Anion binding studies of fluorinated expanded calixpyrroles

The anion binding properties of fluorinated calix[n]pyrroles (n = 4-6) in aprotic solvents (acetonitrile and DMSO) and modified reaction conditions allowing for the synthesis and isolation of the hitherto missing dodecafluorocalix[6]pyrrole from the condensation of 3,4-difluoro-1H-pyrrole and acetone are described. In acetonitrile solution containing 2% water, the association constants for the 1:1 binding interaction between octafluorocalix[4]pyrrole and chloride anion obtained with isothermal titration calorimetry (ITC) and (1)H NMR titration methods were found to match reasonably well. As compared to its nonfluorinated congener, octafluorocalix[4]pyrrole was found to display enhanced binding affinities for several representative anions in pure acetonitrile as judged from ITC analyses. Similar analyses of the fluorinated calix[n]pyrroles revealed an increase in the relative affinity for bromide over chloride with increasing macrocycle size, as manifest in a decrease in the binding ratio K(a(Cl))/K(a(Br)). Anion binding studies in the solid state, involving single-crystal X-ray diffraction analyses of the chloride and acetate anion complexes of octafluorocalix[4]pyrrole and decafluorocalix[5]pyrrole, respectively, confirmed the expected hydrogen bond interactions between the pyrrolic NH protons and the bound anions.     

Anion-Sensing Properties of Cyclopentaphenylalanine

Cyclic pentaphenylalanine was studied as an efficient anion sensor for halides, thiocyanate and oxoanions in acetonitrile and methanol. Stability constants of the corresponding complexes were determined by means of fluorimetric, spectrophotometric, ¹H NMR, and microcalorimetric titrations. A detailed structural overview of receptor–anion complexes was obtained by classical molecular dynamics (MD) simulations. The results of ¹H NMR and MD studies indicated that the bound anions were coordinated by the amide groups of cyclopeptide, as expected. Circular dichroism (CD) titrations were also carried out in acetonitrile. To the best of our knowledge, this is the first example of the detection of anion binding by cyclopeptide using CD spectroscopy. The CD spectra were calculated from the structures obtained by MD simulations and were qualitatively in agreement with the experimental data. The stoichiometry of almost all complexes was 1:1 (receptor:anion), except for dihydrogen phosphate where the binding of dihydrogen phosphate dimer was observed in acetonitrile. The affinity of the cyclopeptide receptor was correlated with the structure of anion coordination sphere, as well as with the solvation properties of the examined solvents.     

Anion Recognition with Antimony(III) and Bismuth(III) Triaryl-Based Pnictogen Bonding Receptors

The synthesis and characterisation of a library of acyclic antimony(III) and bismuth(III) triaryl pnictogen bonding (PnB) receptor systems are reported. In the first-generation receptor series, quantitative ¹H NMR chloride titration experiments in THF solvent media reveal halide anion binding potency is intimately correlated with both the electronic-withdrawing nature of the aryl- substituent and the polarisability of the PnB donor. Further extensive anion binding investigations with the most potent Sb- and Bi-based PnB receptors: 1⋅Sb^2CF3 and 1⋅Bi^2CF3 , reveal novel selectivity profiles, both displaying Cl⁻ selectivity relative to the heavier halides and, impressively, to a range of highly basic oxoanions. The synthesis and preliminary chloride anion binding studies of a series of novel tripodal tris-proto-triazole triaryl Sb(III) and Bi(III) mixed PnB-HB receptor systems are also described. Whereas parent triphenyl Sb(III) and Bi(III) compounds are incapable of binding Cl⁻ in THF solvent media, the PnB-triazole HB host systems exhibit notable halide affinity.     

