Catalytic Csp3-H functionalization via carbene insertion meets sustainability: Developing an unprecedented Iron methodology

Project Information

FeCHACT

Grant agreement ID: 794160

DOI

10.3030/794160

Project terminated on 31 May 2019

EC signature date 2 March 2018

Start date 1 January 2019

End date 31 December 2020

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 170 121,60

EU contribution

€ 170 121,60

Coordinated by

UNIVERSITAT DE GIRONA
Spain

Periodic Reporting for period 1 - FeCHACT (Catalytic Csp3-H functionalization via carbene insertion meets sustainability: Developing an unprecedented Iron methodology)

Reporting period: 2019-01-01 to 2020-12-31

Summary of the context and overall objectives of the project

The project entitled “Catalytic Csp3-H functionalization via carbene insertion meets sustainability: Developing an unprecedented Iron methodology” will break new ground in Csp3-H functionalization chemistry, developing an unprecedented iron mediated methodology through carbene transference processes. Progress in these areas will generate valuable outputs which will impact not only in academia but also industry and society, in generating new environmental benign and more sustainable catalytic synthetic strategies using a new generation of iron complexes supported by facile tuneable ancillary ligands, and natural abundant alkanes as feedstock. Activation of Csp3-H bonds via carbene transfer have shown excellent promise in chemical synthesis under catalytic regimes using precious metals. However, a key aspect in developing sustainable processes is the nature of the catalytic species employed, including prize, availability and toxicity. Thus, using iron complexes which are low cost, high natural abundance, and low toxicity will open new frontiers in developing more sustainable chemistry. Although selective activation of Csp3-H bonds can be extremely difficult, recent studies on high valent oxo- and nitrene-iron complexes have shown that this may not be an insurmountable challenge, which can be controlled by the nature of the ligands. The design of the catalysts will be delivered rationally, using an iterative approach combining reactivity and kinetic studies. In addition, isolation and characterization of the first non-heme high valent iron-carbene complex will be pursued. This achievement constitutes a milestone in iron chemistry, because it will provide insightful data to control reactivity aspects in carbene transfer processes, and because this information can be used in the design of carbene transfer methodologies employing non-heme oxygenases biocatalysts, similarly to what has been done with the heme counterpart enzymes. From an interdisciplinary point of view this will suppose the establishment of a solid bridgebetween organometallic chemistry and biochemistry, and the ultimate step in the expansion of the toolbox ofenvironmentally friendly and sustainable iron-carbene insertion processes for the synthesis of organic molecules.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During the five months life of the project two work packages have been completely developed and a third one has been set to be readily expanded in the group of Prof. Costas in collaboration with AHG (Dr. Hernán-Gómez). Thus, within the first three months (January-March) WP 1 and 2 have been thoroughly investigated, as detailed in the attached report, leading to a sustainable (low cost, abundant elements and low toxicity) and synergetic Fe/Li catalytic system capable, for the first time, of intramolecular C(sp3)-H alkylation via metallocarbene species.

More specifically, a variety of low coordinate iron compounds supported by “non-inocent” ortho-phenylenediamine ligands were synthesized. Fully study of the electronic configuration of the generated iron compounds by different characterization techniques (X-ray, NMR spectroscopy, Infrared spectroscopy) allowed to identify the most adequate ligand-iron pair for the targeted C-H functionalization reactions. Likewise, studying the interaction between the previous iron compounds and the carbene precursors (diazoester reagents) unravelled the factors behind the long-standing problem of using iron in these processes. Using this information, a new partnership between iron and lithium was born, which enables C(sp3)-H alkylation processes at room temperature. Application of this methodology has led to one-step synthesis of a wide variety of complex carbocyclic (mono and bis) compounds, otherwise requiring tedious and long synthetic protocols. Mechanistic studies were also performed suggesting a concerted process, in which the carbene fragment undergoes insertion into the targeted C-H bond forming two new C-C and C-C bonds, and generating the desired carbocyclic compound. The generated information has set the starting point for the most ambitious part of the proposed project as it is extension of this methodology to the intramolecular version, and isolation of iron-carbene species. Indeed applying the system derived from the previous study functionalization of plain hydrocarbons as pentane, hexane and cyclohexane has been achieved. Initial attempts to isolate iron-carbene intermediate species have proved to be feasible, evidenced by UV-Vis spectrophotometry. Encouraged by this observation we are trying to isolate these species and characterize them by single crystal X-ray crystallography.

Overall the worked performed in these five months fulfils the core of the project, aiming to develop a methodology capable to functionalize inert C(sp3)-H bonds present in nature as saturated alkanes (vast and low cost feedstock for organic synthesis). The generated data about intramolecular C-H functionalization iron mediated is under review for publication in a high impact factor journal.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Up to know, the developed iron methodologies (inter- and intra-molecular) for carbene insertion into C(sp3)-H bonds were limited to weak allylic, benzylic and adjacent to heteroatom C(sp3)-H bonds (BDE < 90 Kcal/mol), using a heme like iron (III) phtalocyanine catalysts, and laboratory evolved P-450 enzymes. Going beyond these rigid systems, we have developed an ortho-phenylenediamide iron compound of electrophilic nature, which in combination with a lithium salt, as Lewis acid, enables unprecedented iron catalyzed intra- and inter-molecular carbene insertion into a variety of non-activated aliphatic C-H bonds, via iron-carbene intermediates under mild conditions (25ºC). Remarkably this Fe/Li system exhibits activity and selectivity levels comparable to rhodium carboxylate catalysts.

The generated advances in the field are expected to have a major impact, appealing to the broad spectrum of synthetic chemists (organic, inorganic, organometallic, green) spanning both academia and industry, since a new atom-economical, sustainable, mild temperature and selective methodology for functionalising Csp3-H bonds has been achieved. Furthermore, considering that iron-mediated organic synthesis constitutes a hot topic, due to sustainability reasons, it is envisaged that these results will lead to high impact scientific results, with publication in high-ranking academic journals.