Exploiting Supramolecular Interactions to Control Isomer Distributions in Reduced-Symmetry [Pd2L4]4+ Cages.

High-symmetry metallosupramolecular architectures (MSAs) have been exploited for a range of applications including molecular recognition, catalysis, and drug delivery. Recently, there have been increasing efforts to enhance those applications by generating reduced-symmetry MSAs. Here we report our attempts to use supramolecular (dispersion and hydrogen-bonding) forces and solvophobic effects to generate isomerically pure [Pd2(L)4]4+ cage architectures from a family of new reduced-symmetry ditopic tripyridyl ligands. The reduced-symmetry tripyridyl ligands featured either solvophilic polyether chains, solvophobic alkyl chains, or amino substituents. We show using NMR spectroscopy, high-performance liquid chromatography, X-ray diffraction data, and density functional theory calculations that the combination of dispersion forces and solvophobic effects does not provide any control of the [Pd2(L)4]4+ isomer distribution with mixtures of all four cage isomers (HHHH, HHHT, cis-HHTT, or trans-HTHT, where H = head and T = tail) obtained in each case. More control was obtained by exploiting hydrogen-bonding interactions between amino units. While the cage assembly with a 3-amino-substituted tripyridyl ligand leads to a mixture of all four possible isomers, the related 2-amino-substituted tripyridyl ligand generated a cis-HHTT cage architecture. Formation of the cis-HHTT [Pd2(L)4]4+ cage was confirmed using NMR studies and X-ray crystallography.

Can 2-Pyridyl-1,2,3-triazole "Click" Ligands be Used to Develop Cu(I)/Cu(II) Molecular Switches?

Molecular switching processes are important in a range of areas including the development of molecular machines. While there are numerous organic switching systems available, there are far less examples that exploit inorganic materials. The most common inorganic switching system remains the copper(I)/copper(II) switch developed by Sauvage and co-workers over 20 years ago. Herein, we examine if bidentate 2-(1-benzyl-1H-1,2,3-triazol-4-yl)pyridine (pytri) and tridentate 2,6-bis[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]pyridine (tripy) moieties can be used to replace the more commonly exploited polypyridyl ligands 2,2'-bypyridine (bpy)/1,10-phenanthroline (phen) and 2,2';6',2″-terpyridine (terpy) in a copper(I)/(II) switching system. Two new ditopic ligands that feature bidentate (pytri, L1 or bpytri, L2) and tridentate tripy metal binding pockets were synthesized and used to generate a family of heteroleptic copper(I) and copper(II) 6,6'-dimesityl-2,2'-bipyridine (diMesbpy) complexes. Additionally, we synthesized a series of model copper(I) and copper(II) diMesbpy complexes. A combination of techniques including nuclear magnetic resonance (NMR) and UV-vis spectroscopies, high-resolution electrospray ionization mass spectrometry, and X-ray crystallography was used to examine the behavior of the compounds. It was found that L1 and L2 formed [(diMesbpy)Cu(L1 or L2)]2+ complexes where the copper(II) diMesbpy unit was coordinated exclusively in the tridenate tripy binding site. However, when the ligands (L1 and L2) were complexed with copper(I) diMesbpy units, a complex mixture was obtained. NMR and MS data indicated that a 1:1 stoichiometry of [Cu(diMesbpy)]+ and either L1 or L2 generated three complexes in solution, the dimetallic [(diMesbpy)2Cu2(L1 or L2)]2+ and the monometallic [(diMesbpy)Cu(L1 or L2)]+ isomers where the [Cu(diMesbpy)]+ unit is coordinated to either the bidentate or tridentate tripy binding sites of the ditopic ligands. The dimetallic [(diMesbpy)2Cu2(L1 or L2)](PF6)2 complexes were structurally characterized using X-ray crystallography. Both complexes feature a [Cu(diMesbpy)]+ coordinated to the bidentate (pytri or bpytri) pocket of the ditopic ligands (L1 or L2), as expected. They also feature a second [Cu(diMesbpy)]+ coordinated to the nominally tridentate tripy binding site in a four-coordinate hypodentate κ2-fashion. Competition experiments with model complexes showed that the binding strength of the bidentate pytri is similar to that of the κ2-tripy ligand, leading to the lack of selectivity. The results suggest that the pytri/tripy and bpytri/tripy ligand pairs cannot be used as replacements for the more common bpy/phen-terpy partners due to the lack of selectivity in the copper(I) state.

6,6'-Ditriphenylamine-2,2'-bipyridine: Coordination Chemistry and Electrochemical and Photophysical Properties.

