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Catalytic Foldamers: Engineering a Second Coordination
Sphere Around a Hydrogenase Mimic

Final Report Summary - CATAMERS (Catalytic Foldamers: Engineering a Second Coordination Sphere Around a Hydrogenase Mimic)

Nature relies on networks of non-covalent interactions to promote chemical transformations with both high selectivities and turnover frequencies. The amino acids in the protein matrix of enzymes work to fine tune the reactivity of groups in the active site. In metalloenzymes, the protein surrounding the metal site can provide direct effects by binding the metal in a first coordination sphere fashion or indirect effects through non-covalent interactions to the ligands or metal site. This latter method, second coordination sphere interactions, has been the main interest of the work under FP7-MC-IIF project No. 275209. Our work on the development of CATAMERS, helical foldamer capsules that contain a catalytically active moiety, serves as a method to design and study similar interactions between a supramolecular host and a small molecule catalyst. The ultimate goal in doing so is to enhance or alter the catalytic activity of the guest.

We have proposed using aromatic amide foldamers (oligomeric molecules capable of forming an ordered structure in solution through non-covalent interactions) to assemble an artificial second coordination sphere around a small molecule biomimetic of the [FeFe]-hydrogenase enzyme active site. Under the grant proposal, the project has been broken down into the following tasks:

1) design and synthesise foldamer bound hydrogenase models / monomer synthesis;
2) analyse structural and spectroscopic properties;
3) analyse electrochemical / electrocatalytic properties; and
4) dissemination.

Over the last two years, the synthetic component of the project has constituted the majority of the work effort. In order to develop the foldamers, two new monomer units needed to be synthesised: one for attaching the diiron complex (AFe) and another that would provide a large enough area to house the catalyst, AH. As a result of the work done on this project, the synthesis of both of these monomers has been accomplished on the multigram scale and in reasonable yield. Additionally, as a result of the methods used to synthesise these monomers, a wide array of functional groups have been introduced into the nine position of the anthracene allowing greater diversification of the foldamer scaffolds in the future.

With the optimisation of these monomes, the synthesis of oligomers containing the diiron complex could proceed. The AH monomer was coupled to form a dimer of anthracenes. By combining this with a sequence established in the Huc group for work on helical capsules, Q3PN2 and the diiron monomer, AFe, a variety of sequences could be obtained. Owing to their high crystallinity, these compounds were all able to be characterized by X-ray diffraction studies. In the solid state, the oligomers all adopt a helical structure which partially surrounds the diiron complex to different degrees. However, only minimal distortions in the structural parameters of the diiron complex are observed. Additionally, there is no indication of any hydrogen bonding or close steric interactions between the complex and the foldamer scaffolds. Rather the complex seems free to turn from an orientation where the diiron bond vector is oriented along the helical axis to one where it is perpendicular.

The fluxionality of these compounds is supported by 13C NMR studies which show only a single CO resonance for all six carbonyls, indicating not only the rapid exchange between apical and basal units but also that the complex rotates at a rate fast enough to equilibrate each iron site on the NMR timescale. Additionally, no significant distortions in the symmetry of the complex are observed by IR studies focused on the v(CO) stretches.

Despite what appears to be minimal control of the complex by the initial foldamer scaffold designs, there does appear to be an effect on the electrochemical properties of the diiron complex as a model second coordination sphere is built around it. The monomer containing the iron complex shows a similar first reduction potential (-1.81 V) when compared to a standard small molecule diiron complex, (µ-SCH2NBnCH2S-)[Fe(CO)3]2, ((µ-pmbadt)[Fe(CO)3]2), (-1.82 V). However, when the sequence of the foldamer is eleongated a significant positive shift in the first reduction is observed ranging from 120 - 200 mV. Because of the limited interactions observed in the solid state and solution studies, the cause of this shift is tentatively attributed to a change in the local electrostatic environment relative to the bulk solution; however more studies will need to be done to definitively assign the cause.

The fact that the foldamer is capable of causing such changes despite minimal interactions boast well of the ability of foldamers to fine tune the reactivity of metal complexes and future work in this area by the host group and researcher should lead to novel transition metal based catalytic foldamers. The applicability of this research, beyond the expanding the fundamental knowledge in this area, extends into both academic and industrial sectors. It would be ideal to have base metal catalysts capable of activating / producing small molecules at levels of efficiency nearing that of enzymes for replacing current high cost or low efficiency processes of high economic value such as hydrogen production / oxidation, nitrogen reduction, or methane oxidation. It is expected that the application of well ordered and tunable solid supports such as the aromatic oligoamides used in this project could one day play an important role in development of such systems.