Phosphonate Cavitands Research Articles

Inherently chiral phosphonate cavitands as enantioselective receptors for mono-methylated L-amino acids

The properties of two inherently chiral cavitands in enantioselective recognition of N-methyl-leucine was studied in solution, through 1H and 31P NMR experiments, and in the solid state, through co-crystallisation experiments. The inherent chirality of the receptors was obtained through the desymmetrization of the rigid concave cavity by introducing three different bridging groups at the upper rim: two inward P=O groups, one inward P=S moiety and one methylene bridge in the AABC mode. For the solution studies, N-methyl-L-leucine was used as pure enantiomer and partial enantioselectivity was observed in the presence of an excess of a racemic mixture of cavitand receptor. Centrosymmetric crystals consisting of the complexes cR-cav1·N-methyl-D-leucine and cS-cav1·N-methyl-L-leucine were obtained from co-crystallisation of the racemic mixture of cR-cav/cS-cav 1 and N-methyl-D/L-leucine. Differently to the solution case, in the solid state the enantioselectivity of the chiral cavitand is complete and only the two enantiopure mirror complexes were obtained.

The Origin of Selectivity in the Complexation of N-Methyl Amino Acids by Tetraphosphonate Cavitands.

We report on the eligibility of tetraphosphonate resorcinarene cavitands for the molecular recognition of amino acids. We determined the crystal structure of 13 complexes of the tetraphosphonate cavitand Tiiii[H, CH3, CH3] with amino acids. (1)H NMR and (31)P NMR experiments and ITC analysis were performed to probe the binding between cavitand Tiiii[C3H7, CH3, C2H5] or the water-soluble counterpart Tiiii[C3H6Py(+)Cl(-), CH3, C2H5] and a selection of representative amino acids. The reported studies and results allowed us (i) to highlight the noncovalent interactions involved in the binding event in each case; (ii) to investigate the ability of tetraphosphonate cavitand receptors to discriminate between the different amino acids; (iii) to calculate the Ka values of the different complexes formed and evaluate the thermodynamic parameters of the complexation process, dissecting the entropic and enthalpic contributions; and (iv) to determine the solvent influence on the complexation selectivity. By moving from methanol to water, the complexation changed from entropy driven to entropy opposed, leading to a drop of almost three orders in the magnitude of the Ka. However, this reduction in binding affinity is associated with a dramatic increase in selectivity, since in aqueous solutions only N-methylated amino acids are effectively recognized. The thermodynamic profile of the binding does not change in PBS solution. The pivotal role played by cation-π interactions is demonstrated by the linear correlation found between the log Ka in methanol solution and the depth of (+)N-CH3 cavity inclusion in the molecular structures. These findings are relevant for the potential use of phosphonate cavitands as synthetic receptors for the detection of epigenetic modifications of histones in physiological media.

The effect of number and position of P=O/P=S bridging units on cavitand selectivity toward methyl ammonium salts.

The present work reports the synthesis and complexation properties of five mixed bridge P=O/P=S cavitands toward N,N-methyl butyl ammonium chloride (1) as prototype guest. The influence of number and position of P=O and P=S groups on the affinity of phosphonate cavitands toward 1 is assessed via ITC titrations in DCE as solvent. Comparison of the resulting Kass values, the enthalpic and entropic contributions to the overall binding with those of the parent tetraphosphonate Tiiii and tetrathiophosphonate TSiiii cavitands allows one to single out the simultaneous dual H-bond between the cavitand and the salt as the major player in complexation.

Chemoselective recognition with phosphonate cavitands: the ephedrine over pseudoephedrine case

Complete discrimination of ephedrine and pseudoephedrine, both in solution and in the solid state, was achieved with a phosphonate cavitand receptor. The molecular origin of the epimer discrimination was revealed by the crystal structure of the respective complexes.

