Final Report Summary - FESUSTCAT (Redox Ligands and Iron Complexes for Sustainable Catalysis)
Summary
The goal of the project, entitled “Redox ligands and iron complexes for sustainable catalysis”, was to develop novel, cost effective, efficient and sustainable catalysts for use in the synthesis of bioactive molecules. The synthetic scope of these catalysts was first to be assessed in cycloisomerisation reactions followed by radical reactions. The project aimed to take an interdisciplinary approach, exploiting both experimental and computational chemistry.
Research
Since the beginning of the project two major research themes have been pursued.
1. The first research theme aimed to develop redox active iron-based catalysts and apply these novel catalysts to a range of cycloisomerisation reactions.
The investigation commenced with the synthesis of a known redox-active iron catalyst (bis(iminopyridine) iron bis(dinitrogen complex). This was employed as part of the investigation to provide proof-of-concept that redox-active iron complexes may be suitable for cycloisomerisation reactions, as only a limited number of examples can be found in the literature. In conjunction with this complex, a broader range of structurally related imine-type ligands were synthesised, and strategies devised and tested to assess the catalytic activity of the iron complexes. These included: in situ generation of the iron complex (from the iron salt and ligand), synthesis of defined iron complexes (to ensure precatalyst was formed) and synthesis of cationic iron complexes (to explore differences in reactivity compared with the neutral precatalysts). A variety of reaction conditions were investigated including: iron salt, reducing agent, additive, solvent and temperature. For these investigations we looked at two different types of reactions (a [2+2+2] cycloaddition and a dimethylmalonate cycloisomerisation reaction) which had both been reliably used in the literature to establish catalytic conditions with other transition metals.
The catalytic conditions screened showed only limited reactivity. Optimisation of the most promising systems was attempted but did not yield vast improvements. It became apparent to us that the limited mechanistic understanding of this reaction in the presence of an iron complex was restricting the progress of this project. Following the end of our focussed investigation, a report appeared in the literature for an iron catalysed reductive cycloisomerisation reaction.[1] In this case, activation of the iron precatalyst was achieved through a specific combination of strong metal reducing agents. Even under these conditions the dimalonate substrate (identical to the substrate we had employed in our own screening reactions) was completely unreactive. This supports our conclusion that reactivity is extremely sensitive and dependent on both the substrate and exact reaction conditions, requiring much more mechanistic insight in order to develop more general and widely applicable catalytic conditions with iron complexes.
Interestingly, in concurrent investigations within the group, it was found redox active iron catalysts were able to mediate some C-H activation reactions.
2. The second research theme aimed to develop iron-based catalysts and explore their reactivity in radical chemistry.
The Fensterbank group recently discovered a novel iron mediated reductive radical cyclisation reaction[2] and it was proposed that this methodology could be significantly improved and elaborated. The scope of the reaction was investigated and a variety of substrates synthesised and screened for reactivity.[3] A less reactive halide (bromide) showed similar reactivity to the original iodide employed in this reaction. This substrate was subsequently used for optimisation of reaction conditions, as it is a more generally useful substrate. To thoroughly optimise the reaction conditions, the following were screened: iron salts, iron purity, catalyst loading, reducing agent and reducing agent loading.
An hydridoiron species has been synthesized, fully characterised and employed as a precatalyst for the reaction of interest. CV studies have shown that iron(III) can undergo a two step reduction process, therefore acting with the same mechanism as iron(II). Reactivity of the bromide substrate is shown to be significantly less reactive than the equivalent iodide. NMR studies have been successfully employed to study the reaction in situ. These mechanistic experiments have confirmed the nature of the iron precatalyst formed, thereby providing strong support for the proposed mechanism of reaction. Differences in the reactivity of iron catalysts have been observed in the presence of different ligands. Computational investigations reveal that the most energetically favourable mechanistic pathway is via reduction followed by hydride transfer. Calculated redox potentials predicted the reduction strength of different ligands.
