Paulo J. Costa

Fluorescent Charge-Assisted Halogen-Bonding Macrocyclic Halo-Imidazolium Receptors for Anion Recognition and Sensing in Aqueous Media

The synthesis and anion binding properties of a new family of fluorescent halogen bonding (XB) macrocyclic halo-imidazolium receptors are described. The receptors contain chloro-, bromo-, and iodo-imidazolium motifs incorporated into a cyclic structure using naphthalene spacer groups. The large size of the iodine atom substituents resulted in the isolation of anti and syn conformers of the iodo-imidazoliophane, whereas the chloro- and bromo-imidazoliophane analogues exhibit solution dynamic conformational behavior. The syn iodo-imidazoliophane isomer forms novel dimeric isostructural XB complexes of 2:2 stoichiometry with bromide and iodide anions in the solid state. Solution phase DOSY NMR experiments indicate iodide recognition takes place via cooperative convergent XB-iodide 1:1 stoichiometric binding in aqueous solvent mixtures. (1)H NMR and fluorescence spectroscopic titration experiments with a variety of anions in the competitive CD(3)OD/D(2)O (9:1) aqueous solvent mixture demonstrated the bromo- and syn iodo-imidazoliophane XB receptors to bind selectively iodide and bromide respectively, and sense these halide anions exclusively via a fluorescence response. The protic-, chloro-, and anti iodo-imidazoliophane receptors proved to be ineffectual anion complexants in this aqueous methanolic solvent mixture. Computational DFT and molecular dynamics simulations corroborate the experimental observations that bromo- and syn iodo-imidazoliophane XB receptors form stable cooperative convergent XB associations with bromide and iodide.

Halogen bond anion templated assembly of an imidazolium pseudorotaxane

Halogen bonding has been exploited in the assembly of an interpenetrated molecular system. The strength of chloride-anion-templated pseudorotaxane formation with a 2-bromo-functionalized imidazolium threading component and an isophthalamide macrocycle (see picture) is significantly enhanced compared to hydrogen-bonded pseudorotaxane analogues. (Figure Presented).

Chloride, carboxylate and carbonate transport by ortho-phenylenediamine-based bisureas

Highly potent but structurally simple transmembrane anion transporters are reported that function at receptor to lipid ratios as low as 1:1000000. The compounds, based on the simple ortho-phenylenediamine-based bisurea scaffold, have been studied for their ability to facilitate chloride/nitrate and chloride/bicarbonate antiport, and HCl symport processes using a combination of ion selective electrode and fluorescence techniques. In addition, the transmembrane transport of dicarboxylate anions (maleate and fumarate) by the compounds was examined. Molecular dynamics simulations showed that these compounds permeate the membrane more easily than other promising receptors corroborating the experimental efflux data. Moreover, cell based assays revealed that the majority of the compounds showed cytotoxicity in cancer cells, which may be linked to their ability to function as ion transporters.

Sulfate anion templated synthesis of a triply interlocked capsule

Sulfate templation has been used in the synthesis of a novel tris-urea-based triply interlocked capsule, whose structure has been verified by DOSY NMR, mass spectrometry and molecular modelling investigations.

A Catenane Assembled through a Single Charge‐Assisted Halogen Bond

Interlocked molecules have captured chemists’ imagination owing to their nontrivial topology and the promise of their potential nanotechnological uses as molecular machines[1] and in chemical sensor applications.[2] The synthesis of such sophisticated architectures is a challenge, and as a consequence this has necessitated the implementation of imaginative cation,[3] anion,[4] and neutral[5] templation methodologies, which use a combination of complementary Lewis acid–base, electrostatic, and hydrogen-bonding interactions for component assembly. Halogen bonding (XB) is the attractive highly directional, noncovalent interaction between an electron-deficient halogen atom and a Lewis base.[6] The scope of XB in solid-state crystal engineering has been intensively explored for a number of years,[7] however, in spite of the complementary analogy to ubiquitous hydrogen bonding, it is only in recent times that investigations into the application of solution-phase XB interactions to molecular recognition processes, self-assembly, and catalysis have resulted in this field developing rapidly.[8] Indeed, in conjunction with anion templation, we have used XB to assemble interpenetrated and interlocked molecular frameworks.[8b–d]

[Re(η5-C5H5)(CO)3]+ Family of 17-Electron Compounds : Monomer/Dimer Equilibria and Other Reactions