Design of differently P-substituted 4iPO fluorescent tetraphosphonate cavitands

Experimental approaches to tetraphosphonate cavitands bearing fluorenyl-phosphonate bridges are reported. Different routes are described depending on the substitution on the cavitand structure. Tetra-, tri- and di-bridged phosphonate cavitands have been prepared as precursors of fluorescent hosts, for which the stereochemistry is highly dependent on the substitution at the wide rim of the resorcin[4]arene scaffold. The conformational change in 3io tetraphosphonate cavitands has been characterised by X-ray diffraction. These new molecular receptors have been used for the recognition of acetylcholine.

Supramolecular sensing of short chain alcohols with mixed-bridged thio-phosphonate cavitands

The possibility to enhance the selectivity of phosphonate cavitands toward short-chains alcohols, namely methanol and ethanol, reducing the size of the cavity with the introduction of bulky thio-phosphonate bridging units at the upper rim is here presented. Three new mixed bridged thio-phosphonate cavitands 3POiii1PSi[H, CH3, Ph], AB-2POii2PSii[H, CH3, Ph] and AC-2POii2PSii[H, CH3, Ph] were designed, synthesized and tested as QCM sensors. The measurements show that the presence of two bulky H-bond silent PS bridges makes the resulting AB/AC-2POii2PSii[H, CH3, Ph] cavitands effective in discriminating methanol and ethanol with respect to their longer analogs. The QCM measurements also show that the substitution of a single PO bridge with a PS one, as in 3POiii1PSi[H, CH3, Ph], is not sufficient, as it reduces the responses without affecting the selectivity pattern. The crystal structures of the AB-2POii2PSii[H, CH3, Ph]·MeOH and the AC-2POii2PSii[H, CH3, Ph]·MeOH complexes show that the key factors affecting the sensing performances toward alcohols of these new class of mixed-bridged phosphonate cavitands are synergistic CH–π and H-bonding interactions, as in the parent tetraphosphonate cavitands.

Supramolecular Sensing with Phosphonate Cavitands

Molecular recognition is a recurrent theme in chemical sensing because of the importance of selectivity for sensor performances. The popularity of molecular recognition in chemical sensing has resulted from the progress made in mastering weak interactions, which has enabled the design of synthetic receptors according to the analyte to be detected. However, the availability of a large pool of modular synthetic receptors so far has not had a significant impact on sensors used in the real world. This technological gap has emerged because of the difficulties in transferring the intrinsic molecular recognition properties of a given receptor from solution to interfaces and in finding high fidelity transduction modes for the recognition event. This Account focuses on the ways to overcome these two bottlenecks, and we recount our recent efforts to produce highly selective supramolecular sensors using phosphonate cavitands as receptors. Through two examples, we present an overview of the different operating strategies that are implemented depending on whether the interface is vapor-solid or liquid-solid. First we describe the selective detection of short chain aliphatic alcohols in the vapor phase. In this example, we solved a key issue common to all sensors for organic vapors: the dissection of the specific interaction (between cavitand and the alcohol) from ubiquitous nonspecific dispersion interactions (between the analytes and interferents in the solid layer). We removed responses resulting from the nonspecific interactions of the analytes with interferents by directly connecting the recognition event at the interface to the transduction mechanism (photoinduced charge transfer). The second example addresses the specific detection of sarcosine in urine. Recent research has suggested that sarcosine can serve as reliable biomarker of the aggressive forms of prostate cancer. Tetraphosphonate cavitands can complex N-methyl ammonium salts with impressive selectivity in solution, and we used this property as a starting point. The sensor implementation requires that we first graft the cavitand onto silicon and gold surfaces as monolayers. The exclusive recognition of sarcosine by these supramolecular sensors originates from their operation in aqueous environments, where synergistic multiple interactions with the phosphonate cavitand are possible only for N-methyl ammonium derivatives. We couple that selectivity with detection modes that probe the strength of the complexation either directly (microcantilever) or via exchange with molecules that have comparable affinity for the cavity (fluorescence dye displacement).

