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Ammonium ion/carboxylate ion pairing is a key interaction ubiquitous in biological systems, but amine recognition by ionizable molecular receptors, mediated by host-to-guest proton transfer, has too often been overlooked as a design element for molecular recognition. This survey will show that proton transfer mediated recognition is a powerful and versatile tool that can be made to work with different amines and diverse macrocyclic scaffolds, such as crown ethers, calixarenes or pillararenes. We will trace the history of this recognition motif since Cram's first report half a century ago down to the latest applications in supramolecular sensing, drug-delivery and materials science, highlighting along the way the impact of host-to-guest proton transfer on self-assembly and molecular recognition.

The hierarchical assembly, in aqueous solution, of a new multi-metalloporphyrin/calixarene aggregate has been accomplished. In this supramolecular system transfer of chirality, from the outermost components to the central porphyrin reporter, takes place as a result of favorable and fully noncovalent long-range electronic communication.

A four component system consisting of two water-soluble calix[5]arenes (1 and 2) with differently substituted upper-rims and two α,ω-alkanediyldiammonium ions of different lengths (NC8N and NC10N) was found to assemble in a high-fidelity fashion providing exclusively the two homocalixarene capsules 1⊃NC8N⊂1 and 2⊃NC10N⊂2, irrespective of the order of guest addition. When the longer linker (NC10N) was left out from the mixture altogether, however, 1⊃NC8N⊂2 heterocapsules were formed.

A calix[5]arene monomer bearing two different ammonium sites assembles into a supramolecular polymer that self-sorts into a polypseudorotaxane upon addition of dibenzo-24-crown-8, but only in the presence of superweak counterions.

A novel bis-pillar[5]arene dicarboxylic acid self-assembles in the presence of 1,12-diaminododecane to yield overall neutral, internally ion-paired supramolecular polymers. Their aggregation, binding mode, and morphology can be tuned by external stimuli such as solvent polarity, concentration, and base treatment.

Two novel tetrathiacalix[2]arene[2]triazines 1a,b have been synthesized and investigated as halide ionophores. UV–vis titrations showed that these macrocycles have a high affinity for fluoride over other halide ions; 1H NMR spectroscopy revealed that only upon fluoride (and not chloride or bromide) ion addition does the spectrum undergo a dramatic loss of symmetry. Finally, a comprehensive DFT (B3LYP/6–311 + G(d,p)) investigation suggested that fluoride ions likely form σ-complexes upon binding to 1a and 1b.

Through-the-annulus threading of calix[5]arene penta-O-ethers by dialkylammonium cations coupled to the loosely coordinating superweak TFPB– anion has been achieved. 1H NMR titration data show that preorganization of the calix[5]arene scaffold leads to great thermodynamic stability of the pseudorotaxane complexes as well as to a favorable threading kinetic. Thus, calix[5]arene 1c, bearing tert-butyl groups at the wide rim, was threaded by all of the cations under study (with the exception of the dibenzylammonium 2b+) more tightly than the other derivatives under investigation (Ka’s up to 2.02 ± 0.2 × 105 M–1) because of its preorganized cone conformation. According to DFT calculations, van der Waals interactions between the tert-butyl groups of 1c and the alkyl chain of the cationic axle are likely responsible for the remarkable stability observed. The threading of the calix[5]arene wheels with the asymmetric pentylbenzylammonium axle 2c+ led to the toposelective formation of the endo-pentylpseudorotaxane...

Nanosized supramolecular assemblies were observed in diluted solutions (below the cmc) of amphiphilic p-tert-butylcalix[5]arene penta-O-butylsulfonato 1 and in mixtures of 1 and bola-type α,ω-alkanediyldiammonium ions of different lengths. SEM analyses and light scattering experiments revealed that these dications are able to modulate the size and the superficial charge of the colloidal systems under investigation. Comparison with NMR data unveiled the nature of the host/guest recognition events taking place, disclosing the formation of supra-amphiphilic surfactant species. The stoichiometry of the calixarene/diammonium ion inclusion complexes was found to be strongly dependent on the length and the number of equivalents of the guest used. The selective formation of endo-cavity “supramolecular bola-amphiphiles” and the additional interplay of electrostatic/hydrophobic interactions yielded “NMR-visible” and “NMR-invisible” supramolecular assemblies of different natures. The supramolecular bola-amphiphile derived from 1 and the hexadecanediyldiammmonium ion was seen to act as a promising solubilising agent, by significantly increasing the solubility of anticancer drug tamoxifen in water (>1000 fold).

