetrahydroxydioxocalix[4]arenes 7 and 9 adopt the partial cone and 1,2-alternate conformations, respectively. In the crystal structure of 7.2EtOAc the dioxocalixarene adopts a partial cone conformation, whereas 9 adopts in the crystal a 1,2-alternate conformation. In both conformations, pairs of geminal rings connected to a carbonyl are oriented in an anti fashion. The relative stability of the partial cone and 1,2-alternate conformations of 7 and 9 is underestimated by MM3 calculations. The topomerization barriers of 7 and 9 are 12.8 and 13.6 kcal mol(-)(1), respectively.     

Band intensity in the IR spectra and conformations of calix[4]arene and thiacalix[4]arene

The experimental IR and Far IR spectra of the calix[4]arene, p-tert-butylcalix[4]arene, thialcalix[4]arene and p-tert-butylthiacalix[4]arene were examined at different temperatures and interpreted. The band frequencies and intensities in the IR spectra of the calix[4]arene and thialcalix[4]arene were calculated. The absorption curves of the four possible calix[4]arene conformations: cone, partial cone, 1,2- and 1,3-alternate were computed. The bands characteristic for each conformation are defined and assigned. The obtained spectra-structure correlation can be used for the characteristic of calixarenes conformation.     

Intramolecular hydrogen bonding effect on metal ion complexation of homooxacalix[4]arene bearing tetraamides

N,N-Dipentylamido homooxacalix[4]arene (3) in the C-1,2-alternate conformation provided Pb²⁺ ion selectivity over other metal cations. N-Monopentylamido homooxacalix[4]arene in C-1,2-alternate conformation has an intramolecular hydrogen bonding, causing decrease of the metal ion complex ability.     

Exchange coupling mediated through-bonds and through-space in conformationally constrained polyradical scaffolds: calix[4]arene nitroxide tetraradicals and diradical

Calix[4]arenes constrained to the 1,3-alternate conformation and functionalized at the upper rim with four and two tert-butylnitroxides have been synthesized and characterized by X-ray crystallography, magnetic resonance (EPR and (1)H NMR) spectroscopy, and magnetic studies. The 1,3-alternate nitroxide tetraradical and diradical provide unique polyradical scaffolds for dissection of the through-bond and through-space intramolecular exchange couplings. In addition, detailed magnetic studies of the previously reported calix[4]arene nitroxide tetraradical, which possesses cone conformation in solution, reveal conformational dependence of exchange coupling. Through-bond coupling between the adjacent nitroxide radicals is mediated by the nitroxide-m-phenylene-CH(2)-m-phenylene-nitroxide coupling pathway, and through-space coupling is found between the diagonal nitroxide radicals at the conformationally constrained N...N distance of 5-6 A. Magnetic studies of the calix[4]arene polyradical scaffolds in frozen solutions show that the through-bond exchange coupling in the 1,3-alternate calix[4]arene tetraradical is antiferromagnetic, while that in cone calix[4]arene tetraradical is ferromagnetic. The through-space exchange couplings are antiferromagnetic in both cone and 1,3-alternate calix[4]arene tetraradical, as well as in the 1,3-alternate calix[4]arene diradical. The exchange coupling constants (|J/k|) are of the order of 1 K.     

Tetra-TTF calix[4]pyrrole: a rationally designed receptor for electron-deficient neutral guests

A calix[4]pyrrole incorporating four appended tetrathiafulvalene (TTF) units has been synthesized, and its receptor abilities toward neutral electron-deficient guests, such as 1,3,5-trinitrobenzene, tetrafluoro-p-benzoquinone, and tetrachloro-p-benzoquinone, have been studied in solution by UV-vis and 1H NMR spectroscopies as well as in the solid-state by X-ray crystallography. In its 1,3-alternate conformation a 1:2 sandwich-like complex-stabilized by charge transfer and hydrogen bonding interactions-is formed between the tetra-TTF calix[4]pyrrole and the guest molecules. However, upon addition of chloride ions to the complex the 1,3-alternate conformation is changed in favor of a cone conformation which serves to effect a release of the guests from the tetra-TTF calix[4]pyrrole.     