Highly Selective Chemical Vapor Sensing by Molecular Recognition: Specific Detection of C1–C4 Alcohols with a Fluorescent Phosphonate Cavitand

Fiat lux on alcohols: Molecular-level resolution was achieved for the detection of short-chain alcohols in the vapor phase using a fluorescent cavitand sensor. The transduction mechanism, activated exclusively by the complexation mode, is provided by the change of the electronic density on the fluorophore caused by the formation of an intracavity hydrogen bond between the cavitand PO and the alcohol OH group.

Highly Selective Chemical Vapor Sensing by Molecular Recognition: Specific Detection of C1–C4 Alcohols with a Fluorescent Phosphonate Cavitand

Feines Gespür: Eine Auflösung auf molekularem Niveau beim Nachweis kurzkettiger Alkohole in der Gasphase bietet ein fluoreszierender Cavitandensensor. Der Transduktionsmechanismus, der ausschließlich duch die Art der Komplexierung aktiviert wird, beruht auf einer Änderung der Elektronendichte im Fluorophor als Folge der Bildung einer Intrakavitäts-Wasserstoffbrücke zwischen der Cavitand-PO- und der Alkohol-OH-Gruppe.

Molecular Recognition with Ditopic Cavitand Re Complexes

AbstractThe synthesis of a series of cavitand receptors bearing increasing numbers of phosphonate groups at their upper rims and of the corresponding Re‐based ditopic complexes is reported. The molecular recognition properties of these phosphonate cavitands towards both monotopic and ditopic N‐methylpyridinium salts were investigated. The numbers and spatial dispositions of P=O units are pivotal for the complexation of guest ions. The removal of a single P=O bridge from the parent tetraphosphonate cavitand was sufficient to reduce the association constant by almost three orders of magnitude. Elimination of a second P=O unit completely abolished complexation in the AC distal isomer, both in monotopic and in ditopic hosts. The preorganised structure obtained by interconnection of two triphosphonate cavitands through a Re system showed moderate positive self‐assembly cooperativity in the inclusion of ditopic N‐methylpyridinium salts in both polar and nonpolar solvents. The speciation profile in ethanol indicates that the clamshell 1:1 complex is dominant at low concentrations (< 10–4 M) whereas the 1:2 complex is preferred at higher concentrations of ditopic guest.

Thermodynamics of host–guest interactions between methylpyridinium salts and phosphonate cavitands

In this work, the properties of complexation of tetraphosphonate cavitands towards methylpyridinium guests were investigated via isothermal titration calorimetry (ITC). For this purpose, Tiiii[C3H7, CH3, Ph], Tiiii[C3H7, H, Ph], TSiiii[C3H7, H, Ph] hosts and three different methylpyridinium guests were synthesised. The role of the following parameters in the host–guest complexation was investigated: (i) solvation, (ii) nature of the guest counterion, (iii) presence of substituents in the apical positions of the receptor, and (iv) P = O versus P = S bridging units. The results showed that (i) switching from dichloroethane to methanol leads to a decrease of the association constant due to the competitive nature of the solvent, (ii) the guest counterion does not affect the thermodynamics of the process, (iii) the apical methyl groups enhance the binding affinity of the receptor and (iv) the comparison between phosphonate and thiophosphonate hosts clearly demonstrates that cation–dipole interactions are necessary for binding.

Molecular Rotor Inside a Phosphonate Cavitand: Role of Supramolecular Interactions

A supramolecular rotor is designed based on a phosphonate cavitand···methanol/ethanol complex. Density functional theory (DFT) calculations reveal a very small barrier for rotation of methanol insi...