A 2,2'-bipyridine with bulky triphenylamine substituents in the 6 and 6' positions of the ligand (6,6'-ditriphenylamine-2,2'-bipyridine, 6,6'-diTPAbpy) was generated. Despite the steric bulk, the ligand readily formed bis(homoleptic) complexes with copper(I) and silver(I) ions. Unfortunately, efforts to use the 6,6'-diTPAbpy system to generate heteroleptic [Cu(6,6'-diTPAbpy)(bpy)]+ complexes were unsuccessful with only the [Cu(6,6'-diTPAbpy)2](PF6) complex observed. The 6,6'-diTPAbpy ligand could also be reacted with 6-coordinate metal ions that featured small ancillary ligands, namely, the [Re(CO)3Cl] and [Ru(CO)2Cl2] fragments. While the complexes could be formed in good yields, the steric bulk of the TPA units does alter the coordination geometry. This is most readily seen in the [(6,6'-diTPAbpy)Re(CO)3Cl] complex where the Re(I) ion is forced to sit 23° out of the plane formed by the bpy unit. The electrochemical and photophysical properties of the family of compounds were also examined. 6,6'-diTPAbpy exhibits a strong ILCT absorption band (356 nm, 50 mM-1 cm-1) which displays a small increase in intensity for the homoleptic complexes ([Cu(6,6'-diTPAbpy)2]+; 353 nm, 72 mM-1 cm-1, [Ag(6,6'-diTPAbpy)2]+; 353 nm, 75 mM-1 cm-1), despite containing 2 equiv of the ligand, attributed to an increased dihedral angle between the TPA and bpy moieties. For the 6-coordinate complexes the ILCT band is further decreased in intensity and overlaps with MLCT bands, consistent with a further increased TPA-bpy dihedral angle. Emission from the 1ILCT state is observed at 436 nm (τ = 4.4 ns) for 6,6'-diTPAbpy and does not shift for the Cu, Ag, and Re complexes, although an additional 3MLCT emission is observed for [Re(6,6'-diTPAbpy)(CO)3Cl] (640 nm, τ = 13.8 ns). No emission was observed for [Ru(6,6'-diTPAbpy)(CO)2Cl2]. Transient absorption measurements revealed the population of a 3ILCT state for the Cu and Ag complexes (τ = 80 ns). All assignments were supported by TD-DFT calculations and resonance Raman spectroscopic measurements.

Cavity-Containing [Fe2L3]4+ Helicates: An Examination of Host-Guest Chemistry and Cytotoxicity.

Two new di(2,2'-bipyridine) ligands, 2,6-bis([2,2'-bipyridin]-5-ylethynyl)pyridine (L1) and bis(4-([2,2'-bipyridin]-5-ylethynyl)phenyl)methane (L2) were synthesized and used to generate two metallosupramolecular [Fe2(L)3](BF4)4 cylinders. The ligands and cylinders were characterized using elemental analysis, electrospray ionization mass spectrometry, UV-vis, 1H-, 13C and DOSY nuclear magnetic resonance (NMR) spectroscopies. The molecular structures of the [Fe2(L)3](BF4)4 cylinders were confirmed using X-ray crystallography. Both the [Fe2(L1)3](BF4)4 and [Fe2(L2)3](BF4)4 complexes crystallized as racemic (rac) mixtures of the ΔΔ (P) and ΛΛ (M) helicates. However, 1H NMR spectra showed that in solution the larger [Fe2(L2)3](BF4)4 was a mixture of the rac-ΔΔ/ΛΛ and meso-ΔΛ isomers. The host-guest chemistry of the helicates, which both feature a central cavity, was examined with several small drug molecules. However, none of the potential guests were found to bind within the helicates. In vitro cytotoxicity assays demonstrated that both helicates were active against four cancer cell lines. The smaller [Fe2(L1)3](BF4)4 system displayed low µM activity against the HCT116 (IC50 = 7.1 ± 0.5 µM) and NCI-H460 (IC50 = 4.9 ± 0.4 µM) cancer cells. While the antiproliferative effects against all the cell lines examined were less than the well-known anticancer drug cisplatin, their modes of action would be expected to be very different.

Self-Assembly of a Redox Active, Metallosupramolecular [Pd3 L6 ]6+ Complex Using a Rotationally Flexible Ferrocene Ligand.

