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To date, molecular imprinting has proven to be the most efficient and versatile technique for incorporating specific molecular recognition sites into polymers leading to polymeric artificial receptors. The resultant molecularly imprinted polymers MIPs have found use in a wide range of applications encompassing the fields of separation processes chromatography, capillary electrophoresis, solid phase extraction, and membrane separation , immunoassays, antibody mimics, artificial enzymes, sensors, catalysis, organic synthesis, drug delivery, drug development, and even cell imaging.

In addition, chemists have also demonstrated that artificial supramolecular systems can be designed that exhibit molecular recognition. For example, the crown ethers, one of the earliest synthetic receptor, are capable of selectively binding specific cations.

Undoubtedly, supramolecular chemistry is another important molecular recognition domain that has also showen plenty of applications, including materials technology, catalysis, medicine, data storage and processing. Therefore, this Research Topic is intended to provide an opportunity for researchers from different perspectives to publish recent advances in molecular recognition.

Researchers using different chemical methods including molecular imprinting, host-guest chemistry, coordinative chemistry and supramolecular chemistry, etc. We hope that researchers from different areas, such as polymer chemistry, organic chemistry, analytical chemistry, material chemistry, and even biochemistry , biotechnology, etc. Keywords : Molecular imprinting, Host-guest chemistry, Coordinative chemistry, Cell recognition, Supramolecular assembly. Important Note : All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements.

Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review. With their unique mixes of varied contributions from Original Research to Review Articles, Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area!

Find out more on how to host your own Frontiers Research Topic or contribute to one as an author. Nierengarten et al. In addition to the ammonium—crown ether recognition, they found intramolecular stacking of the fullerene moiety to the porphyrin subunit. The value is consistent with association constants reported for associates resulting from ammonium—crown ether interactions []. Figure Porphyrin-crown ether conjugate 73 and fullerene-ammonium ion guest The broad variability of crown ethers allows manifold adaption for specific tasks: A variety of crown ether receptors for co-operative recognition of ammonium moieties in diamines, for transport and effective enantioselective recognition of amino acids, as esters or in zwitterionic form have been described.

Crown ethers have been widely used for the recognition of primary organoammonium compounds as found in amino acids, neurotransmitters such as GABA and other biological important molecules like dopamine 2. Calixarenes are versatile host molecules for ammonium ions with unique structure and complexation properties. In this chapter we discuss approaches for ammonium ion recognition with calixarenes and related molecules. We will start our survey with simpler substitution patterns and proceed with more complex substituted calixarenes for enantiodiscrimination, for colorimetric assays and capped structures.

Resorcinarenes and deeper cavities, ditopic receptors, and capsules are also included. Several books and reviews covering their synthesis, structural properties and applications have been published []. A variety of methods for the synthesis and functionalization of the macrocycles has been developed [,]. Likewise, the synthesis and application of resorcinarenes and O-alkylated derivatives have been comprehensively summarized [].

Calixarenes, e. They may form many conformational isomers by the rotation of the phenol units through the annulus, thus affording a large number of unique cavities of different size and shape. Together with the structurally related resorcin[ n ]arenes example 75c and calixpyrroles, calixarenes are used in a variety of applications, such as chromo- and fluorophores [,] for metal ion binding in solution [,] , anion complexation [] and binding of neutral guests [] , as potentiometric sensors [] in ion selective electrodes [] or as molecular switches [].

Based on the magnitude of the shifts of the different host signals, conclusions can be drawn on the preferred orientation of the guest in the cavity []. Gutsche et al. Proton transfer from OH-groups of the calixarene to the amine, followed by association and inclusion is a different binding situation: The guest is co-ordinated by a tripodal H-bonding [,,,].

The complexation behavior seems to be mainly determined by the conformational mobility of the calix. Control of the conformational properties of these macrocycles is crucial for their applications in supramolecular chemistry. Figure Typical guests for studies with calixarenes and related molecules. Similar to larger crown ethers crown-8 and larger or cyclodextrins, calixarenes may also be threaded to form rotaxane like structures.

Background

A common guest for this is paraquat. The reader is referred to the literature covering this topic []. We discuss now some recent examples in ammonium ion recognition with the calixarene class of receptors and focus on the recognition of these ammonium targets e. The binding of metal ions is not covered and has been already reviewed [].

For detailed thermodynamic data we recommend the articles of Izatt et al. Recognition of biochemical targets was recently covered comprehensively by Ludwig []. Biros and Rebek have summarized the application of water soluble resorcinarenes for the recognition of ammonium ions in their recent review []. In the simplest case, only one side of the calixarene skeleton is substituted.

Figure Lower rim modified p - tert -butylcalix[5]arenes Similar to the unsubstituted calixarenes such examples are only poorly soluble in water and polar substituents are required to increase water solubility. Several examples of water soluble calixarenes bearing phosphonate [] , amino acid [] or neutral groups [] at the upper rim have been reported already in the s. Arduini et al. It carries four carboxylate groups at the lower rim but shows no inclusion of neutral molecules in water []. Figure The first example of a water soluble calixarene.

Figure Sulfonated water soluble calix[ n ]arenes that bind ammonium ions. Later, the investigated scope was expanded to the corresponding calix[5]arene 84d. The inclusion of tetramethylammonium and ditopic trimethylammonium cations was studied at neutral pH by 1 H NMR and compared to the homologous tetrasulfonatocalix[4]arene 84a [].