Synthesis and interaction with copper(II) cations of cyano- and aminoresorcin[4]arenes

Following our studies on resorcin[4]arenes, we synthesized new macrocycles containing cyanomethyl and aminomethyl side chains. Three stereoisomers (2a-c) of the former were obtained by BF3*Et2O tetramerization of the corresponding trans-cinnamic acid derivative and were shown to be in the 1,2-alternate, cone, and 1,3-alternate conformations. Conversely, the tetraamino derivative 6a in the cone conformation was prepared from the corresponding tetrabromide 3a. The interactions with Cu(II) cations of the new compounds were analyzed by measurements of 1H NMR and EPR spectra in parallel with molecular modeling calculations.     

Di-ionizable calix[4]arene-1,3-crown-4 ligands in 1,3-alternate,cone, and partial-cone conformations: synthesis and metal ion extractions

Di-ionizable calix[4]arene-1,3-crown-4 compounds locked in 1,3-alternate, cone, and partial-cone conformations are synthesized for evaluation in metal ion separations. The ionizable functions include carboxylic acid and N-(X)sulfonyl carboxamide groups in which the acidity is tuned by variation of the electron-withdrawing ability of X. Similar synthetic routes were employed for preparation of the cone and 1,3-alternate ligand series. A different preparative route utilizing protection and deprotection was required to obtain the partial-cone analogues. Ligand conformations were confirmed by their proton and/or carbon NMR spectra. X-ray diffraction verified an unusual 1,2-alternate conformation in the solid-state for one synthetic intermediate. Effects of ligand conformation and ionizable group variations on competitive solvent extractions of alkali and alkaline earth metal cations from aqueous solutions into chloroform were assessed. Single species solvent extractions of Hg²⁺ and Pb²⁺ were also performed.     

The hydrogen bonding and conformations of p-tert-butylcalix[4]arene as studied by IR spectroscopy and by DFT calculations

IR and far IR spectra of p-tert-butylcalix[4]arene were recorded at various temperatures between 16 and 180 degrees C and spectra of solutions and crystalline solids were obtained. Ab initio density functional calculations gave vibrational frequencies and infrared intensities for four conformers: cone, partial cone, 1,2- and 1,3-alternate. Complete assignments were made for experimental IR spectra of the cone conformer. The bands characteristic for each conformation were defined. It was revealed that O--H stretching low-frequency shift Deltanu in the cone conformation exceeds Deltanu shifts for other conformers. The effect was stipulated by a cooperative interaction of cyclic hydrogen bonds. The obtained spectra-structure correlation can be used for characteristic of calixarenes conformation.     

Exploring the dynamics of calix[4]pyrrole: effect of solvent and fluorine substitution

Molecular dynamics simulations show that calix[4]pyrrole (CP) and octafluorocalix[4]pyrrole (8F-CP) are extremely flexible molecules. CP mainly adopts the 1,3-alternate conformation in all the solvents, although the percentage of alternative conformations increases in polar solvents, especially those with good hydrogen-bonding acceptor properties. However, in the case of 8F-CP, the cone conformation is the most populated in some solvents. Transitions between conformers are common and fast, and both CP and 8F-CP can adopt the cone conformation needed for optimum interaction with anions more easily than would be predicted on the basis of previous gas-phase calculations. Furthermore, the present studies show that when a fluoride anion is specifically placed initially in close proximity to CP and 8F-CP in their respective 1,3-alternate conformations, an extremely fast change to the cone conformation is observed in both cases. The results suggest that preorganization does not represent a major impediment to anion-binding for either CP or 8F-CP, and that ion-induced conformational changes can follow different mechanisms depending on the solvent and the chemical substituents present on the calix[4]pyrrole beta-pyrrolic positions.     