Anion binding behavior of heterocycle-strapped calix[4]pyrroles

A comparative study of the halide and benzoate anion binding properties of a series of phenyl, pyrrole, and furan-strapped calix[4]pyrroles has been carried out. These receptors, which have previously been shown to bind the chloride anion (Yoon et al., Angew. Chem., Int. Ed. 47(27):5038–5042, 2008), were found to bind bromide and benzoate anion (studied as the corresponding tetrabutylammonium salts) with near equal affinity in acetonitrile, albeit less well than chloride, as determined from ITC measurements or NMR spectroscopic titrations. This stands in marked contrast to the parent octamethylcalix[4]pyrrole, where the carboxylate anion affinities are substantially higher than those for bromide anion under identical conditions. This finding is rationalized in terms of tighter binding cavity present in the strapped systems. For all three anions for which quantitative data could be obtained (i.e., Cl^?, Br^?, PhCO₂ ^?), the pyrrole-strapped system displayed the highest affinity, although the relative enhancement was found to depend on the anion in question. In the specific case of fluoride anion binding to the pyrrole-strapped receptor, two modes of interaction are inferred, with the first consisting of binding to the calix[4]pyrrole via NH-anion hydrogen bonds, followed by a process that involves deprotonation of the strapped pyrrolic NH proton. A single crystal X-ray diffraction analysis provides support for the first of these modes and further reveals the presence of a methanol molecule bound to the fluoride anion.     

Clipping and stoppering anion templated synthesis of a [2]rotaxane host system

A new [2]rotaxane host system containing nitro-isophthalamide macrocycle and polyether functionalised pyridinium axle components is prepared via clipping and stoppering synthetic methodologies using chloride anion templation. After removing the chloride anion template, (1)H NMR titration experiments reveal the unique interlocked host cavity to be highly selective for binding chloride and bromide in preference to basic oxoanions in competitive aqueous solvent mixtures. The rotaxane host system proved to be a superior anion complexant in comparison to the individual macrocycle and axle components. The anion binding affinity of the novel rotaxane is also investigated via molecular dynamics simulations and in general the structural data obtained corroborates the experimental solution anion recognition behaviour.     

Dipyrrolyl-functionalized bipyridine-based anion receptors for emission-based selective detection of dihydrogen phosphate

New cationic anion receptors, based on the use of pyrrole-substituted bipyridine and coordinated to transition metals, are described. Specifically, polypyridine-ruthenium and -rhodium cores have been functionalized to generate an anion binding site. The design was chosen to probe the influence of the pyrrole-to-pyrrole separation on anion-binding affinities and selectivities; this distance is greater in the new systems of this report (receptors 1 and 2) relative to that present in related dipyrrolyl quinoxaline based receptors 3 and 4. Solution-phase anion-binding studies, carried out by means of (1)H NMR spectroscopic titrations in [D(6)]DMSO and isothermal titration calorimetry (ITC) in DMSO, reveal that 1 and 2 bind most simple anions with substantially higher affinity than either 3 or 4. In the case of chloride anion, structural studies, carried out by means of single-crystal X-ray diffraction analyses, are consistent with the solution-phase results and reveal that receptors 1 and 2 are both able to stabilize complexes with this halide anion in the solid state.     

Anion recognition by neutral macrocyclic amides

Although amides often serve as anchoring groups in natural and synthetic anion receptors, the structure-affinity relationship studies of amide-based macrocyclic receptors are still very limited. Therefore, we decided to investigate the influence of the size of the macroring on the strength and selectivity of anion binding by uncharged, amide-based receptors. With this aim, we synthesized a series of macrocyclic tetraamides derived from 2,6-pyridinedicarboxylic acid and aliphatic alpha,omega-diamines of different lengths. X-ray analysis shows that all ligands studied adopt expanded conformations in the solid state with the convergent arrangement of all four hydrogen-bond donors. 1H NMR titrations in DMSO solution revealed a significant effect of the ring size on the stability constants of anion complexes; the 20-membered macrocyclic tetraamide 2 is a better anion receptor than its both 18- and 24-membered analogues. This effect cannot be interpreted exclusively in terms of matching between anion diameter and the size of macrocyclic cavity, because 2 forms the most stable complexes with all anions studied, irrespective of their sizes. However, geometric complementarity manifests in extraordinarily high affinity of 2 towards the chloride anion. The results obtained for solutions were interpreted in the light of solid-state structural studies. Taken together, these data suggest that anion binding by this family of macrocycles is governed by competitive interplay between their ability to adjust to a guest, requiring longer aliphatic spacers, and preorganization, calling for shorter spacers. The 20-membered receptor 2 is a good compromise between these factors and, therefore, it was selected as a promising leading structure for further development of anion receptors. Furthermore, the study of an open chain analogue of 2 revealed a substantial macrocyclic effect. X-ray structure of the acyclic model 14 suggests that this may be due to its ill-preorganized conformation, stabilized by two intramolecular hydrogen bonds.     