The more flexible host exhibits a more efficient and selective complexation of ditopic methylammonium ions compared to the more pre-organized calix[4]arene receptors 84a. This is a rare case of molecular recognition by induced fit enhancing affinity and selectivity. Utilizing the outstanding complexation properties of calixarenes for quaternary ammonium ions, the binding of acetylcholine 3 has attracted much interest due to its biological importance as a neurotransmitter.

Upon displacement of the fluorescent pyrene cation by 3 , the binding event is signalled by the increased fluorescence intensity of 85 in solution []. Figure Displacement assay for acetylcholine 3 with a sulfonato-calix[6]arene 84b. For higher calixarenes, only weak interactions at the faces of the flattened macrocycles occur.

This binding is in contrast to the inhibition of protein—protein interactions by the calixarenes where the calix[6]arene and calix[8]arene sulfonates show much stronger effects []. Figure Amino acid inclusion in p -sulfonatocalix[4]arene 84a. Their application as glycosylaminoglycan GAG mimicry [] was demonstrated by the binding thermodynamics towards certain di- and tripeptides bearing lysine 81c or arginine residues in aqueous buffer at pH 8.

Due to their key role in these peptide sequences present in GAG recognition sites, arginine 81d and lysine 81c were also used as guests in the titration microcalorimetry and NMR studies. With the corresponding dipeptides there was a of 3 to 4 fold increase in binding, with the tripeptide of 5 to 8 fold increase was observed in comparison to Arg or Lys, respectively. More interaction sites were involved in their binding.

Mixed Arg-Lys-peptides were bound more strongly and were sequence independent. The apolar part of the peptide inserts into the cavity. Ungaro et al. From compound 83 to 86a a significant increase in log K ass values for the binding of organic ammonium ions was observed: 1. The inclusions were enthalpically driven and disfavored for entropy reasons. Figure Calixarene receptor family 86 with upper and lower rim functionalization.

Calix[5]arenepentasulfonates 86b bind trimethylammonium ions in water pD 7. The alkylammonium group is completely immersed in the cavity []. The corresponding calix[6]arene 86c binds a variety of amino acids in water. Coleman et al.

Journal of Molecular Recognition: Early View

These most stable complexes resulted from the double H-bonding, which is known from carboxylate dimers. Similar contributions could be observed for arginine 81d and lysine 81c. The more polar compound 86b binds non-polar guests weaker. Figure Calix[6]arenes 87 with one carboxylic acid functionality. Receptors with acid functionality 88a , 89a and 90a often show higher binding values for the basic amino acids. Figure Sulfonated calix[ n ]arenes with mono-substitution at the lower rim systematically studied on their response to amino acids.

Figure Sulfonated calix[ n ]arenes with mono-substitution at the lower rim systematically studied on their r For tetraalkylammonium ions, the hosts reveal the same stability trend as has been reported for the complexes of p -sulfonatocalix[4]arene 84a. The K ass values, reaching 2.

A similar behavior is observed for amino acids. The basic representative lysine 81c is bound best in a complex with the host with a K ass value of 2. Figure Cyclotetrachromotropylene host 91 and its binding to lysine 81c. The non-covalent phosphate—ammonium interaction not only plays a key role in living systems for many critical molecular recognition processes, it can also inspire the design of water-soluble artificial receptors.

The influence of phosphonic acids groups instead of sulfonate groups at the upper rim of calix[4]arenes has also been investigated. Witt et al. The host molecules were intended to mimic the adrenergic receptor. The participation of the calixarene hydrophobic cavity was confirmed and the structural requirements for the binding of the ammonium ion guests were investigated. Figure Calixarenes 92 and 93 with phosphonic acids groups. A similar receptor for amino acids was studied by Zielenkiewicz et al. Free amino acids as well as dipeptides gave strong complexes. Neutral aliphatic and aromatic amino acids were better bound than basic ones.

The complexation phenomenon was found to be driven by electrostatic interactions between the protonated N -terminal amino group of the guest and the calixarene phosphoryl groups. The salts of these inherently chiral calixarene phosphoric acids with the chiral amines are easily separated into diastereomeric forms. Based on the results of the former investigations, studies with 92b were extended to amino acid derivatives and also compared to a series of calix[4]arene phosphonic acids [].

The influence of the calixarenes conformation flexibility and its hydrophobic cavity shape dependent on the lower rim substitution pattern on the complexation process was monitored by 1 H NMR spectroscopy in deuterated phosphate buffer at pD 7. Only mixed and host—guest complexes were observed for compound 92b.

More H-bonding sites increase the binding strength. Modification of the lower rim of the calix[4]arene skeleton by bridging ligands lowered the complexation ability of the more rigid molecule 93b although its binding selectivity was preserved. Figure Calix[4]arene tetraphosphonic acid 94a and a double bridged analogue 94b. Binding constants in methanol ranged from 7. Consequently, this host molecule was used in lipid monolayers for recognition of peptides and basic protein surfaces in buffered aqueous solution [,] HEPES , and the binding events monitored with the aid of a Langmuir film balance.

Figure Calix[4]arene tetraphosphonic acid ester 92c for surface recognition experiments. In the later case the substituents can participate in complexation and recognize the aromatic side chains of amino acids. In addition, phosphorylated calixarenes have been used to bind uracils K ass up to 5. Together with the examples 92 and 94 , a whole series of phosphonate substituted calixarenes for amino acids binding has been reported, which have proved to be more versatile than the p -sulfonatocalix[ n ]arenes and applicable at pH values closer to those found under physiological conditions.

