Bio-inspired oxidation catalysts : towards environmentally friendly chemistry – BIOXICAT

It is in this context that our project is aiming at developing artificial catalytic systems taking into consideration the two main characteristics of these enzymes: (i) activation of molecular oxygen, and (ii) specific input of electrons during catalysis. In order to reach our goal, we plan to take lessons from Mother Nature and design macromolecular catalytic systems composed of both, iron centers to activate O2, and redox cofactors to deliver electrons accurately to the metallic center. These two cofactors will be kept in close proximity via their incorporation into a water soluble polymeric matrix, also providing an “enzyme-like” locally hydrophobic microenvironment.The polymer of choice to design such system is the multi-branched polyethyleneimine (PEI); a water soluble polymer, which can easily be decorated with aliphatic and ionic chains. The incorporation of iron complexes in this polymer, via electrostatic interactions, will generate interesting new macromolecular catalysts, and their reactivity with hydrogen peroxide will first provide good insights about the effect of hydrophobic microenvironment during oxidation catalysis. Additional incorporation of redox cofactors, such as flavin compounds in the polymer, will then potentially enable a steady and accurate input of electrons toward the iron complexes and allow multi-turnover catalysis using molecular oxygen as oxidant.

The first strategy envisioned, in order to allow the reductive activation of dioxygen, was to associate a diiron(III) complex, capable of activating O2 at its diiron(II) state, with a photosensitive ruthenium complex. Using this system, we demonstrated that the irradiation of the ruthenium complex, in the presence of sacrificial electron donors, could reduce the diiron(III) complex into its diiron(II) counterpart, allowing therefore the reductive activation of dioxygen. Since ruthenium wasn’t the most cheap and environmentally friendly system, we replaced it by another redox cofactor such as the FMN, a flavin cofactor. In this case, the incorporation of the FMN into the structure of a PEI modified with alkyl and ganidinium groups, allowed to collect electrons from NADH in solution and transfer then towards metallic cofactors such as manganese porphyrins, just as natural reductase do in the case of cytochrome P450. Once reduced, the metallic cofactor can then activate dioxygen and catalyse the oxidation of small organic molecules.

Once the catalytic activity will have been evaluated in water in the presence and absence of the polymer, we will have to incorporate the redox cofactors, such as ruthenium complexes, and study the photo-assisted reduction of iron complexes coupled to the reduction activation of dioxygen. This concept was evaluated previously in organic solvent, and we have now to confirm its validity in water. Every iron complexes previously synthesized will have to be tested in order to find the best conditions and move to the final system including all the partners.

Since the project was built on successive tasks such as the synthesis of the polymers and of the metallic catalysts, the incorporation of the catalysts and the redox cofactors into the polymer, and then the functional studies of the system, we did publish regularly all along the project. A first proof of concept based on a diiron complex as oxidation catalyst and a ruthenium complex as a redox cofactor was first published. (Angew. Chem. Int. Ed. 2013, 52, 13, 3634–3637). The synthesis of other iron complexes also allowed the publication of connected projects connected to this ANR in more specialized journals (Dalton Trans. 2015, 44, 5966-5968 et J. Mol. Catal. A. Chem. 2015, 396, 40-46) and the main results with a much larger scientific impact have been published in journals with a broader readership and high impact factor. (Nature Communications 2015, 6, 5809). Finally, this project also led to intensive literature search which ended with the publication a review manuscript about O2 activating diiron enzymes. (Coord. Chem. Rev. 2016, 322, 142–158). Other results related to this project are still unpublished and three more papers are under preparation at the present time.

The main objective of this proposal is the development of catalytic systems able to perform selective oxidation directly using molecular oxygen in water under mild conditions. The current industrial processes for such reactions require harsh conditions, associated with strong oxidants and potentially harmful catalysts. In the present context of “sustainable growth”, the chemical industry is facing the daunting challenge to rethink most of its well-proven oxidation processes in order to develop environmentally friendly new ones. Yet, Nature has figured out an elegant manner to catalyze such reactions by reductive activation of molecular oxygen at the iron(II) centers present in multi-component enzymatic systems called monooxygenases. These enzymes are made of one catalytic sub-unit containing the catalytic iron(s), and one redox sub-unit providing a steady input of electrons during the catalytic cycle. The development of bio-inspired catalysts, mimicking these enzymes activity, is therefore a promising path for the development of environmentally friendly new oxidation processes.
Intensive research has been carried out regarding the creation of such enzyme mimics, and the reductive activation of molecular oxygen by low-molecular-weight models is now better understood. However, the creation of functional mimics with multi-turnover activity is still elusive due to the incapacity of small catalysts to provide a steady and accurate input of electrons toward the iron centre during catalysis. It is in this context that our project is aiming at developping artificial catalytic systems taking into consideration the two main characteristics of these enzymes: (i) activation of molecular oxygen, and (ii) specific input of electrons during catalysis. In order to reach our goal, we plan to take lessons from Mother Nature and design macromolecular catalytic systems composed of both, iron centers to activate O2, and redox cofactors to deliver electrons accurately to the metallic center. These two cofactors will be kept in close proximity via their incorporation into a water soluble polymeric matrix, also providing an “enzyme-like” locally hydrophobic microenvironment.
The polymer of choice to design such system is the multi-branched polyethyleneimine (PEI); a water soluble polymer, which can easily be decorated with aliphatic and ionic chains. The incorporation of iron complexes in this polymer, via electrostatic interactions, will generate interesting new macromolecular catalysts and their reactivity with hydrogen peroxide will provide good insights about the effect of hydrophobic microenvironment during oxidation catalysis. The grafting of chiral groups on the polymer would also generate a new family of enantioselective catalysts for oxidation reactions. Additional incorporation of redox cofactors, such as flavin compounds in the polymer, will then potentially enable a steady and accurate input of electrons toward the iron complexes and allow multi-turnover catalysis. The catalytic proficiency of these systems will be evaluated on various substrates and may, in a near future, constitute good candidate for the creation of environmentally friendly industrial process.