The pivotal role played by potassium ions in the noncovalent synthesis of discrete porphyrin-calixarene nanostructures has been examined. The flattened-cone conformation adopted by the two cavities of octa-cationic calix[4]tube C4T was found to prevent the formation of complexes with well-defined stoichiometry between this novel water-soluble calixarene and the tetra-anionic phenylsulfonate porphyrin CuTPPS. Conversely, preorganization of C4T into a C4v-symmetrical scaffold, triggered by potassium ion encapsulation (C4T@K+), allowed us to carry out an efficient hierarchical self-assembly process leading to 2D and 3D nanostructures. The stepwise formation of discrete CuTPPS/C4T@K+ noncovalent assemblies, containing up to 33 molecular elements, was conveniently monitored by UV/vis spectroscopy by following the absorbance of the porphyrin Soret band.

A combined DOSY and XRD study indicates that a carboxylcalix[5]arene receptor is able to encapsulate alpha,omega-diamines of appropriate length by means of a proton-transfer-mediated recognition process followed by salt-bridge-assisted bis-endo-complexation.

A new type of coating, based on carboxylato-pillar[5]arene/poly(allylamine hydrochloride) multilayer films, for the sustained release of antibiotics with in vitro antiadhesive and antimicrobial activity against Gram-positive and Gram-negative bacteria is described.

Covalent bonding of 7-chloro-4-quinolylazo-octamethoxypillar[5]arene molecules to silylated quartz substrates readily produced a new chromogenic reusable pillararene-coated quartz slide, for the direct UV detection of “transparent” analytes in solution. This device provides an analyte-selective optical response towards linear (di)amines with a highly reproducible optical read-out.

Amphiphilic PEGylated calix[5]arenes 1 and 2 were obtained in one step from the parent p-tert-butylcalix[5]arene and p-methylcalix[5]arene. Very low critical micellar concentrations (0.5 and 4.5 μM for 1 and 2 respectively) were determined by the Rose Bengal micellization method. Aggregation features were studied by means of 1H and DOSY NMR as well as by AFM. Release of Rose Bengal from the micellar environment was accomplished by increasing the temperature.

The self-assembly of internally ion-paired, neutral AA/BB-type supramolecular polymers composed of complementary di-ionizable homoditopic pairs of monomers is reported. Host-to-guest double-proton transfer mediates the recognition between bis-calix[5] arenedicarboxylic acids and a, w-diaminoalkanes to yield cyclic, doughnut-shaped assem-blies with morphologies (i.e., cyclic vs. linear) that can be controlled by means of external chemical stimuli. The behavior of these intriguing aggregates, both in solution and on surfaces, has been investigated by a combination of H-1 and DOSY NMR spectroscopy, light-scattering, and atomic force microscopy.

The remarkable affinity of deca-carboxylatopillar[5]arene WP5 towards the aminoglycoside antibiotic, amikacin, in aqueous media is reported; in vitro studies on Gram-positive bacteria (Staphylococcus aureus) show that drug entrapment inside WP5 also takes place in the presence of the microrganisms, thus pointing to WP5 as an appealing carrier for amikacin targeted delivery.

Tritopic tris-calix[4]arene TC4 – possessing three divergent cavities linked to a tris-aminophenylamine core – forms, in the presence of tetra-anionic Cu(II) porphyrins CuTPPS or a combination of different metallo-porphyrins (CuTPPS, NiTPPS and MnTPPS), discrete 3 : 1 porphyrin/tris-calixarene complexes. The 3 : 1-(CuTPPS/TC4) complex in particular is shown to be a key building block for the assembly of supramolecular architectures of increasing complexity. Directional (radial vs. stacked) self-assembly of these nanostructures was achieved by alternate addition of selected hetero-components in a programmed fashion. Addition of TC4 and CuTPPS, in turn, leads to a radial growth of the assembly, whereas, addition of single-cavity calix[4]arene C4 stoppers followed by a CuTPPS topping, promotes a stacked growth. In the latter case, the use of chiral (R)- or (S)-C4 stoppers is seen to induce chirality in the whole assembly. Circular dichroism data ultimately suggest that porphyrin molecules located above/below the 3 : 1 core complex act as a “molecular glue”, by making the interaction between chiral calix[4]arenes (R)- or (S)-C4 and the achiral 3 : 1-(CuTPPS/TC4) complex stronger.