The binding constants for amino acids in water are of the same order of magnitude for both functionalizations, where comparable. The preference for basic amino acids is evident. Calixarenes have been modified to exhibit special properties such as optical readout by chromophoric groups, enabling quick and easy monitoring of guest binding, or by groups supplying chirality for enantiodiscrimination. In addition, the cavity has been expanded or rigidified by bridges or even caps to improve binding properties. Often no sharp dividing line can be drawn between these concepts.

We present now the current approaches, where we try to keep the direction, starting with optical readout systems, followed by calixarenes for chiral recognition and then go on to more complex systems ending with capped moieties with additional functionalities. Bridging of calixarenes and resorcinarenes with ethyleneglycol chains leads to calixcrowns and resorcinarene crowns, or even calixcryptands []. The synthesis, structure and fundamental properties of such systems have been reviewed []. We will point out their application in ammonium ion recognition in comparison to other calixarenes with selected examples.

Such homocalixarenes are structurally similar to crown ethers 4 and can bind primary ammonium ions []. Figure A bridged homocalix[3]arene 95 and a distally bridged homocalix[4]crown Two typical examples have been described by Chen et al.

Predicting Macrocyclic Molecular Recognition with Machine Learning

Homocalix[3]arene 97a , reported by Tsubaki et al. The resulting betaine structure shows long wavelength charge transfer absorption observable in the visible spectrum. Only compound 97a , and not the dye E T 1 97b itself, showed a color change upon addition of amines or an alkaline earth acetate. This confirms a binding process and excludes a simple deprotonation reaction as the origin of the color change.


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Due to steric reasons, primary amines are preferentially bound over secondary and tertiary amines. Diazo-bridges in calix[4]arenes also allow distinguishing the binding of amines and diamines or triamines by color changes, caused by host—guest proton transfer []. Various amines were added to 98 in DMSO resulting in distinct color changes. For instance, tert -butyl amine induced bathochromic shift of the absorption of 84 nm, whilst the addition of aromatic amines did not induce any color change or shift in the absorption maxima.

The yellow color was restored upon acidification of a solution of the 98 - tert -butylamine complex. This indicated that the color change could be attributed to the ionization of hydroxyl groups of Conductometric titration gave further evidence: On addition of the guest, the conductivity continuously increased until it reached a plateau at equimolar concentration of amine. Figure Chromogenic diazo-bridged calix[4]arene In an earlier publication, Arduini et al. The parent calix[4]arene was used by Huang to develop an amine receptor with optical readout.

Figure Calixarene receptor 99 by Huang et al. As in the previous examples, the binding of the amine by the resulting phenolate ion is crucial for the development of the color. Because of two phenols being deprotonable per calixarene, it is not surprising that the authors identified a receptor to amine stoichiometry. For this class of receptors a clear preference for binding of primary amines over branched, secondary and tertiary guests was observed. Enantioselective analysis and separation of amino acids was addressed using chiral calixarene type macrocycles: A pseudo- C 2 -symmetrical homooxacalix[3]arene discriminates between chiral amino acids [] , whilst chiral calix[4]crown ethers were used for the binding of alkylammonium ions [].

Amino acid esters were separated in liquid membrane transport experiments with an efficiency dependent on their hydrophobicity, with preference to S -Phe- and S -Trp- ester showing the highest flux []. A calix[5]arene related to 82 for attempted enantiodiscrimination was reported by Parisi et al. Figure Calixarenes reported by Parisi et al. The free rotation around the aromatic- N - urea -bond allows the urea unit to act as a hydrogen bond acceptor to bind ammonium ions and as a hydrogen bond donor for carboxylate binding. However, a comparison of the binding constants shows that carboxylate ions are bound more tightly.

The chirality of the receptors b and c did not lead to any enantiodifferentiation of chiral guest molecules. The complexation occurred exclusively through the interaction of the calixarene cavity with the apolar groups of the guests []. Figure Different N -linked peptido-calixarenes open and with glycol chain bridges. Introduction of chirality by the insertation of an amino acid into the ring of the calixarene moiety potentially enables enantiodiscrimination properties by the formation of diastereomeric complexes with racemic ammonium ions [].

For the visual discrimination between enantiomers, Kubo et al. Upon binding of the enantiomers, two different bathochromic spectral shifts of the two chromophores attached to the binding cavity were observed, with significant optical response only for one enantiomer. The formation of a complex was confirmed by mass spectroscopy.

Other amino acids enantiomers, such as the those from phenylglycine, were distinguishable with the system. Diamond et al. Compound shows some selectivity for R phenylethylamine and also discriminates between the enantiomers of phenylglycinol in methanol. Figure A chiral ammonium-ion receptor based on the calix[4]arene skeleton. The extraction properties of the two homochiral receptors a and b for some amino acid methyl esters and amino alcohols were studied by liquid—liquid extraction. The results show that these derivatives were excellent extractants for all the amino acids and amino alcohols, but only a weak or no chiral discrimination of the guests was found.

The inclusion of quaternary ammonium cations in the cavity of calixarenes with more enclosing substituents, has been extensively studied over the years in the gas phase, in solution and in the solid state [,]. The next step is to close the cavity from one side, to bridge or cap the moiety. Bridging of the upper rim of a calixarene may lead to altered selectivity and higher binding constants due to the pre-organized and fixed cavity.

Figure Capped homocalix[3]arene ammonium ion receptor Figure Two C 3 symmetric capped calix[6]arenes and Extraction and competitive binding experiments gave values that were, at that time, the highest ever obtained with a calixarene-type host. Quaternary ammonium ions were not complexed in chloroform. The free base of a is able to complex cationic ammonium guests. Figure Phosphorous-containing rigidified calix[6]arene Reinaud et al.