A new ferrocene-containing [Pd3 (L4EFc )6 ]6+ (X- )6 (C ⋅ BF4 and C ⋅ SbF6 where X=BF4 - or SbF6 - ) self-assembled double-walled triangle has been synthesized from the known, rotationally flexible, 1,1'-bis(4-pyridylethynyl)ferrocene ligand (L4EFc ), and characterized by 1 H, 13 C and diffusion ordered (DOSY) NMR spectroscopies, high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), X-ray crystallography and cyclic voltammetry (CV). The molecular structures confirmed that double-walled triangle cage systems (C ⋅ BF4 and C ⋅ SbF6 ) were generated. C ⋅ BF4 was shown to interact with the anionic guest, p-toluenesulfonate. CV experiments revealed that the triangles were redox active, however addition of the guest did not influence the redox potentials.

Redox active [Pd2L4]4+ cages constructed from rotationally flexible 1,1'-disubstituted ferrocene ligands.

Two new ferrocene-containing [Pd2(LFc)4]4+(X-)4 (where X- = BF4- or SbF6-) self-assembled cages (C·BF4 and C·SbF6) were synthesised from the known, rotationally flexible, 1,1'-bis(3-pyridylethynyl)ferrocene ligand (LFc), and characterised by 1H, 13C and diffusion ordered (DOSY) NMR and UV-visible absorption spectroscopies, high resolution electrospray ionisation mass spectrometry (HR-ESI-MS), elemental analysis, X-ray crystallography and cyclic voltammetry (CV). The molecular structures confirmed that cage-like systems (C·BF4 and C·SbF6) were generated. Similar to related [Pd2L4]4+(X-)4, C·SbF6 was able to interact with a range of neutral and anionic guests, with p-toluenesulfonate showing the strongest association constant. Cyclic voltammetry studies revealed that the cage systems were redox active. However, the redox potential of the cage was unperturbed upon the addition of guests.

Anticancer Activity and Cisplatin Binding Ability of Bis-Quinoline and Bis-Isoquinoline Derived [Pd2L4]4+ Metallosupramolecular Cages.

New bis-quinoline (L q) and bis-isoquinoline-based (L iq) ligands have been synthesized, along with their respective homoleptic [Pd2(L q or L iq)4]4+ cages (C q and C iq). The ligands and cages were characterized by 1H, 13C and diffusion ordered (DOSY) NMR spectroscopies, high resolution electrospray ionization mass spectrometry (HR-ESIMS) and in the case of the bis-quinoline cage, X-ray crystallography. The crystal structure of the C q architecture showed that the [Pd2(L q)4]4+ cage formed a twisted meso isomer where the [Pd(quinoline)4]2+ units at either end of the cage architecture adopt the opposite twists (left and right handed). Conversely, Density Functional Theory (DFT) calculations on the C iq cage architecture indicated that a lantern shaped conformation, similar to what has been observed before for related [Pd2(L tripy)4]4+ systems (where L tripy = 2,6-bis(pyridin-3-ylethynyl)pyridine), was generated. The different cage conformations manifest different properties for the isomeric cages. The C iq cage is able to bind, weakly in acetonitrile, the anticancer drug cisplatin whereas the C q architecture shows no interaction with the guest under the same conditions. The kinetic robustness of the two cages in the presence of Cl- nucleophiles was also different. The C iq cage was completely decomposed into free L iq and [Pd(Cl)4]2- within 1 h. However, the C q cage was more long lived and was only fully decomposed after 7 h. The new ligands (L iq and L q) and the Pd(II) cage architectures (C iq and C q) were assessed for their cytotoxic properties against two cancerous cell lines (A549 lung cancer and MDA-MB-231 breast cancer) and one non-cancerous cell line (HDFa skin cells). It was found that L q and C q were both reasonably cytotoxic (IC50S ≈ 0.5 µM) against A549, while C iq was slightly less active (IC50 = 7.4 µM). L iq was not soluble enough to allow the IC50 to be determined against either of the two cancerous cell lines. However, none of the molecules showed any selectivity for the cancer cells, as they were all found to have similar cytotoxicities against HDFa skin cells (IC50 values ranged from 2.6 to 3.0 µM).

Strategies for Reversible Guest Uptake and Release from Metallosupramolecular Architectures.

The cavities of metallosupramolecular cages can be used to mimic the central spaces of naturally occurring proteins and bind a wide variety of molecular guests. A range of potential applications have arisen from this capacity for host-guest chemistry. However, to truly harness the opportunities thus afforded, methodologies to controllably allow the release and reuptake of guests from the cavities of metallosupramolecular cages are required. Methods to accomplish this have centered upon reversibly altering the character of either the guest or host. This minireview outlines the current approaches used to carry out the binding and release of guests from metallosupramolecular hosts using important examples from the field.