Hydrogen Bonding in Phosphonate Cavitands: Investigation of Host–Guest Complexes with Ammonium Salts

The H-bonding in alkylammonium complexes of phosphonate cavitands were studied by mass spectrometric methods and theoretical calculations. The alkylammonium ions included primary, secondary, and tertiary methyl- and ethylammonium ions. Their complexation with mono-, tetra-, and two di-phosphonate cavitands, which differ according to the number and position of H-bond acceptor P = O groups, was evaluated by using different competition experiments, energy-resolved CID, gas-phase H/D-exchange, and ligand-exchange reactions, together with ab initio theoretical optimization of the complexes. The phosphonate cavitands with two or more adjacent P = O groups were found to be selective towards secondary alkylammonium ions, due to simultaneous formation of two stable hydrogen bonds. In the ion-molecule reactions (both H/D- and ligand-exchange), the formation of two stable hydrogen bonds was observed either to slow down the reaction or to completely prevent it. This was, however, limited to situations where two hydrogen bonds are formed between the H-bond donor sites of the alkyl ammonium ion and the vicinal H-bond acceptor sites of the cavitand.

Self-Complementary Phosphonate Cavitands

iii-Phosphorylated cavitands incorporating an N-methylpyridinium guest moiety as the fourth bridging unit form supramolecular associations by inclusion of the charged CH(3)N(+)-pyridinium head into a neighboring host cavity. The dimeric association is favored in solution and was characterized by NMR, mass spectrometry, DOSY experiments, and single crystal X-ray analysis.

Highly Selective Monomethylation of Primary Amines Through Host−Guest Product Sequestration

This Communication reports the highly selective monomethylation of primary amines through host-guest product sequestration. Complete control of the outcome of the N-methylation reaction has been achieved by adding to the reaction medium stoichiometric amounts of a teraphosphonate phosphonate cavitand Tiiii, capable of selectively and quantitatively trapping the monomethylated ammonium salt formed. The synergistic combination of ion-dipole, H-bonding, and CH(3)-pi interactions provide the high association constants (K(ass) > 10(9)) and the specific complexation mode necessary for the exclusive sequestration of the monomethylated intermediate reaction product.

Supramolecular Sensing with Phosphonate Cavitands

Phosphonate cavitands are an emerging class of synthetic receptors for supramolecular sensing. The molecular recognition properties of the third-generation tetraphosphonate cavitands toward alcohols and water at the gas-solid interface have been evaluated by means of three complementary techniques and compared to those of the parent mono- and diphosphonate cavitands. The combined use of ESI-MS and X-ray crystallography defined precisely the host-guest association at the interface in terms of type, number, strength, and geometry of interactions. Quartz crystal microbalance (QCM) measurements then validated the predictive value of such information for sensing applications. The importance of energetically equivalent multiple interactions on sensor selectivity and sensitivity has been demonstrated by comparing the molecular recognition properties of tetraphosphonate cavitands with those of their mono- and diphosphonate counterparts.

Host–Guest Driven Self‐Assembly of Linear and Star Supramolecular Polymers

Supramolecular plasticity: The remarkable host–guest properties of phosphonate cavitands have been exploited in the self-assembly of supramolecular polymers (see picture) that feature guest-triggered reversibility and template-driven conversion from linear into star-branched forms. The structurally similar but complexation-inefficient thiophosphonate cavitand acts as chain stopper to control the degree of polymerization. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2008/z801002_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Fully reversible guest exchange in tetraphosphonate cavitand complexes probed by fluorescence spectroscopy

We report here the monitoring of reversible guest inclusion in phosphonate cavitands through a large increase in luminescence intensity caused by the modulation of the exoergonicity of an electron-transfer reaction.

Synthesis and configurational analysis of phosphonate cavitands

Synthesis, separation and configurational analysis of phosphonated and partially phosphonated cavitands derived from resorcinarenes are described. The configuration of all diastereomers has been elucidated by their 1H, 31P NMR spectra and 13C relaxation times. In all cases the course of the bridging reaction favours the formation of the sterically more crowded stereoisomers having the PO groups oriented outward with respect to the cavity.