7,7′‐Diamino‐2,2′‐diindolylmethane: A Building Block for Highly Efficient and Selective Anion Receptors—Studies in Solution and in the Solid State

The easy‐to‐make 7,7′‐diamino‐2,2′‐diindolylmethane was used as a building block for the construction of anion receptors operating by hydrogen bonds. Its various bisamide and bisurea derivatives were designed and synthesised as acyclic as well as macrocyclic molecules, then their structural and anion binding properties were studied in solution and in the solid state. The bisamide receptors demonstrate high affinity towards oxoanions in highly polar and partially aqueous solutions (DMSO with up to 25 % H₂O) with significant selectivity for dihydrogen phosphate. Remarkably, the bisurea‐based molecules are able to bind anionic guests even in pure methanol and show selectivity toward tetrahedral oxoanions, that is, hydrogen sulphate and dihydrogen phosphate. X‐ray analysis revealed that both classes of molecules adopt a similar conformation in the solid state: a bent sheet shape with a binding pocket equipped with hydrogen‐bond donors (four for the amides and six for the bisureas), whose orientation is particularly tailored for oxoanions. The results of ROESY NMR experiments are in agreement with the findings for the solid state and confirmed that both bisamides and bisureas can easily adapt the conformation with convergent hydrogen‐bond donors, which is highly suitable for anion binding.     

Synthesis and X-ray Structures of Novel Macrocycles and Macrobicycles Containing N,N-Di(pyrrolylmethyl)-N-methylamine Moiety: Preliminary Anion Binding Study

The [2 + 2] Schiff base condensation reactions between the newly synthesized dialdehyde, N,N-di(α-formylpyrrolyl-α-methyl)-N-methylamine), and ethylenediamine or p-phenylenediamine dihydrochloride readily afforded the 30- and 34-membered large size macrocycles in very high yields. Subsequent reduction reactions of these macrocycles with NaBH(4) gave the corresponding saturated macrocyclic hexaamines in good yields. The analogous reaction of the new dialdehyde with a triamine molecule afforded the [3 + 2] Schiff base macrobicycle in high yield, which was then reduced by reaction with NaBH(4) to give the saturated macrobicycle. All these compounds were characterized by spectroscopic methods. The anion binding properties of the saturated macrocycles having the ethylene and the phenylene linkers in CDCl(3) were studied by NMR titration methods. Although they have similar pyrrolic and amine NH groups their binding properties are different and interesting, owing to the conformational flexibility or rigidness rendered by the ethylene or phenylene groups, respectively. The macrocycle having the ethylene linkers binds anions in a 1:1 fashion, while the other receptor having the phenylene linkers prefers to bind anions in a sequential 1:2 fashion and has a multiple equilibria between a 1:1 and a 1:2 complexes, as shown by their binding constants, curve fittings by EQNMR, and Job plots. The X-ray structures of the 1:2 methanol, the aqua and the benzoate anion complexes of the macrocycles show two cavities in which the guests are bound, correlating with the high affinity found for the formation of stable 1:2 complexes in solution. The X-ray structure showed that the macrobicycle Schiff base adopts an eclipsed paddle-wheel shaped conformation and exhibits an out-out configuration at the bridgehead nitrogen atoms.     

