Periodic Reporting for period 1 - Au-MLC (Cooperative Au catalysis with chemically non-innocent ligands.)
Reporting period: 2019-08-01 to 2021-07-31
Homogeneous catalysis represents one of the most powerful set of tools for organic synthesis, on the industrial scale as well as on the laboratory one; in this field, homogeneous gold catalysis has seen an exponential growth of interest in the last quarter century, and is nowadays one of the most lively field of research, given its relative novelty, its positioning in the intersection between synthetic chemistry and organometallic chemistry, and its unique properties; in particular, the investigation of Au(III) species has been widely overlooked by the community, and represents today a source of ground-breaking development.
Much in the same way, Metal-Ligand-Cooperation (MLC) is a relatively young field of research, yet has provided tremendous improvement in the efficiency of known catalytic methods, as well as disclosing new, unexpected reaction patterns. MLC strategies have been applied only scarcely to gold chemistry, and exclusively to Au(I) catalysts; the discovery of MLC-competent Au(III) species would represent a paramount breakthrough, granting advancement in many of the fields of research on gold chemistry.
The Au-MLC project aimed at elaborating a library of well-defined Au(III) complexes with MLC characteristics, taking advantage of their rich behaviour to gain insight on their fundamental properties, as well as on their catalytic aptness.
The action succeeded in the development of Au(III) complexes with MLC properties, although their catalytic applications were not achieved. During the development of the project, we also found that their synthesis involve a novel, base-triggered oxidative addition to Au(I), which represents a fascinating discovery on its own, given the interest that the oxidative addition to gold has attracted in recent times. We therefore devoted much effort to the comprehension of the process, providing new insights that will be valuable for both fundamental applied (catalytic) developments of gold chemistry.
Much in the same way, Metal-Ligand-Cooperation (MLC) is a relatively young field of research, yet has provided tremendous improvement in the efficiency of known catalytic methods, as well as disclosing new, unexpected reaction patterns. MLC strategies have been applied only scarcely to gold chemistry, and exclusively to Au(I) catalysts; the discovery of MLC-competent Au(III) species would represent a paramount breakthrough, granting advancement in many of the fields of research on gold chemistry.
The Au-MLC project aimed at elaborating a library of well-defined Au(III) complexes with MLC characteristics, taking advantage of their rich behaviour to gain insight on their fundamental properties, as well as on their catalytic aptness.
The action succeeded in the development of Au(III) complexes with MLC properties, although their catalytic applications were not achieved. During the development of the project, we also found that their synthesis involve a novel, base-triggered oxidative addition to Au(I), which represents a fascinating discovery on its own, given the interest that the oxidative addition to gold has attracted in recent times. We therefore devoted much effort to the comprehension of the process, providing new insights that will be valuable for both fundamental applied (catalytic) developments of gold chemistry.
Access to Au(III) species is not generally a straightforward task. Two strategies have been designed to achieve this objective: a) oxidation of a Au(I) complex of a tridentate ligand, with subsequent formation of the bifunctional site necessary for MLC, namely a (quinolino)methylphosphine, and b) intramolecular oxidative addition of Au(I) onto a carbon-halogen bond, on a ligand scaffold bearing a Secondary Phosphine Oxide (SPO), a functional group with known MLC properties. The first strategy did not afford the desired results, while the second did, and the resulting (C,P)-cyclometalated complexes showed promising properties.
a) Base triggered oxidative addition on C–Halogen bonds
The ligands discovered by this action were based on the properties of the peri-substituent of a naphthalene scaffold: in these compounds, the iodide moiety is geometrically pre-arranged, favouring the proximity of the Au(I) atom coordinated by the SPO P-atom. However, such proximity is not sufficient to promote the oxidative addition step: the Au(I) precursors were found to be stable for days in solution, and would react sluggishly and non-univocally upon heating.
The desired Au(III) complex was obtained upon treating the Au(I) precursor with bases: in these conditions, we could observe via NMR the activation of the complex, and then we could follow its conversion into the desired product at room temperature. It is noteworthy that oxidative addition to Au(I), considered a challenging fundamental organometallic reaction, has never been achieved in such mild conditions, and this base-triggered mechanism, to the best of our knowledge unique to SPO ligands, is unknown to date in the literature.
b) Study of the MLC properties of the complexes
The study of the properties of the new complexes, in particular their basicity and nucleophilicity, was performed. Their reactivity towards electrophilic chlorosilane species was tested with excellent results: the experiments performed confirmed the ability of the complexes to act as strong nucleophiles. Moreover, the products obtained in this way could not be obtained reversing the order of the reactions, namely by performing the oxidative addition on the previously silylated ligand. Their basicity towards Brønsted acids was also successfully tested: the protonation of the anionic complexes was smoothly performed. The reactivity of the SPO moiety is a key feature of these species, proving that they are good candidates for MLC activity
c) Dissemination of the results.
The first paper resulting from this project is currently in preparation and will be submitted in due course; a review on naphthalene-based cyclometalated complexes is also in the work. Two additional high-impact papers are expected to be published in the near future.
a) Base triggered oxidative addition on C–Halogen bonds
The ligands discovered by this action were based on the properties of the peri-substituent of a naphthalene scaffold: in these compounds, the iodide moiety is geometrically pre-arranged, favouring the proximity of the Au(I) atom coordinated by the SPO P-atom. However, such proximity is not sufficient to promote the oxidative addition step: the Au(I) precursors were found to be stable for days in solution, and would react sluggishly and non-univocally upon heating.