Multicavity Metallosupramolecular Architectures.

Discrete metallosupramolecular systems are often macrocyclic or cage-like architectures with an accessible internal cavity. Guest molecules can reside within these cavities and much of the interest in these systems is derived from these fascinating host-guest interactions. A range of potential applications stem from the ability of these metallosupramolecular architectures to encapsulate guests. These applications include catalysis or acting as molecular reaction flasks, the molecular scavenging of pollutants, storage of reactive species, and drug delivery. Multicavity metallosupramolecular architectures combine the ability of large hollow assemblies to bind multiple guests concurrently with the binding specificity associated with small cages. A variety of different approaches to generating separate compartments within a single metallosupramolecular assembly have emerged. These include interpenetrated cages, cages with polytopic ligands that have a long backbone, and molecules that have two or more clefts. This review examines these approaches, and highlights key contributions to the field.

Solid-State Gas Adsorption Studies with Discrete Palladium(II) [Pd2 (L)4 ]4+ Cages.

The need for effective CO2 capture systems remains high, and due to their tunability, metallosupramolecular architectures are an attractive option for gas sorption. While the use of extended metal organic frameworks for gas adsorption has been extensively explored, the exploitation of discrete metallocage architectures to bind gases remains in its infancy. Herein the solid state gas adsorption properties of a series of [Pd2 (L)4 ]4+ lantern shaped coordination cages (L = variants of 2,6-bis(pyridin-3-ylethynyl)pyridine), which had solvent accessible internal cavities suitable for gas binding, have been investigated. The cages showed little interaction with dinitrogen gas but were able to take up CO2 . The best performing cage reversibly sorbed 1.4 mol CO2 per mol cage at 298 K, and 2.3 mol CO2 per mol cage at 258 K (1 bar). The enthalpy of binding was calculated to be 25-35 kJ mol-1 , across the number of equivalents bound, while DFT calculations on the CO2 binding in the cage gave ΔE for the cage-CO2 interaction of 23-28 kJ mol-1 , across the same range. DFT modelling suggested that the binding mode is a hydrogen bond between the carbonyl oxygen of CO2 and the internally directed hydrogen atoms of the cage.

Functional metallosupramolecular architectures using 1,2,3-triazole ligands: it's as easy as 1,2,3 "click".

Self-assembled metallosupramolecular architectures have become an increasingly popular area of inorganic chemistry. These systems show a range interesting biological, electronic and photophysical properties. Additionally, they display extensive host-guest chemistry that could potentially be exploited for drug delivery and catalysis. To fully realise these types of applications the ability to generate more functionalised metallosupramolecular architectures is required. In this perspective review we examine the exploitation of 1,2,3-triazole ligands, generated using the Cu(i)-catalysed 1,3-cycloaddition of organic azides with terminal alkynes (the CuAAC "click" reaction), for the assembly of discrete functional metallosupramolecular architectures. These "click" ligands have been used to generate metallomacrocycles, cages and helicates. Some of the architectures have shown promise as anti-cancer and anti-bacterial agents while others have been exploited for small molecule activation and catalysis.

Oxidatively Locked [Co2L3]6+ Cylinders Derived from Bis(bidentate) 2-Pyridyl-1,2,3-triazole "Click" Ligands: Synthesis, Stability, and Antimicrobial Studies.

A small family of [Co2(Lpytrz)3]6+ cylinders was synthesised from bis(bidentate) 2-pyridyl-1,2,3-triazole "click" ligands (Lpytrz) through an "assembly-followed-by-oxidation" method. The cylinders were characterised using ¹H, 13C, and DOSY NMR, IR, and UV-Vis spectroscopies, along with electrospray ionisation mass spectrometry (ESMS). Stability studies were conducted in dimethyl sulfoxide (DMSO) and D2O. In contrast to similar, previously studied, [Fe2(Lpytrz)3]4+ helicates the more kinetically inert [Co2(Lpytrz)3]6+ systems proved stable (over a period of days) when exposed to DMSO and were even more stable in D2O. The triply stranded [Co2(Lpytrz)3]6+ systems and the corresponding "free" ligands were tested for antimicrobial activity in vitro against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) microorganisms. Agar-based disk diffusion and Mueller-Hinton broth micro-dilution assays showed that the [Co2(Lpytrz)3]6+ cylinders were not active against either strain of bacteria. It is presumed that a high charge of the [Co2(Lpytrz)3]6+ cylinders is preventing them from crossing the bacterial cell membranes, rendering the compounds biologically inactive.