The compound behaved as a single proton sponge and appeared reluctant to undergo polyprotonation, unlike classical tris 2-pyridylmethyl amine tmpa derivatives. Figure Calix[6]azacryptand The monoprotonated derivative behaved as a good receptor for amines, leading to inclusion complexes, and as a good host for ammonium ions. Interestingly, it strongly binds sodium ions and neutral guest molecules, such as ureas, amides, or alcohols, co-operatively. It displayed five fold selectivity in favor of propylammonium hydrochloride over the corresponding ethyl- and two fold selectivity over the butyl—guest in chloroform.

Even larger structures, based on this trimethoxy-calix[6]arene scaffold triple-bridged with a cyclotriveratrylen or connected to dimers via alkyl bridges, were applied for ammonium ion pair inclusion []. The use of such ditopic receptors and capped calixarenes with enhanced strength by ion-pair recognition has been an emerging field. In succession of the presented examples, a second generation of the hosts has been introduced []. The host—guest properties of receptors a and b toward the picrate and chloride salts of propylammonium ion were studied by 1 H NMR spectroscopy and compared to This highlights that the simultaneous binding of the anion by the urea groups of the ditopic receptor b enhances the endocomplexation of the ammonium ion and consequently a much larger binding constant should be observed compared to the first generation molecule Figure Further substituted calix[6]azacryptands Their interior is much smaller than that of cucurbituril.

Figure Resorcin[4]arene 75c and the cavitands The monomeric resorcinarene 75c and its simple derivatives show recognition properties, but their shallow curvatures cannot provide sufficient surface contacts for selecting between targets. Nevertheless, they bind ammonium ions, choline 76 , acetylcholine 3 , and carnitine 77a in protic solvents [].

Significant interactions to the ammonium ion can also occur via hydrogen bonds to the phenolic OH-groups. In unsubstituted resorcinarenes, these are preferably formed intramolecularily involving two neighboring OH groups of the host. Figure Tetrasulfonatomethylcalix[4]resorcinarene Molecular modeling calculations confirmed the results.

Similar pyrrogallol[4]arenes carrying long alkyl chains were applied as amphiphilic receptors in an aqueous micelle system and their interaction with dopamine 2 and acetylcholine 3 studied by NMR methods []. The binding constants observed for acetylcholine 3 were 2 to 2. This was attributed to the larger contact area and a more suitable p K a value of the resorcinarene in consequence to the strong electron withdrawing effect of the cyano groups.

With increasing pH, acetylcholine 3 was bound more strongly by the receptors, with a K ass of up to 10 6 in phosphate buffer at pH 8. Figure Displacement assay for acetylcholine 3 with tetracyanoresorcin[4]arene The dual nature of the cavity formed between the crown bridge at one end and the two hydroxyl groups at the other offers a better fit to acetylcholine 3 compared to the smaller tetramethylammonium cation.

The binding of acetylcholine 3 to was investigated by an 1 H NMR titration technique in CDCl 3 and showed host—guest complex formation. Figure Tetramethoxy resorcinarene mono-crown-5 By covalent bridging of the OH groups of two neighboring aromatic subunits by aromatic moieties, a resorcinarene can be made more rigid and the cavity formed can enclose guest molecules completely. One way of achieving this is the use of phosphonate-cavitands [].

As displaceable guest they used compound , consisting of a methylpyridinium unit as recognition moiety connected to a pyrene probe via a diester. Figure Components of a resorcinarene based displacement assay for ammonium ions. Binding constants were not reported, but in several ESI-experiments the proton bonded diastereomeric complexes with amino acid guests exhibited a pronounced selectivity towards the enantiomers of tyrosine methyl ester and amphetamine. An additional kinetic study on the base-induced displacement of the guest revealed that the S -Tyr-OMe and R -amphetamine enantiomer was displaced faster from the heterochiral complex than from the homochiral one.

Figure Chiral basket resorcin[4]arenas Cavitands [] and carcerands [] are additional examples of resorcin[4]arene based supramolecular host systems. Ideally, a synthetic receptor should provide a congruent surface and chemical complementarity to the target molecule.

Cavitands with hetero- arene linker between the resorcin[ n ]arene oxygen atoms, thus adding three or four walls to the resorcinarene skeleton, form a larger and deeper cavity than the according alkyl or glycol chain bridged homologues [,]. Non-functionalized resorcin[4]arenes are dominated by hydrogen bonding as driving force for complex formation and aggregation.

Thus, their binding properties and selectivities can be enhanced []. The molecule can be seen as a further development of the calixarene tetrasulfonate of Shinkai et al. Figure Resorcinarenes with deeper cavitand structure Deprotonation in alkaline aqueous media afforded a negatively charged receptor which interacted more strongly by means of charge—charge attraction.

NMR titration gave the stability constant of 0. The tetraethylammonium chloride was bound with a similar affinity, whilst the larger tetrapropylammonium chloride showed a sharp decrease in affinity. In alkaline media 0. In dipolar aprotic solvents such as DMSO, the ammonium salt is recognized as a close contact ion pair. Consequently, the chloride may also interact with the receptor []. Figure Resorcinarene with partially open deeper cavitand structure Rebek et al. The absence of a fourth wall allows the binding of bulky ammonium groups []. Such guests with small hydrophobic regions are accommodated with the trimethylammonium group positioned deep inside the cavity.

The hydroxyl and carboxylate functions can then provide hydrogen bonding interactions with the groups at the rim. The ester group of acetylcholine 3 appears unable to reach such binding sites. Cavitand exists as dimer or larger, kinetically unstable aggregates. With an excess of 1-adamantanol the aggregates break up and providing a sharp NMR-spectrum of a complex. Other guests are not included or disassemble the aggregates. Figure Water-stabilized deep cavitands with partially structure , If the reaction product is water soluble, it is easily released []. Cavitand c can distinguish between several substituted adamantyl residues [].