Concurrent studies developed novel methodology to mediate atom transfer radical addition reactions with iron(0) nanoparticles. A thorough and extensive scope and optimisation study has been completed. The active species for this reaction has been characterised by a variety of techniques including Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM).
Conclusions
The main research aims set out for this project have been achieved as discussed above. Novel iron catalysts were developed for use in the synthesis of heterocycles. The synthetic scope of these catalysts was assessed in cycloisomerisation reactions. Methodology was developed employing novel iron-based catalysts for reductive radical cyclisation reactions and atom transfer radical addition reactions. The project was interdisciplinary and exploited experimental (synthetic organic, organometallic, physical-organic, physical, inorganic) and computational chemistry.
One peer-reviewed journal publication is the major quantifiable result achieved thus far.[3]
Expected final results
Three peer-reviewed manuscripts relating to the results of this project are in preparation. Each will be submitted to high quality chemistry journals to ensure the broadest readership may view this research. It is anticipated that this chemistry will be employed widely in synthetic organic chemistry. The research provides knowledge to organometallic chemistry.
Potential impact and use
The project was innovative in its development of novel iron-based catalysts for synthetic reactions. In particular the use of iron as viable and environmentally benign replacement for toxic tin residues was achieved for radical reactions. Future use of iron catalysts has the potential of improving the safety and cost effectiveness of important synthetic processes. This in turn will impact positively on industries that rely on heterocyclic molecules (e.g. pharmaceuticals and materials science) and therefore have a positive socio-economic impact worldwide.
References
[1] A. Lin, Z.-W. Zhang, J. Yang, Org. Lett. 2014, 16, 386–389
[2] A. Ekomié, G. Lefèvre, L. Fensterbank, E. Lacôte, M. Malacria, C. Ollivier, A. Jutand, Angew. Chem., Int. Ed. 2012, 51, 6942–6946
[3] C. Aubert, M. Barbazanges, A. Jutand, S. H. Kyne, C. Ollivier, and L. Fensterbank, Pure Appl. Chem. 2014, 86, 273–281
The goal of the project, entitled “Redox ligands and iron complexes for sustainable catalysis”, was to develop novel, cost effective, efficient and sustainable catalysts for use in the synthesis of bioactive molecules. The synthetic scope of these catalysts was first to be assessed in cycloisomerisation reactions followed by radical reactions. The project aimed to take an interdisciplinary approach, exploiting both experimental and computational chemistry.
Research
Since the beginning of the project two major research themes have been pursued.
1. The first research theme aimed to develop redox active iron-based catalysts and apply these novel catalysts to a range of cycloisomerisation reactions.
The investigation commenced with the synthesis of a known redox-active iron catalyst (bis(iminopyridine) iron bis(dinitrogen complex). This was employed as part of the investigation to provide proof-of-concept that redox-active iron complexes may be suitable for cycloisomerisation reactions, as only a limited number of examples can be found in the literature. In conjunction with this complex, a broader range of structurally related imine-type ligands were synthesised, and strategies devised and tested to assess the catalytic activity of the iron complexes. These included: in situ generation of the iron complex (from the iron salt and ligand), synthesis of defined iron complexes (to ensure precatalyst was formed) and synthesis of cationic iron complexes (to explore differences in reactivity compared with the neutral precatalysts). A variety of reaction conditions were investigated including: iron salt, reducing agent, additive, solvent and temperature. For these investigations we looked at two different types of reactions (a [2+2+2] cycloaddition and a dimethylmalonate cycloisomerisation reaction) which had both been reliably used in the literature to establish catalytic conditions with other transition metals.