The interactions between hydrochloride salts of biologically relevant amines and micelles formed by a water-soluble p-tert-butylcalix[5]arene were investigated by means of 1H NMR spectroscopy, using a combination of NOESY and DOSY techniques. DOSY measurements were conveniently employed to assess the micelle affinity towards the target guests (phenylethylamine ≈ histamine ≈ serotonin > tyramine > dopamine > norepinephrine), whereas NOESY studies revealed the approximate position of these cationic guests within the different micellar regions. In general, all the guests were located in the palisade region of the micelle, with the exception of phenethylamine and histamine, the former being bound to the micellar core as well as the palisade, the latter preferring the outer shell of the micelle.

Co-crystallization of a carboxylcalix[5]arene in the presence of n-butylamine afforded the corresponding host–guest carboxylate–butylammonium salt-bridged complex as a result of a proton transfer process assisted by a second non-ionized calixarene molecule. The crystals isolated consist of a supramolecular pseudo-dimer in which a host–guest inclusion complex is connected to a formally neutral receptor molecule – hosting a solvent molecule in the aromatic cavity – via a strong negative charge-assisted H-bond between the carboxyl/carboxylate substituents present at the narrow rim of the two interacting calixarene molecules.

This chapter focuses on calix[5]arene-based supramolecular oligo/polymers and, in doing so, examines the genesis and the evolution of this subgroup of the greater calixarene family from the viewpoint of the intermolecular host-guest interactions held to be responsible for first securing capsular complex self-assembly and subsequently polymer formation.

Polycationic oxacalix[4]arene 1·4HCl was found to be able to recognise, in water, the neutral π-rich aromatic guest 2,7-dihydroxynaphthalene, despite earlier studies indicating that the binding cleft of the oxacalixarene is π rich in nature. 1H NMR titrations at different pH values demonstrate that the tricationic receptor 1·3H+ displays the highest affinity towards DHN. According to a combination of NMR data and semiempirical (PM6) calculations, hydrophobic interactions play a prominent role in the formation of the complex.

The biogenic tetraamines, spermine and norspermine, are efficiently encapsulated in the solid state by two molecules of carboxylcalix[5]arene, by means of a highly regioselective proton-transfer followed by bis-endo-cavity inclusion, providing overall-neutral complexes with a 70–72% packing coefficient, despite the modest affinity shown in solution.

The first water-soluble polycationic oxacalix[4]arene molecular tweezers able to recognize – under pH control – the paraquat dication as a result of a delicate balance between electrostatic repulsion, Coulombic shielding and attractive π-stacking interactions are reported.

Supramolecular aggregates formed through the association of an amphiphilic tetra-O-butylsulfonate calix[4]arene 1 were investigated in aqueous solution by a combination of different techniques (NMR, DLS and AFM). The ability of the micellar aggregates of calixarene 1 to increase the solubility of poorly water-soluble drugs was studied.

Host–guest complexes of an amphiphilic water-soluble p-tert-butylcalix[5]arene bearing 4-sulphonatobutoxy groups at the narrow rim with trace amines (2-phenylethylamine and tyramine) and a neurotransmitter (dopamine), originally investigated via 1H NMR, have been re-examined via ITC in order to double check the reliability of the values obtained through a van’t Hoff analysis of the NMR data. The calorimetrically determined data confirm the existence of a 1:1 host–guest species; however, there are inconsistencies between the van’t Hoff derived values and the values determined via direct calorimetry. These discrepancies do not result from proton displacement due to inclusion, but rather result from the temperature dependence of the van’t Hoff enthalpies.

Ion-pair recognition-complexation of monoamine neurotransmitters and trace amine hydrochlorides takes place - with outstanding efficiency and selectivity - within the π-rich cavity and the pocket formed at the lower rim by the two ureido moieties of the tailor-made dihomooxacalixarene receptors 1 and 2. The solid-state structure of 1 is also reported.

A combined XRD and 1H NMR study revealed that two molecules of tetrakis-(tert-butyloxycarbonylmethoxy)-calix[5]arene carboxylic acid are able to efficiently encapsulate α,ω-diaminoalkanes of suitable length as a result of proton-transfer-mediated recognition. In the case of 1,10-diaminodecane and 1,11-diaminoundecane, rim-to-rim attractive van der Waals interactions drive the formation of capsular complexes with a packing coefficient close to 70%. The two calixarene bowls in these capsules are seen in an eclipsed conformation. On the other hand, when the longer 1,12-diaminododecane guest is used, a quasi-capsular complex is formed in which the capsule seal is lost and the two calixarenes are arranged in a staggered conformation as a result of a reciprocal rotation of the two facing macrocyclic cavities. A comparison with similar capsular complexes confirms that a hydrophobic ‘bayonet-mount’ fastening is mandatory for the encapsulation of suitably sized guests.