Figure Charged cavitands for tetralkylammonium ions. Studies of c with choline 76 , acetylcholine 3 and carnithine 77a were later extended. Binding mode and properties of these guest complexes were studied by NMR and calorimetry in water at pH 7. It was found, that c preferably binds choline 76 , 2. The binding of carnithine is in comparison negligibly small 1. The guest is inserted with its tetramethylammonium substituent deep in the cavity with the other end pointing to the carboxylic acid groups at the upper rim of the host.

Enhancing the binding strength and the selectivity can also be achieved by adding more binding sites. Using only one connection point makes the molecule sufficiently flexible to bind a bis-ammonium guest. Some recent examples of calixarenes following this concept have been published. Figure Ditopic calix[4]arene receptor capped with glycol chains. The binding abilities of a head-to-head linked bis-calix[4]arene-bis crown-3 fixed in the rigid cone conformation with bridges of different nature and length was described []. As a result a substantial decrease in the K ass values was observed: association constants were generally almost an order of magnitude lower for all guests, due to CD 3 CN competing for the binding sites in the host.

What is molecular self-assembly?

The double calixarenes have been found to exhibit efficiencies much higher than that of the corresponding reference cavitand calix[4]arene-bis crown The bridge present in these double calix[4]arenes dictated the orientation and distance between the two rigid caps and thus determine the efficiency and selectivity of binding. The two rigid caps could adapt in response to a potential guest and possibly co-operate in binding by forming a capsule. Another ditopic receptor was described by the Parisis group []. The use of non-protic solvents showed a beneficial effect of the ureido functions by loosening the ion-paired salt and the association of the anion by formation of six-membered chelate rings with halide or picrate anions and eight-membered chelate rings with carboxylate anions.

Figure A calix[5]arene dimer for diammonium salt recognition. Table 7: Binding constants of different guests with the ditopic receptor Biological molecules often possess ionic moieties as well as functional groups capable of forming hydrogen bonding interactions within the same molecule. It is quite appealing to consider ditopic cavities as binding sites based on this principle. Even larger structures can be assembled by complementary recognition of receptor parts to each other [] — a more specialized case of recognition involving self assembly [].

From NMR titration, the stability constants K ass of the assembly 92c and a was 7. Figure Calixarene parts 92c and for the formation molecular capsules. Zadmard et al. Inclusion of Phe, aniline, tetramethylammonium salts and other organic molecules into the capsule cavity in methanol was investigated []. Since the capsules were far more stable than the complex with the guest molecule, 10 5 vs. Resorcinarene can also form dimers by a self assembling process, in which the cavity is filled [].

This was nicely evidenced by mass spectroscopy and by examining several crystal structures of smaller tetraalkylammonium cations with unsubstituted resorcinarenes such as 75c with different alkyl chain lengths. Competitive mass spectrometric studies clearly indicated the preference for the tetramethylammonium cation over the tetraethylammonium cation and especially, the tetrabutylammonium cation.

The two resorcinarene units are held together mediated by hydrogen-bonded networks via solvent molecules of methanol and water []. Expanding the studies, Cohen et al.

Molecular recognition of organic ammonium ions in solution using synthetic receptors

These selected, recent examples give an impression of the possibilities for ammonium recognition with calixarenes and resorcinarenes utilizing self assembly. A discussion of all options possible is beyond the scope of this review. The reader is referred to the appropriate literature [].

Larger capsules for the inclusion of a variety of guests were recently described by the Rebek group []. The advantages of calixarenes as hosts for ammonium ion binding in comparison with other synthetic macrocycles is obvious: good accessibility, the possibility of tuning shape and size of the inner cavity and the introduction of various functional groups to address nearly any ammonium ion guest selectivity. Calixarenes are often used for the synthesis of more complicated and elaborated structures, to enclose or strongly complex larger guests with high selectivities and outstanding binding strengths.

Calixarenes often achieve selectivities in cation binding which are superior to crown ethers due to the guest inclusion being controlled by steric factors and various interactive forces of host and guest. Some calixarene-based artificial receptors show remarkable selectivities for amine isomer recognition.

This was applied in assays for such important biomolecules as acetylcholine 3. A considerable number of synthetic receptors based on a calixarene framework for amino acids derivatives has been designed and studied in organic media, but only a few examples have been reported in aqueous solution. Calixarenes are able to select precisely basic or aromatic amino acids in aqueous solution. Because of this property, they can be applied even as enzyme mimetics.

Because of the resemblance of the barrel-shaped molecule to a pumpkin, the investigators gave the macrocyclic methylene-bridged glyconuril oligomers the name cucurbiturils, derived from the Latin name of the plant family cucurbitacae. Figure Structure and schematic of cucurbit[6]uril CB[6], a. Crystalline complexes incorporating various metal salts and some dyes were observed and consequently cucurbiturils were investigated as receptors by Mock and Shih []. Alkylammonium ions were the first organic guests to be reported for CB[6] a []. Mock [] , Buschmann and co-workers [,] , and Kim et al.

Cucurbiturils bind their guests by hydrogen-bonding or ion-dipole interactions in combination with the hydrophobic effect of the cavity. The rigidity of the structure enables selective recognition of hydrophobic residues or cations. The selectivity strongly depends on the inner size of the cavity and possible guest orientations therein, as in cyclodextrins and calixarenes: para -methylbenzylamine is bound, while the ortho - and meta -isomers are not []. Isaacs et al. The ammonium cations are symmetrically located in the centre of a ring formed by the carbonyl oxygens.

