Macrocyclic fishing: Combinatorial approach to metal selectors

Dynamic metal

Chemists in Europe have used dynamic combinatorial libraries (DCLs) to fish out macrocycles that are selective for different heavy metal ions. This classic supramolecular work extends an approach used widely in pharmaceutical drug discovery to good effect in an unrelated field. The team used NMR spectroscopy, X-ray diffraction and other techniques to study the optimal four macrocycles.

Jörg Klein, Vittorio Saggiomo and Jeremy Sanders of the University of Cambridge, UK and colleagues Lisa Reck and Ulrich Lüning of the Otto-Diels-Institut für Organische Chemie, in Kiel, Germany, explain how heavy metal ions are part of everyday life. Some are involved in biological processes at trace levels, others are toxic and environmentally harmful. The extraction of such ions from organic or aqueous effluents has become important in terms of understanding their ecological impact. Moreover, given the recent elevated interest in radioactive heavy metal ions, such as strontium-90 and caesium-137 released by power station incidents in Japan, there is a need for highly selective agents to trap these ions from samples for analysis.

The use of organic macrocyclic species for the specific extraction of metal ions has been prominent in supramolecular chemistry for decades from crown ethers and cryptands onwards. Finding novel species that can isolate specific elemental heavy metal ions in a complex mixture that might contain other heavy metals remains a challenge. Now, Sanders' team has turned to dynamic combinatorial chemistry to assist. The researchers pioneered the use of DCC for generating new and useful compounds in the early 2000s.

Combined effort

The team describes the process as follows: "Dynamic combinatorial chemistry is concerned with mixtures of building blocks under thermodynamic control. The building blocks can assemble to give different combinations, but the assembly process is reversible thus making the mixture dynamic." They add that the resulting adaptable mixtures, dynamic combinatorial libraries, respond to external stimuli, such as temperature, pressure, or the presence of a template ion or molecule. The result is that the distribution of product molecules shifts so as to minimise the total energy of the system, as one might expect. "The increase in concentration of a particular species is referred to as amplification," the team adds. "Amplification reflects stabilisation of a particular species and has guided the discovery of new receptors."

The team has now exploited "hydrazone exchange" and metal-ligand interactions to create different macrocycles through the combination of a dialdehyde and a dihydrazide species in solution together with a specific metal ion acting as template. In preliminary work, the researchers developed a macrocyclic ligand containing a 2,6-bis-hydrazonopyridine core, which had a "striking" selectivity for barium ions over calcium ions or alkali metal ions and so demonstrated the potential of such macrocyclic ligands based on this type of core for selecting metal ions in mixtures.

The team has now built novel variations on this theme using DCC with an additional building block, a dihydrazide containing a diethyleneglycol linker. The macrocycles were templated with alkali and alkaline earth metal ions to create a library of potential candidates. The equilibrium was then shifted by the addition of strontium or barium ions to nudge the library towards species that were selective for these ions instead. " After the isolation (using a kinetic trap in the system) and characterisation of four different macrocycles, binding studies of the larger 2 + 2 macrocycles by high-resolution mass spectrometry, nuclear magnetic resonance and UV-Vis spectroscopy confirmed the selectivity of the macrocycles for [strontium and barium ions]," the team says.

"Hydrazone DCLs provide a useful platform for the discovery of metal ion receptors with unpredictable selectivities," the team concludes. "This opens a potential route to new receptors for the extraction of heavy metal ions."

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