A calix[5]arene-based heterotetratopic host for molecular recognition of long-chain, ion-paired a,?-alkanediyldiammonium salts Angewandte Chemie-International Edition 44(31), 4892 2005 The anions went in two by two: Sep. ion-pair binding of nano-sized a,?-alkanediyldiammonium dichloride salts is achieved in org. media with high efficiency and selectivity by a heterotetratopic receptor that comprises two converging calix[5]arene units to tightly encapsulate the linear dication, as well as two ureido side functions to simultaneously bind the chloride counteranions through hydrogen bonding.

Novel dimeric capsules are generated from the non-covalent assembly of cone calix[5]arenes and alkyldiammonium ions [H 3 N-(CH 2 ) n -NH 3 ] 2+ featuring an appropriate length of the spacer joining the two charged end groups. 1 H NMR spectroscopy and electrospray ionisation mass spectrometry provide evidence that in the capsule a single ditopic guest holds together a pair of calix[5]arene units, which are oriented rim-to-rim to form a closed cavity encapsulating the shape-complementary dication.

The molecular recognition in water of neurotransmitter monoamine and trace amine hydrochlorides by p-tert-butylcalix[5]-arene 1 – bearing 4-sulphonatobutoxy groups at the lower rim – has been investigated. According to 1H NMR measurements, the hydrophobic cavity of receptor 1 best binds tyramine hydrochloride, K a = 5370 ± 870 M− 1.

Novel (1,2-3,5)-calix[5]arene-bis-crown-3 and (1,3)-calix[5]arene-crown-3 derivatives, bearing one or three ureido moieties at the lower rim, respectively, have been synthesized and investigated as heteroditopic receptors for inorganic and organic salts. Tris-ureido-calix[5]arene-crown-3 10, in particular, efficiently binds 2-phenylethylamine hydrochloride (PEA.HCl) as a spatially separated ion pair.

Homoditopic building blocks 1, featuring two π-rich cone-like calix[5]arene moieties connected at their narrow rims by a rigid o-, m-, or p-xylyl spacer in a centrosymmetric divergent arrangement, show a remarkable tendency to spontaneously and reversibly self-assemble with the complementary homoditopic α,ω-alkanediyldiammonium dipicrate guest salts C8−C12·2Pic through iterative intermolecular inclusion events, forming supramolecular assemblies whose composition and dynamics strongly depend upon the length of the connector, the geometry of the spacer, as well as the concentration and/or molar ratios between the two components. 1H NMR spectroscopy and ESI-MS studies of 1/Cn·2Pic modular homoditopic pairs support the formation of discrete (bis)-endo-cavity assemblies with the shorter C8 and C9 connectors, and/or (poly)capsular assemblies with the longer C10−C12 components under appropriate concentrations and molar ratios (50 mM equimolar solutions). 1H NMR titration experiments and diffusion NMR studies pro...

A mixture of partial cone 2,4-bis[(2-pyridylmethyl)oxy]-(1,3)-p-tert-butylcalix[4]crown-6, hexadecafluoro-1,8-diiodooctane and CsI in EtOH produces a crystalline ‘supramolecular salt’. In the solid state the caesium ion of the ‘supercation’ is encapsulated inside the cavity created by the crown ether loop, the picolyl and the inverted phenyl moieties, while the two iodide ions of the ‘superanion’ form a discrete five-component aggregate held together by co-existing hydrogen and halogen bonds. Similar calix/CsI/iodofluorocarbon adducts are shown to exist also in solution. In a prototypical study, a combination of this calixcrown and liquid octafluoro-1,4-diiodobutane acts as an effective ‘binary host’ system for the selective extraction of CsI from aqueous to fluorous phase.