The benzene ring is rotationally disordered in the cavity between two orientations []. The upper and the lower regions of the cucurbituril — the occuli — bear at least six urea carbonyl groups, representing an area of negative charge accumulation, co-ordinating to cationic species such as alkanediamines. The high specificity for ammonium ions is explained mainly by this electrostatic ion-dipole attraction assisted by hydrogen bonding. Substituents fitting the size of the cavity are bound with the highest strength and affinity; longer chains protrude into the second oculus of the cucurbituril, interfering with the carbonyl dipoles and their solvation sphere [,].

In contrast to the moderate to good water soluble related host molecules with a comparable cavity size, the cyclodextrins [55,,,] , the poor solubility of CB[6] a in common solvents and water makes it difficult to study its host—guest chemistry in solution. During the s it was discovered that CB[6] is readily soluble in aqueous solutions containing alkali or alkaline earth metal ions.

Since then, such aqueous solutions have often been employed for studies on complexation properties of CB[6] a [,]. Typical binding constants for ammonium guests, e. Not only simple amines, but also many amino acids and amino alcohols have been employed as guests. The situation changes completely in the case of amino alcohols. Reaction enthalpies and entropies are influenced by the number of methylene groups: 3-aminopropanol formed the most stable complex.

With an increasing number of methylene groups the stability of the complexes decreased, which is attributed to entropic factors []. Paraquat and its derivatives are typical guests for cucurbit[ n ]urils []. Many homologues from cucurbit[5]uril to cucurbit[10]uril, as well as derivatives, congeners and analogues are available, even exceeding the cavity size span of the cyclodextrin family.

Their chemistry has been discussed in several books [] and reviews [,]. In the following part, some recent examples of the molecular recognition of ammonium ions will be discussed. Various cucurbit[ n ]uril derivatives have been synthesized by introducing alkyl groups at the equator of the molecules to improve their solubility in water and other commonly used organic solvents [].

Different reactive functional groups have been introduced directly onto the surface of the cucurbit[ n ]urils to improve their solubility, and for further modification [,,]. Complexation properties with various organic mono- and diammonium ions were studied by isothermal titration calorimetry and 1 H NMR spectroscopy []. The hexamethylene chain conformation is twisted to allow strong ion—dipole interactions between both ammonium groups and the carbonyl groups at the portals.

The selectivities match with those of a. The cavity dimensions are essentially the same as in CB[6] a. Cucurbit[ n ]urils strongly bind amino acids. The protonated amino moiety is located at the portal of the host whilst the side chain carboxyl anion moiety is included in the cavity of A combination of hydrogen bonding and ion—dipole interactions of the ammonium group and the portal carbonyls of the host were seen as the driving force for the complex formation.

In addition, the carboxyl moiety of the amino acid located at the portal of the host could interact with the portal carbonyl of the host through hydrogen bonding. Unsubstituted cucurbiturils are not fluorescent. This analogue shows good molecular recognition properties for a variety of guests in aqueous sodium acetate buffer at pH 4. The best examples were benzidine with an association constant of 4. Due to the larger size of the indole ring compared to that of the monocyclic systems, tryptophan 81b was bound more tightly.

Figure Structure of the cucurbituril-phthalhydrazide analogue The displacement of colored or fluorescent dyes such as methylene blue a , pyronine b and acridine orange c led to discrimination among primary, secondary, tertiary, aliphatic, aromatic, linear and branched amines by color change or by the increase in fluorescence. The combination of the images obtained from visible and UV light identified each of the 14 analytes investigated. Figure Organic cavities for the displacement assay for amine differentiation. Jump to Figure Nau and co-workers introduced a general supramolecular assay principle in which amino acid decarboxylase activity can be continuously monitored by measuring changes in fluorescence, which results from the competition of the enzymatic product and the dye for forming a complex with a cucurbit[ n ]uril macrocycle [].

Due to a complexation-induced p K a shift, a large dual fluorescence response fold increase at nm and 9-fold decrease at nm accompanied by a color change upon supramolecular encapsulation in cucurbit[6]uril a is observed. Figure Displacement assay methodology for diammonium- and related guests involving cucurbiturils and some guests. Figure Displacement assay methodology for diammonium- and related guests involving cucurbiturils and some Addition of amino acids has little effect on the fluorescence intensity of the CB7-Dapoxyl reporter pair.

Addition of low-micromolar concentrations of amines lead to a steep decrease in fluorescence as a result of competitive binding. This allows real-time monitoring of enzymatic activity by a switch-off fluorescence response in 10 mM NH 4 OAc buffer at pH 6. Decarboxylation produces the corresponding amines cadaverine a , agmatine c , histamine 1 or putrescine b , so increases the net positive charge and thereby the affinity of the competitor by removal of the carboxylate group.

This tandem assay principle has millimolar sensitivity. The versatile approach was extended to aromatic guests and applied for enantiodiscrimination, respectively resolution []. Time-dependent fluorescence response monitoring of S -lysine decarboxylation with varying S -lysine enantiomeric excess allowed accurate determination of optical purity of the amino acid over a wide range of ee 64— Only the S -enantiomer is accepted by the enzyme as a substrate and is converted to the product that is responsible for the observed fluorescence signal.

No response and no conversion by the enzyme are observed with the R -enantiomer. Recently, Isaacs et al. Host undergoes diastereoselective complexation up to with chiral amines including amino acids and amino alcohols as well as with meso-diamine e. Toward amino acids 81f and 81a and amino alcohol 81g minimal higher values were observed.