The desired Au(III) complex was obtained upon treating the Au(I) precursor with bases: in these conditions, we could observe via NMR the activation of the complex, and then we could follow its conversion into the desired product at room temperature. It is noteworthy that oxidative addition to Au(I), considered a challenging fundamental organometallic reaction, has never been achieved in such mild conditions, and this base-triggered mechanism, to the best of our knowledge unique to SPO ligands, is unknown to date in the literature.
b) Study of the MLC properties of the complexes
The study of the properties of the new complexes, in particular their basicity and nucleophilicity, was performed. Their reactivity towards electrophilic chlorosilane species was tested with excellent results: the experiments performed confirmed the ability of the complexes to act as strong nucleophiles. Moreover, the products obtained in this way could not be obtained reversing the order of the reactions, namely by performing the oxidative addition on the previously silylated ligand. Their basicity towards Brønsted acids was also successfully tested: the protonation of the anionic complexes was smoothly performed. The reactivity of the SPO moiety is a key feature of these species, proving that they are good candidates for MLC activity
c) Dissemination of the results.
The first paper resulting from this project is currently in preparation and will be submitted in due course; a review on naphthalene-based cyclometalated complexes is also in the work. Two additional high-impact papers are expected to be published in the near future.
The action Au-MLC has resulted in the discovery of an hitherto-unknown mechanism for the oxidative addition of Au(I) to carbon-halogen bonds. Our study on the reaction conditions, including the ligand design, has provided valuable new information on this elementary step, which is nowadays being exploited in increasingly sophisticated synthetic methodologies. We expect that the impact of our finding will reach many fields of catalysis, with applications ranging from protein derivatization in biochemistry, to an increase of efficiency in the already-known methods, to the development of entirely new reactions and synthetic strategies.
Moreover, the project resulted in the isolation and characterisation of the first Au(III) complexes bearing an SPO as ancillary ligand. Given the unique properties of SPOs as ligands (H-bonding ability, nucleophilicity, basicity), and the ever-expanding role of Au(III) in material and medicinal chemistry, our findings can realistically be expected to be exploited by research groups working in these fields, both in academia and in industry.
Impact for the fellow
The training received by the fellow on the design, synthesis and characterization, combining experimental and theoretical studies, of novel and original organometallic species, and the study of their fundamental properties has widened his knowledge and skillset in transition metal chemistry and organic synthesis. Combined with his previous high-level expertise in catalytic methodology, the fellow has gained an excellent background in diverse areas of chemistry (inorganic, organic, organometallic and catalysis), expanding his possibilities for his independent career.
Additionally, the researcher has provided tutoring to junior students, and has been spearheading the preparation of all manuscripts that arised from the project (and is still involve din first person for all those that will follow); he was also involved in first person in the financial management was also of the fellowship, paving the way for his future career as independent researcher.
Impact in the scientific community and society
Direct beneficiaries of the results arised from this project are researchers in the fields of organometallic chemistry (Nevado, Tilset), catalysis (Hashmi, Toste, Patil), and biological and medicinal chemistry (Spokoyny, Casini) across the globe. Besides, the fundamental knowledge deriving from a novel switchable oxidative addition step, and the well-defined, stable complexes it produces, will disclose new patterns of reactivity in the fields of fundamental organometallic chemistry, in cross coupling catalysis, advanced materials, and in biological applications.
Moreover, the project resulted in the isolation and characterisation of the first Au(III) complexes bearing an SPO as ancillary ligand. Given the unique properties of SPOs as ligands (H-bonding ability, nucleophilicity, basicity), and the ever-expanding role of Au(III) in material and medicinal chemistry, our findings can realistically be expected to be exploited by research groups working in these fields, both in academia and in industry.
Impact for the fellow
The training received by the fellow on the design, synthesis and characterization, combining experimental and theoretical studies, of novel and original organometallic species, and the study of their fundamental properties has widened his knowledge and skillset in transition metal chemistry and organic synthesis. Combined with his previous high-level expertise in catalytic methodology, the fellow has gained an excellent background in diverse areas of chemistry (inorganic, organic, organometallic and catalysis), expanding his possibilities for his independent career.
Additionally, the researcher has provided tutoring to junior students, and has been spearheading the preparation of all manuscripts that arised from the project (and is still involve din first person for all those that will follow); he was also involved in first person in the financial management was also of the fellowship, paving the way for his future career as independent researcher.
Impact in the scientific community and society
Direct beneficiaries of the results arised from this project are researchers in the fields of organometallic chemistry (Nevado, Tilset), catalysis (Hashmi, Toste, Patil), and biological and medicinal chemistry (Spokoyny, Casini) across the globe. Besides, the fundamental knowledge deriving from a novel switchable oxidative addition step, and the well-defined, stable complexes it produces, will disclose new patterns of reactivity in the fields of fundamental organometallic chemistry, in cross coupling catalysis, advanced materials, and in biological applications.