Structure-activity relationships in tripodal transmembrane anion transporters: the effect of fluorination

A series of easy-to-make fluorinated tripodal anion transporters containing urea and thiourea groups have been prepared and their anion transport properties studied. Vesicle anion transport assays using ion-selective electrodes show that this class of compound is capable of transporting chloride through a lipid bilayer via a variety of mechanisms, including chloride/H(+) cotransport and chloride/nitrate, chloride/bicarbonate, and to a lesser extent an unusual chloride/sulfate antiport process. Calculations indicate that increasing the degree of fluorination of the tripodal transmembrane transporters increases the lipophilicity of the transporter and this is shown to be the major contributing factor in the superior transport activity of the fluorinated compounds, with a maximum transport rate achieved for clog P = 8. The most active transporter 5 contained a urea functionality appended with a 3,5-bis(trifluoromethyl)phenyl group and was able to mediate transmembrane chloride transport at receptor to lipid ratios as low as 1:250000. Proton NMR titration and single crystal X-ray diffraction revealed the ability of the tripodal receptors to bind different anions with varying affinities in a 1:1 or 2:1 stoichiometry in solution and in the solid state. We also provide evidence that the most potent anion transporters are able to induce apoptosis in human cancer cells by using a selection of in vitro viability and fluorescence assays.     

Triazole- and triazolium-containing porphyrin-cages for optical anion sensing

Triazole and triazolium groups have been integrated into a zinc(II) metalloporphyrin-based structural framework to produce two porphyrin-cages for anion sensing applications. UV/visible spectroscopic titration investigations reveal both host systems exhibit strong anion binding affinities, with the positively-charged triazolium-porphyrin cage capable of colorimetric sensing halides, fluoride and chloride, and oxoanions in acetone-water solvent mixtures.     

Cyclic triureas--synthesis, crystal structures and properties

The synthesis of 24-membered macrocycles is described, in which rigid xanthene units (X) and/or diphenyl ether units (D) as flexible analogues are linked via urea groups. All four possible combinations (XXX, XXD, XDD, DDD) have been obtained with yields of 40-72% for the cyclisation step. In two cases, the respective cyclic hexamers (XXDXXD, XXXXXX) were also isolated. Two compounds have been characterised by a single crystal X-ray analysis of the free triurea (XXD, XDD) and one example (DDD) by its complex with tetrabutylammonium chloride. It shows the chloride anion in the centre of the macrocycle, held by six NH...Cl- hydrogen bonds. The interaction with various other anions has been studied by 1H NMR. Complexation constants for chloride, bromide and acetate have been measured for all trimers by UV spectrophotometry. Molecular dynamics simulations have been carried out to determine the conformation of the free receptors in chloroform and acetonitrile. They show that in chloroform, intramolecular hydrogen bonding occasionally facilitated by trans-->cis isomerisation of an amide bond dominates the conformation of the macrocycles while in acetonitrile (the solvent used for complexation measurements), the ligating urea NH protons are properly arranged for the complexation of anions, however, their strong solvation is counteractive to the complexation.     

Conformational control of selectivity and stability in hybrid amide/urea macrocycles

The anion-binding properties of two similar hybrid amide/urea macrocycles containing either a 2,6-dicarboxamidophenyl or a 2,6-dicarboxamidopyridine group are compared. Significant differences in anion affinity and mode of interaction with anions are attributed to the presence of intramolecular hydrogen bonds in the pyridine system. In fact, remarkably, the phenyl macrocycle undergoes amide hydrolysis under neutral conditions in DMSO/water. The anion binding abilities of the receptors are compared to those of acyclic analogues of the macrocycles that show that the phenyl receptor behaves in a similar fashion to acyclic urea-containing receptors (i.e., showing little selectivity amongst oxo anions), whilst the pyridine-containing receptor shows a high affinity and selectivity for carboxylates.     