A chiral guest added to the solution of cucurbit[6]uril-based complexes with enantiopure amines can replace one of the originally bound amines achieving an enantiodifferentiation by accommodating two different chiral guests inside a self assembled achiral capsule. In this way significant enantiomeric and diastereomeric discrimination by incorporating a strong chiral binder is possible []. Comprehensive studies on the chiral recognition of guests were performed: Dissolving cucurbit[6]uril CB[6] in an aqueous solution of an enantiopure organic amine, such as R - or S methylpiperazine MP or R , R - or S , S - trans -1,2-diaminocyclohexane DC , led to the formation of the respective enantiopure complex, i.

Figure The cucurbit[6]uril based complexes for chiral discrimination. The discrimination of dipeptides was not possible with the previously discussed system. The cavity size of cucurbit[7]uril enables the molecule to bind ferrocenyl and adamantyl substituted amines strongly as complexes: Rimantadin, an amino adamantyl derivative, which is used as an anti-viral drug, is included in aqueous buffer at pD 4.

Figure Cucurbit[7]uril c and its ferrocene guests opposed. Two different series, also giving K ass values for other interesting ammonium guests, were pursued. All amines were protonated under the conditions of the study. Table 8: Two series of binding constants for different guests to CB[7] c. The values for a and b are 3. The extremely large affinities of the complexes surveyed are due to a large enthalpic gain, originating from the tight fit of the ferrocene core to the rigid CB[7] cavity achieving optimal van der Waals contacts, critically assisted by the entropic gain arising from the extensive host desolvation, and largely uncompensated by losses in configurational entropy.

The crystal structure of the complex shows the complete inclusion of the ferrocenyl residue in the CB[7] cavity and the almost ideal positioning of each of the trimethylammonium groups maximizing ion—dipole interactions with the carbonyl rims on each of the host portals. The acetyl-substituent is included in the cavity and the quaternary ammonium ion is co-ordinated by the carbonyl functions of c. In the case of phosphonium groups, these substituents are generally included in the cavity additionally stabilized by van der Waals contacts. Figure Cucurbit[7]uril c guest inclusion and representative guests.

The protonated forms are bound more strongly in acidic solution. Upon protonation the cucurbit[7]uril sits around the aromatic unit of a — c , in the deprotonated case it includes the alkylated amine centre. Figure Cucurbit[7]uril c binding to succinylcholine and different bis-ammonium and bis-phosphonium guests. Figure Cucurbit[7]uril c binding to succinylcholine and different bis-ammonium and bis-phosphon The vast majority of host—guest complexes of CB[7] c with cationic guests, such as paraquat [,] , assemble with the cationic part of the guest located outside of the cavity, adjacent to the oxygens of the portal carbonyls.

The remaining hydrophobic region of the guest is positioned inside the cavity. Kim and co-workers report that d can bind to aromatic guests, such as tryptophan 81b , tyrosine, and dopamine 2 as observed by the resulting changes in visible color and in their NMR spectra [,]. In the crystal structures of the inclusion complexes of S -tyrosine S -Tyr , S -histidine 81e , S -His , S -leucine S -Leu in cucurbit[8]uril d a host:guest ratio was found [].

It is common, that the ammonium moiety is always located at the portal of the host, co-ordinated by hydrogen bonding and ion—dipole interaction with the carbonyl groups of the host. The host can include not only the stacked aromatic moieties, but also the alkyl moieties of the amino acids. A comprehensive examination of the 20 genetically encoded amino acids was carried out by 1 H NMR spectroscopy and isothermal titration calorimetry in aqueous solution [].

The amino acid to host stoichiometry is controlled by the presence or absence of paraquat Both d and the complex bind measurably to only tryptophan 81b , phenylalanine 81a and tyrosine. Figure Paraquat-cucurbit[8]uril complex For the binding of Trp 81b and its derivatives, a binding stoichiometry was observed in all experiments. N -Terminal tryptophan residues are bound with higher affinity than C-terminal or internal tryptophan residues.

In addition, cucurbit[8]uril d was reported to be a remarkably synthetic host for selective recognition and non-covalent dimerization of N -terminal aromatic peptides in aqueous solution []. Cucurbiturils are known to recognize N -terminal tryptophan over internal and C-terminal sequence isomers. Both peptides are bound in a stepwise manner, the latter with positive co-operativity. The crystal structures revealed the structural basis for selective recognition as the inclusion of the hydrophobic aromatic side chain and chelation of the proximal N -terminal ammonium group by carbonyl oxygens on the cucurbituril.

In view of application the authors pointed out the potential study of dimer-mediated biochemical processes and the potential use for the separation of peptides and proteins. Compound b forms thin tubules in chloroform and vesicles in water, with the possibility of surrounding the guest. Aggregates of the chiral host b bind catecholamines and aromatic amino acids in water and are able to discriminate between their enantiomers. The calculated binding constants were moderate to high and a remarkable enantioselectivity for the corresponding enantiomers of R -tyrosine 1.

Figure Gluconuril-based ammonium receptors The rigid structure and capability of forming stable complexes with a wide range of molecules and ions, mediated by ammonium ion co-ordination in combination with inclusion of the side chains make cucurbit[ n ]urils very attractive not only as a synthetic receptor. As previously stated, self assembly systems is outwith the scope of this review, but it has to be mentioned since nearly as many papers as published for molecular recognition with cucurbit[ n ]urils are found using the macrocycles as building blocks for the construction of supramolecular architectures, often relying on the interaction with an ammonium species.