The catalytic conditions screened showed only limited reactivity. Optimisation of the most promising systems was attempted but did not yield vast improvements. It became apparent to us that the limited mechanistic understanding of this reaction in the presence of an iron complex was restricting the progress of this project. Following the end of our focussed investigation, a report appeared in the literature for an iron catalysed reductive cycloisomerisation reaction.[1] In this case, activation of the iron precatalyst was achieved through a specific combination of strong metal reducing agents. Even under these conditions the dimalonate substrate (identical to the substrate we had employed in our own screening reactions) was completely unreactive. This supports our conclusion that reactivity is extremely sensitive and dependent on both the substrate and exact reaction conditions, requiring much more mechanistic insight in order to develop more general and widely applicable catalytic conditions with iron complexes.
Interestingly, in concurrent investigations within the group, it was found redox active iron catalysts were able to mediate some C-H activation reactions.
2. The second research theme aimed to develop iron-based catalysts and explore their reactivity in radical chemistry.
The Fensterbank group recently discovered a novel iron mediated reductive radical cyclisation reaction[2] and it was proposed that this methodology could be significantly improved and elaborated. The scope of the reaction was investigated and a variety of substrates synthesised and screened for reactivity.[3] A less reactive halide (bromide) showed similar reactivity to the original iodide employed in this reaction. This substrate was subsequently used for optimisation of reaction conditions, as it is a more generally useful substrate. To thoroughly optimise the reaction conditions, the following were screened: iron salts, iron purity, catalyst loading, reducing agent and reducing agent loading.
An hydridoiron species has been synthesized, fully characterised and employed as a precatalyst for the reaction of interest. CV studies have shown that iron(III) can undergo a two step reduction process, therefore acting with the same mechanism as iron(II). Reactivity of the bromide substrate is shown to be significantly less reactive than the equivalent iodide. NMR studies have been successfully employed to study the reaction in situ. These mechanistic experiments have confirmed the nature of the iron precatalyst formed, thereby providing strong support for the proposed mechanism of reaction. Differences in the reactivity of iron catalysts have been observed in the presence of different ligands. Computational investigations reveal that the most energetically favourable mechanistic pathway is via reduction followed by hydride transfer. Calculated redox potentials predicted the reduction strength of different ligands.
Concurrent studies developed novel methodology to mediate atom transfer radical addition reactions with iron(0) nanoparticles. A thorough and extensive scope and optimisation study has been completed. The active species for this reaction has been characterised by a variety of techniques including Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM).
Conclusions
The main research aims set out for this project have been achieved as discussed above. Novel iron catalysts were developed for use in the synthesis of heterocycles. The synthetic scope of these catalysts was assessed in cycloisomerisation reactions. Methodology was developed employing novel iron-based catalysts for reductive radical cyclisation reactions and atom transfer radical addition reactions. The project was interdisciplinary and exploited experimental (synthetic organic, organometallic, physical-organic, physical, inorganic) and computational chemistry.
One peer-reviewed journal publication is the major quantifiable result achieved thus far.[3]
Expected final results
Three peer-reviewed manuscripts relating to the results of this project are in preparation. Each will be submitted to high quality chemistry journals to ensure the broadest readership may view this research. It is anticipated that this chemistry will be employed widely in synthetic organic chemistry. The research provides knowledge to organometallic chemistry.
Potential impact and use
The project was innovative in its development of novel iron-based catalysts for synthetic reactions. In particular the use of iron as viable and environmentally benign replacement for toxic tin residues was achieved for radical reactions. Future use of iron catalysts has the potential of improving the safety and cost effectiveness of important synthetic processes. This in turn will impact positively on industries that rely on heterocyclic molecules (e.g. pharmaceuticals and materials science) and therefore have a positive socio-economic impact worldwide.
References
[1] A. Lin, Z.-W. Zhang, J. Yang, Org. Lett. 2014, 16, 386–389
[2] A. Ekomié, G. Lefèvre, L. Fensterbank, E. Lacôte, M. Malacria, C. Ollivier, A. Jutand, Angew. Chem., Int. Ed. 2012, 51, 6942–6946
[3] C. Aubert, M. Barbazanges, A. Jutand, S. H. Kyne, C. Ollivier, and L. Fensterbank, Pure Appl. Chem. 2014, 86, 273–281