An All‐Halogen Bonding Rotaxane for Selective Sensing of Halides in Aqueous Media

The synthesis and anion binding properties of the first rotaxane host system to bind and sense anions purely through halogen bonding, is described. Through a combination of polarized iodotriazole and iodotriazolium halogen bond donors, a three‐dimensional cavity is created for anion binding. This rotaxane incorporates a luminescent rhenium(I) bipyridyl metal sensor motif within the macrocycle component, thus enabling optical study of the anion binding properties. The rotaxane topology was confirmed by single‐crystal X‐ray structural analysis, demonstrating halogen bonding between the electrophilic iodine atoms and chloride anions. In 50 % H₂O/CH₃CN solvent mixtures the rotaxane host exhibits strong binding affinity and selectivity for chloride, bromide, and iodide over a range of oxoanions.     

A macrocyclic ligand as receptor and Zn(II)-complex receptor for anions in water: binding properties and crystal structures

Binding properties of 24,29-dimethyl-6,7,15,16-tetraoxotetracyclo[19.5.5.0(5,8).0(14,17)]-1,4,9,13,18,21,24,29-octaazaenatriaconta-Δ(5,8),Δ(14,17)-diene ligand L towards Zn(II) and anions, such as the halide series and inorganic oxoanions (phosphate (Pi), sulfate, pyrophosphate (PPi), and others), were investigated in aqueous solution; in addition, the Zn(II)/L system was tested as a metal-ion-based receptor for the halide series. Ligand L is a cryptand receptor incorporating two squaramide functions in an over-structured chain that connects two opposite nitrogen atoms of the Me(2)[12]aneN(4) polyaza macrocyclic base. It binds Zn(II) to form mononuclear species in which the metal ion, coordinated by the Me(2)[12]aneN(4) moiety, lodges inside the three-dimensional cavity. Zn(II)-containing species are able to bind chloride and fluoride at the physiologically important pH value of 7.4; the anion is coordinated to the metal center but the squaramide units play the key role in stabilizing the anion through a hydrogen-bonding network; two crystal structures reported here clearly show this aspect. Free L is able to bind fluoride, chloride, bromide, sulfate, Pi, and PPi in aqueous solution. The halides are bound at acidic pH, whereas the oxoanions are bound in a wide range of pH values ranging from acidic to basic. The cryptand cavity, abundant in hydrogen-bonding sites at all pH values, allows excellent selectivity towards Pi to be achieved mainly at physiological pH 7.4. By joining amine and squaramide moieties and using this preorganized topology, it was possible, with preservation of the solubility of the receptor, to achieve a very wide pH range in which oxoanions can be bound. The good selectivity towards Pi allows its discrimination in a manner not easily obtainable with nonmetallic systems in aqueous environment.     

Bis-amidopyrrolyl receptors based on anthracene and carbazole

A new set of diamide receptors containing anthracene and carbazole bridging subunits and either pyrrole or phenyl substituents were synthesised. The four systems produced in this way were shown to bind representative anions in DMSO-d ₆ solution and in the solid state. A higher relative affinity for two test oxoanions, namely dihydrogen phosphate and benzoate, over chloride anion was seen in solution, with the anions in question being studied in the form of their respective tetrabutylammonium salts. However, the specifics of the anion recognition process were seen to depend on structure, with the pyrrole-containing systems displaying higher relative affinities than their corresponding phenyl-containing congeners, and the carbazole receptors proving more effective than the anthracene analogues. Such observations provide support for the notion that both the carbazole NH and the pyrrolic NH protons play an important role in stabilising the receptor-bound anions in solution. Structural analyses of several anion complexes of the diamidopyrrole carbazole receptor reveal that this is not necessarily the case in the solid state; specifically, the pyrrole NH protons are seen to interact with the amide oxygen of another molecule. The net result is an extended one-dimensional coordination polymer.     