1,3-Alternate calix[4]arenes, selectively functionalized by amino groups

General strategies are described to synthesize calix[4]arenes which are fixed in the 1,3-alternate conformation and substituted selectively by amino groups. These derivatives are useful starting materials for the attachment of various groups via amide bonds, as demonstrated by several examples, but may be converted also to ureas, imides or azomethines. Four amino groups may be attached to the narrow rim via(several) methylene groups as spacer by O-alkylation with omega-bromophthalimides or omega-bromonitriles. From the resulting tetraethers the amino functions are obtained by cleavage with hydrazine or by hydrolysis, allowing a selective functionalisation of both sides of the molecule (phenolic units A, C versus B, D). Amino functions at the wide rim are introduced by ipso-nitration of the respective t-butylcalix[4]arene derivatives and subsequent reduction. Selective ipso-nitration of a 1,3-diether, followed by O-alkylation with allylbromide to obtain the tetraether in the 1,3-alternate conformation, hydrogenation of allyl and nitro groups (in one step), protection of the amino functions as phthalimides followed by ipso-nitration of the remaining t-butyl phenol rings, allows again to distinguish both sides of the molecule (units A, C versus B, D). Reaction of a wide rim tetraamine in the 1,3-alternate conformation by Boc-anhydride allows not only to obtain the mono- and tri-Boc derivative, but also in nearly 60% yield the C2-symmetrical di-Boc derivative, in which two adjacent phenolic units are protected (distinction of A, B from C, D). This paves the way for the preparation of chiral derivatives or assemblies. O-Alkylation with omega-bromophthalimides followed by ipso-nitration leads to precursors for octaamines in the 1,3-alternate conformation, in which the potential amino functions on both rims can be selectively "activated" by reduction or hydrazinolysis. The structures of the newly synthesized molecules were mainly confirmed by their 1H NMR spectra, which allow a distinction from isomeric derivatives in the cone and partial cone conformation. Single crystal X-ray analyses were obtained for two analogous derivatives in the 1,3-alternate conformation (27, n = 3,4), an isomeric compound in the cone conformation (27, n = 3,4), and a derivative in the partial cone conformation (11).     

Selective synthesis and isolation of all possible conformational isomers of proximally para-disubstituted calix[4]arene

All six possible conformational isomers of the proximally p-dibrominated calix[4]arene tetraalkyl ether, 1a-f*, were selectively synthesized by appropriate control of stereochemistry during di-O-alkylation reactions of 5,11-dibromocalix[4]arene syn-dialkyl ethers, namely, 5,11-dibromo-27,28-dihydroxy-25,26-dipropoxy-, 5,11-dibromo-25,26-dihydroxy-27,28-dipropoxy-, 5,11-dibromo-25,28-dihydroxy-26,27-propoxy-, and 5,11-dibromo-26,28-dihydroxy-25,27-dipropoxycalix[4]arenes. Their conformations were confirmed by (1)H and (13)C NMR spectroscopy and are cone for 1a (u(Br)(Pr), u(Br)(Pr), u(H)(Pr),u(H)(Pr)), partial cone for 1b (u(Br)(Pr), d(Br)(Pr), u(H)(Pr),u(H)(Pr)) and 1d (u(Br)(Pr), u(Br)(Pr), u(H)(Pr),d(H)(Pr)), 1,2-alternate for 1c (u(Br)(Pr), u(Br)(Pr), d(H)(Pr),d(H)(Pr)) and 1e (u(Br)(Pr), d(Br)(Pr), d(H)(Pr),u(H)(Pr)), and 1,3-alternate for 1f (u(Br)(Pr), d(Br)(Pr), u(H)(Pr),d(H)(Pr)). Although both 1c and 1e are in the 1,2-alternate conformation, the conformation of 1e was found to be strongly distorted and distinct from that of 1c.     

Partially O-alkylated thiacalix[4]arenes: synthesis, molecular and crystal structures, conformational behavior

NMR spectroscopy, X-ray diffraction analysis, and quantum chemical calculations were used for conformational behavior study of partially alkylated thiacalix[4]arenes bearing methyl (1), ethyl (2), or propyl (3) groups at the lower rim. The conformational properties are governed by two basic effects: (i) stabilization by intramolecular hydrogen bonds, and (ii) sterical requirements of the alkoxy groups at the lower rim. While the monosubstituted derivatives 1a and 3a adopt the cone conformation in solution, distally disubstituted compounds 1b, 1'b, 2b, 2'b, 3b, and 3'b exhibit several interesting conformational features. They prefer pinched cone conformation in solution, and, except for 3'b, they form also 1,2-alternate conformation, which is flexible and undergoes rather fast transition between two identical structures. The crystal structures of the compounds 1b, 2b, 2'b, and 3b revealed yet quite rare 1,2-alternate conformation forming molecular channels held together by pi-pi interactions. Different channels-with hexagonal symmetry, 0.26 nm wide-are formed in the crystal structure of the pinched cone conformation of 3b. An uncommon hydrogen bonding pattern was found in dimethoxy and dipropoxy derivatives 1'b and 3'b that adopt distorted cone conformations in crystal. Trialkoxy-substituted compounds 1c and 3c adopt the partial cone conformation in solution. A higher mobility of methyl derivative 1c enables also existence of the cone conformer.     