Self-assembly of a calix[5]arene bearing a 12-aminododecyl pendant group on the lower rim into supramolecular oligomers through intermolecular iterative inclusion events is readily triggered by contact with acid solutions and is reversed to the amino monomer precursor by treatment with a base. 1H NMR data are consistent with the formation of head-to-tail assemblies derived from endo-cavity inclusion of the alkylammonium moiety. Diffusion NMR and light-scattering studies provide evidence for the presence of oligomers in solution and show that different counterions and concentrations result in different oligomer sizes, whereas ESI-MS and SEM investigations, respectively, indicate that self-assembly also takes place in the gas phase and in the solid state. The growth of these supramolecular oligomers is concentration-dependent; however, as a consequence of the saline nature of the monomer, it also shows a distinct counterion-dependence owing to ion-pairing/solvation effects.

Exhaustive O-arylation of p-tert -butylcalix[ n ]arenes 2 ( n = 4–8) with an excess of 3-pentadecafluoroheptyl-5-pentafluorophenyl-1,2,4-oxadiazole 3 and K 2 CO 3 in refluxing acetonitrile provides an easy entry to a new family of perfluorinated calix[ n ]arenes 1 . The cyclic tetramer furnishes a mixture of cone , partial cone , and 1,2-alternate conformers, while the larger macrocycles afford single products. The structures of all new compounds are substantiated by NMR techniques and MALDI-TOF mass spectral data. Single-crystal X-ray diffraction studies on the pentamer derivative 1b reveal a distorted cone-in conformation of the calixarene cup.

1,3-Bis(α-picolyloxy)-p-tert-butylcalix[4]crown-5 in the cone conformation (2), 1,8-diiodoperfluorooctane or 1,6-diiodoperfluorohexane, and potassium iodide ternary mixtures undergo in solution self-sorting and afford crystalline “supramolecular salts”. These hybrid materials consist of supercation [K+ ⊂ 2] and superanion [I–(CF2) n –I…I− …I–(CF2) n –I…I− …] (n = 6,8) components. In the supercations the potassium ion is embedded in the ionophoric pocket created by the heteroatoms present at the lower rim. In the superanions the iodide ions form infinite fluorous polyanionic chains as a result of a self-assembly process which relies on halogen bonding. Both cation encapsulation and anion-perfluorocarbon halogen bonding were detected in solution by 1H and 19F NMR, and in the gas phase by ESI MS.

[structure: see text]. Tail-to-tail connection of two cone calix[5]arene moieties by a rigid p-xylyl spacer affords the new exoditopic receptor 3 featuring two pi-rich cavities (assembling cores) in a centrosymmetric divergent arrangement, as established by a single-crystal X-ray analysis. 1H NMR complexation studies of 3 with alkyldiammonium ions support the formation of discrete bis-endo-cavity complexes and/or capsular assemblies along a polymer chain (polycaps), according to the length of the connector.

[reaction: see text] p-tert-Butylcalix[5]arenes in a fixed cone conformation, endowed with a urea functionality at the upper rim, behave as remarkably efficient abiotic receptors of omega-amino acids and biogenic amines, which are bound with one end of the chain within the pi-basic cavity (primary recognition site) and the other grasped by the secondary hydrogen bonding donor/acceptor binding site.

Synthesis and single-crystal X-ray structures of mixed triple and double calixarenes 6 and 7, obtained from the base-catalyzed condensation of calix[5]arene 1 with cone pertosylated calix[4]arene 2, are reported. VT-NMR studies on 7 are consistent with a molecular motion arising from the anti-gauche conformational interconversion of its ethylene linkages.

Tetranitro-oxacalix[4]arenes 1–5, prepared by direct SNAr reaction of 1,5-difluoro-2,4-dinitrobenzene with the appropriate aromatic diol (pyrocatechol, resorcinol, hydroquinone,2,7-dihydroxynaphthalene, and 4,4-dihydroxybiphenyl), were subjected to Raney-nickel reduction to provide the corresponding tetraamino-oxacalix[4]arenes 6–10, which upon treatment with an excess of 1-octyl isocyanate were converted into the title compounds 11–15,featuring a pair of 1,3-bis-[N-(1-octyl)ureido]phenylene moieties doubly connected at their 4,6-positions by rigid spacers of varied geometry. All new oxacalix[4]arenes were characterized by MALDI-TOF spectrometry and NMR spectroscopy. H NMR data and ab initio calculations support saddle-shaped conformations for oxacalix[4]arenes incorporating pyrocatechol, resorcinol and 2,7-dihydroxynaphthalene nucleophilic components, and boatshaped conformations for derivatives possessing hydroquinone and 4,4´-dihydroxybiphenyl spacers.