Rational design of a macrocycle-based chemosensor for anions

A macrocycle-based fluorescence chemosensor has been designed and synthesized from the reaction of dansyl chloride and a hexaaminomacrocycle containing four secondary and two tertiary amines. The new chemosensor has been examined for its binding ability towards phosphate, sulfate, nitrate, iodide, bromide, chloride, and fluoride by fluorescence spectroscopy in DMSO. The results indicate that the compound binds each of the anions with a 1:1 stoichiometry, showing high affinity for oxoanions, chloride, and iodide with binding constants up to four orders of magnitude. Ab initio calculations based on density functional theory (DFT) suggest that the ligand is deformed in order to encapsulate an anion, and each anion, except fluoride, is bonded to the macrocycle through two NH?X⁻ and four CH?X⁻ interactions.     

Cyclic tetraureas with variable flexibility--synthesis, crystal structures and properties

Macrocyclic molecules containing several amide or urea functions may serve as anion receptors. We describe the synthesis of 32-membered macrocycles, in which four rigid xanthene units (X) and/or diphenyl ether units (D) as flexible analogues are linked via urea groups. All six possible combinations of these units (XXXX, XXXD, XXDD, XDXD, XDDD and DDDD) were synthesized and two examples were characterised by single-crystal X-ray analyses (DDDD and two structures for XXXD). Both macrocycles showed distinct differences in their overall conformation and consequently in their hydrogen-bonding pattern. Hydrogen-bonded solvent molecules are found for both compounds and intramolecular hydrogen bonds for the two structures of XXXD, but surprisingly no direct intermolecular hydrogen bonds between the macrocyclic tetraurea molecules. The interaction with various anions was studied by (1)H NMR spectroscopy. Stability constants for all tetramers were determined by UV spectroscopy for complexes with chloride, bromide, acetate and dihydrogenphosphate in acetonitrile-THF (3:1). The strongest binding was found for XXXD and acetate (log beta = 7.4 +/- 0.2), the weakest for XXXX and acetate (log beta = 5.1 +/- 0.5). MD simulations in chloroform and acetonitrile boxes show that all molecules except DDDD adopt very similar conformations characterized by an up-down-up-down arrangement of the spacer groups. Clustered solvation shells of acetonitrile molecules around XXXX and DDDD suggest their preorganization for spherical/planar and tetrahedral/bidentate anions, respectively, which in turn was corroborated by simulation of the corresponding complexes with chloride and dihydrogenphosphate.     

Strapped and other topographically nonplanar calixpyrrole analogues. Improved anion receptors

Calixpyrroles and related macrocycles are non-aromatic synthetic anion receptors that have attracted considerable attention in recent years. The unfunctionalized, parent calix[4]pyrrole system, also known as octamethylporphyrinogen, may be prepared in one step and in high yield from pyrrole and acetone, and is an effective anion receptor, showing a preference for fluoride, phosphate, carboxylate and chloride anions in organic media. Efforts to improve the anion binding affinity of calix[4]pyrrole and to modify its inherent selectivity have led to the synthesis of a variety of new, modified calixpyrroles. Among the most effective of these are derivatives that contain bridging "straps". In this Feature Article, the preparation and properties of these and other topographically nonplanar calixpyrrole analogues are reviewed from the perspective of the anion recognition chemist.     

Amino acid binding by 2-(guanidiniocarbonyl)pyridines in aqueous solvents: a comparative binding study correlating complex stability with stereoelectronic factors

A series of guanidiniocarbonylpyridine receptors has been synthesized, and these compounds bind amino acids (carboxylate forms) in aqueous DMSO with association constants ranging from K = 30 to 460 M(-1) as determined by NMR titration experiments. The differences in the complex stabilities can be correlated with steric and electrostatic effects with the aid of calculated complex structures. For example, the electrostatic repulsion between the pyridine nitrogen lone pair and the bound carboxylate makes anion binding less efficient than with the analogous pyrrole receptors previously introduced by us for carboxylate binding in water. Furthermore, steric interactions between the receptor side chain as in 2 b and the bound substrate also disfavor complexation.