The interested reader is referred to the large body of recent literature []. Generally, the ammonium guests are co-ordinated by the carbonyl groups of the host by electrostatic ion—dipole attraction assisted by hydrogen bonding.


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  6. The non-polar part of the guest is included in the cavity. The binding is governed by hydrophobic effects and van der Waals contacts. The entropic gain upon binding additionally supports the high association constants found with cucurbiturils. Similar facts are also relevant to quaternary ammonium species, which are bound by the same interactions. Here the area of negative charge accumulation, represented by the carbonyl groups, co-ordinates cationic species strongly.

    For a more comprehensive discussion of the binding properties of the cucurbit[ n ]uril family, we recommend the recent review article by Issacs et al. Typical host structures for ammonium guests are macrocyclic, like calixarenes, cyclodextrins or cucurbiturils with polar functionalities organized in a circular manner. However, many suitable synthetic receptors fall in a second category: Non-cyclic compounds, with more open structures.

    These hosts have pockets or cavities into which a guest can fit, but is not completely encapsulated. These clefts, clips and tweezers are discussed in the following section together with tripods and suitably functionalized cyclophanes. In the topic of ammonium ion recognition, it is difficult to draw a dividing line, as both concepts — clefts and cyclophanes — function similarly or were developed in parallel for similar purposes. We will first discuss clefts, clips and tweezers, then tripods and related systems, and finally cyclophanes with ionic functionalities. Vitally important biochemical processes involving ammonium ions rest upon the specific interactions supported by negatively charged substituents such as carbonates, sulfates, or phosphates.

    As demonstrated with several examples before, these charged groups contribute significantly to the substrate binding. For clefts, tweezers and cyclophane structures such substituents are of key importance to complement the ammonium ion binding by ionic and hydrogen bond interactions. Clefts organize polar functionality with hydrogen bonding or ionic co-ordination capabilities at precise distances and orientations.

    This conformational fixation is achieved by covalent and non-covalent constraints. Generally, acylic clefts, clips and tweezers must position functional groups on a rigid molecular scaffold, often of concave shape, to focus these inwards, to assure the desired conformation, and to prevent the collapse of the binding pocket.

    As in macrocycles, proper pre-organization can significantly augment binding strengths. Figure Examples of clefts a , tweezers b, c, d and clips e. For ammonium ion recognition they divide into two different subtypes: Either they are characterized by convergent functional groups directed towards each other, mounted on a rigid backbone with a certain degree of freedom — the space between the functional groups provides the cleft into which a guest can bind — or the cavity of this kind of receptors is made up of two sidewalls connected to each other by a central spacer unit, which can be either flexible or rigid.

    The synthesis and properties of such often chiral molecular clefts and tweezers have been reviewed []. Molecular tweezers were originally developed by Whitlock [,] and Zimmerman []. Hydrophobic interactions also play a significant role in their tight binding to aromatic bis-phenol carboxylates in water. The tweezers constructed by Zimmerman were more rigid and showed high association constants with guests such as polynitroaromatics and 9-alkylated adenines in chloroform.

    The introduction of polar functionality enables the binding of guests by additional interactions, for example, 1,3-dihydroxybenzene [] by H-bonding or nucleosides [] by ionic interactions. Similarly, ammonium ions, diamines [,] or chiral guests [] can be recognized by appropriate functional groups arranged on these scaffolds. Clips, tweezers [,] , related V-shaped molecules [] and their chiral analogs e.

    In the following we will discuss recent examples based on these backbones for inclusion of quaternary ammonium compounds, or, when suitably substituted, for ammonium ion recognition. Due to the convergent carboxyl groups on the cyclohexane ring, condensation of the acid with aromatic amines — one to three aromatic rings are arranged in a linear manner — yields receptors such as b , in which two carboxyl groups are pre-orientated in a convergent, optimal arrangement for the substrate binding.

    Rotation around the C—N bond can be prevented by a methyl group in ortho -position of the aromatic amine. Dicarboxylic acids are linked by hydrogen bonds, similar to those found in carboxcylic acid dimers.

    About this Research Topic

    On binding amino acids, a carboxyl group of the receptor co-ordinates to the carboxyl group of the substrate. In addition, salt formation occurs between the other carboxyl group of the receptor and the amino group of the guest [,]. Figure Amino acid receptor by Rebek et al. Leucine, isoleucine and valine were, however, not transported into the organic phase.

    The mode of binding and the interactions were investigated in detail by a theoretical study and verify the results and conclusions []. Because of the frequent occurance of basic amino acids Lys, Arg, His in biological processes, the molecular recognition of these amino acids by synthetic receptor molecules is of special interest []. Bell et al. Complexation studies were conducted in methanol by 1 H NMR titration for several guanidinium and ammonium ion guests.

    Interesting for ammonium ion recognition is receptor b , which bound lysine 81c better than a. In general, it tends to have higher affinity towards alkylammonium guests than to alkylguanidinium salts. Among guanidinium guests, only arginine 81d bound with very high affinity to b. This selectivity was explained in terms of energies of cavity solvation: The larger cavity of a is more highly solvated prior to binding than the smaller cavity of b. The compact ammonium ion with its higher charge density was expected to form stronger attractive electrostatic interactions.

    In contrast, the alkylguanidinium ion was able to form more H-bonds with the planar receptor a. Figure Hexagonal lattice designed hosts by Bell et al. The amidinium ion is closely related to the ammonium and the guanidinium ion. The amidinium functionality plays an important role in drugs targeting binding pockets for the arginine side chain.