S-alkylation of thiacalixarenes: how the regio- and stereoselectivities depend on the starting conformation

S-alkylation of all four thiacalix[4]arene conformations was accomplished using alkyl triflates. The corresponding sulfonium salts are formed in a highly regio- and stereoselective manner depending on the conformation used. Interestingly, only mono- or disubstituted sulfonium salts can be prepared. Although many regio- and stereoisomers are theoretically possible, only one dialkylated cone and 1,2-alternate derivatives were formed, while only a single isomer of monoalkylated partial cone and 1,3-alternate were isolated. The combination of experimental results with the quantum-chemical approach using the B3LYP/6-311G(d,p) method resulted in the elucidation of the rules governing the regio- and stereochemical outcomes of the alkylation reactions. All S-alkylated compounds represent a novel type of substitution pattern in calixarene chemistry showing the wide-ranging possibility of thiacalixarene skeleton modifications.     

Cascade and commutative self-assembles of nanoscale three-component systems controlled by the conformation of thiacalix[4]arene

In this work, the formation of two- and three-component supramolecular systems based on cone, partial cone, 1,3-alternate stereoisomers of heteroditopic "hosts": p-tert-butylthiacalix[4]arene containing 4-amidopyridine fragments with silver(I) cations and dicarboxylic acids in liquid and solid phases were studied by UV spectroscopy, dynamic light scattering, and atomic force microscopy methods. It has been shown that these macrocycles are coreceptors, capable of simultaneously binding silver(I) cations, dicarboxylic acids (oxalic, malonic, succinic, maleic, fumaric acids), and hydroxyl acids (glycol, tartaric acids). For the first time, by the dynamic light scattering method, it has been shown that the conformation of p-tert-butyl thiacalix[4]arenes significantly affects the type of three-component system formed: cone is characterized by the formation of cascade systems; for partial cone, intermediate systems; and for the 1,3-alternate stereoisomers, three types of three-component systems (cascade, intermediate, and commutative) were observed.     

A "classical" tetrahydroxycalix[4]arene adopting the 1,2-alternate conformation

The first example of a "classical" tetrahydroxycalixarene, which adopts the 1,2-alternate conformation both in solution and in the crystal, is described. Calixarene derivatives with two distal methylene groups substituted in a trans fashion by phenyl (5a) or mesityl (5b) groups were synthesized via addition of PhMgBr/CuCN or MesMgBr/CuCN to the bis(spirodiene) derivative 3. Whereas the phenyl-substituted calixarene derivative 5a adopts the usual "cone" conformation, solution NMR data and X-ray crystallography indicate that the more crowded mesityl derivative 5b adopts a 1,2-alternate conformation with the two mesityl groups located at isoclinal positions of the macrocycle.     

The extraction of thallium(I) and silver(I) ions with 1,3-alternate calix[4]arene derivatives

Tetraallyloxy and tetrabenzyloxy derivatives of calix[4]arenes in cone and 1,3-alternate conformations were synthesised and their capacity to extract thallium(I) and silver(I) ions was investigated. ??Low??-temperature single crystal X-ray structure determinations were recorded for two derivatives in which the calixarene conformation was that of an alternating cone, the aromatic rings lying closely quasi-parallel to the $ \overline{4} $ -axis of the cone. The structure of a tetraallyloxy derivative in the cone conformation was also determined in which a molecule of acetonitrile was included within the calixarene cavity.     

Complexation properties and characterization of four conformers of a [2.1.2.1]metacyclophane

Cone, partial cone, 1,2-alternate, and 1,4-alternate conformers of tetrakis[(ethoxycarbonyl)-methoxy] [2.1.2.1]metacyclophane (MCP,2) were isolated and characterized by¹H-NMR and an X-ray crystal structure analysis of the 1,4-alternate conformer. Of the four conformers, only the cone conformer2d forms a complex with alkali metals. The stability constants of2d with alkali metal ions were determined by the direct¹H-NMR method and UV spectra, and the order observed as potassium cesium, sodium ions.This paper is dedicated to the commemorative issue on the 50th anniversary of calixarenes.