The anodic electrochemical oxidations of ReCp(CO)3 (1, Cp = eta(5)-C5H5), Re(eta(5)-C5H4NH2)(CO)3 (2), and ReCp*(CO)3 (3, Cp* = eta(5)-C5Me5), have been studied in CH2Cl2 containing [NBu4][TFAB] (TFAB = [B(C6F5)4]-) as supporting electrolyte. One-electron oxidations were observed with E(1/2) = 1.16, 0.79, and 0.91 V vs ferrocene for 1-3, respectively. In each case, rapid dimerization of the radical cation gave the dimer dication, [Re2Cp(gamma)2(CO)6]2+ (where Cp(gamma) represents a generic cyclopentadienyl ligand), which may be itself reduced cathodically back to the original 18-electron neutral complex ReCp(gamma)(CO)3. DFT calculations show that the SOMO of 1+ is highly Re-based and hybridized to point away from the metal, thereby facilitating the dimerization process and other reactions of the Re(II) center. The dimers, isolated in all three cases, have long metal-metal bonds that are unsupported by bridging ligands, the bond lengths being calculated as 3.229 A for [Re2Cp2(CO)6]2+ (1(2)2+) and measured as 3.1097 A for [Re2(C5H4NH2)2(CO)6]2+ (2(2)2+) by X-ray crystallography on [Re2(C5H4NH2)2(CO)6][TFAB]2. The monomer/dimer equilibrium constants are between K(dim) = 10(5) M(-1) and 10(7) M(-1) for these systems, so that partial dissociation of the dimers gives a modest amount of the corresponding monomer that is free to undergo radical cation reactions. The radical 1+ slowly abstracts a chlorine atom from dichloromethane to give the 18-electron complex [ReCp(CO)3Cl]+ as a side product. The radical cation 1+ acts as a powerful one-electron oxidant capable of effectively driving outer-sphere electron-transfer reactions with reagents having potentials of up to 0.9 V vs ferrocene.

Rotaxanes Capable of Recognising Chloride in Aqueous Media

A new, versatile chloride-anion-templating synthetic pathway is exploited for the preparation of a series of eight new [2]rotaxane host molecules, including the first sulfonamide interlocked system. (1)H NMR spectroscopic titration investigations demonstrate the rotaxanes capability to selectively recognise the chloride anion in competitive aqueous solvent media. The interlocked hosts halide binding affinity can be further enhanced and tuned through the attachment of electron-withdrawing substituents and by increasing its positive charge. A dicationic rotaxane selectively binds chloride in 35% water, wherein no evidence of oxoanion binding is observed. NMR spectroscopy, X-ray structural analysis and computational molecular dynamics simulations are used to account for rotaxane formation yields, anion binding strengths and selectivity trends.

Towards predictable transmembrane transport: QSAR analysis of anion binding and transport

The transport of anions across biological membranes by small molecules is a growing research field due to the potential therapeutic benefits of these compounds. However, little is known about the exact mechanism by which these drug-like molecules work and which molecular features make a good transporter. An extended series of 1-hexyl-3-phenylthioureas were synthesized, fully characterized (NMR, mass spectrometry, IR and single crystal diffraction) and their anion binding and anion transport properties were assessed using 1H NMR titration techniques and a variety of vesicle-based experiments. Quantitative structure–activity relationship (QSAR) analysis revealed that the anion binding abilities of the mono-thioureas are dominated by the (hydrogen bond) acidity of the thiourea NH function. Furthermore, mathematical models show that the experimental transmembrane anion transport ability is mainly dependent on the lipophilicity of the transporter (partitioning into the membrane), but smaller contributions of molecular size (diffusion) and hydrogen bond acidity (anion binding) were also present. Finally, we provide the first step towards predictable anion transport by employing the QSAR equations to estimate the transmembrane transport ability of four new compounds.

Structural Studies on Dinuclear Ruthenium(II) Complexes That Bind Diastereoselectively to an Antiparallel Folded Human Telomere Sequence.

We report DNA binding studies of the dinuclear ruthenium ligand [{Ru(phen)2}2tpphz]4+ in enantiomerically pure forms. As expected from previous studies of related complexes, both isomers bind with similar affinity to B-DNA and have enhanced luminescence. However, when tested against the G-quadruplex from human telomeres (which we show to form an antiparallel basket structure with a diagonal loop across one end), the ΛΛ isomer binds approximately 40 times more tightly than the ΔΔ, with a stronger luminescence. NMR studies show that the complex binds at both ends of the quadruplex. Modeling studies, based on experimentally derived restraints obtained for the closely related [{Ru(bipy)2}2tpphz]4+, show that the ΛΛ isomer fits neatly under the diagonal loop, whereas the ΔΔ isomer is unable to bind here and binds at the lateral loop end. Molecular dynamics simulations show that the ΔΔ isomer is prevented from binding under the diagonal loop by the rigidity of the loop. We thus present a novel enantioselective binding substrate for antiparallel basket G-quadruplexes, with features that make it a useful tool for quadruplex studies.

Tunable transmembrane chloride transport by bis-indolylureas

A series of bis-indolylureas have been found to mediate chloride transport across vesicle bilayers. The anion transport activity of these receptors may be readily modulated by small structural changes to the receptor scaffold as shown by the combination of experimental chloride efflux studies and molecular dynamics simulations in water and POPC bilayers.