Periodic Reporting for period 1 - NextBase (Base metal-catalytic cross-coupling methodologies towards sustainability)
Periodo di rendicontazione: 2023-10-01 al 2025-09-30
Catalysis is today exploited for preparing ca. 90% of chemical and pharmaceutical products. Use of catalysts allows for efficient chemical transformations, limiting the energy consumption and improving selectivity and atom economy. However, a large number of catalytic systems rely on noble metals (e.g. Pd, Pt, Rh, Ir, Au), with associated sustainability and toxicity issues. Indeed, all these metals are undergoing strong price fluctuations and will face supply limitations in the future. Moreover, given the toxicity of most precious metals, the tolerated thresholds in fine chemicals and active pharmaceutical ingredients are very low, which leads to high purification costs (solvents, energy, generation of waste). For these reasons, replacement of noble metals with the cheaper and generally less toxic 1st row transition metals – such as Mn, Fe, Co, Ni, Cu – is becoming a compelling goal for chemists, as well as a need for society. However, this goal also represents a tremendous challenge, as the typical reactivity of 2nd and 3rd row transition metals cannot be easily transferred to 1st row transition metals, due to their different electronic structure: the so-called "base metals" tend to form high-spin complexes and to engage in single electron transfer rather than in the multielectron redox steps typical of noble metals.
NextBase is an intersectoral consortium of research groups with a strong expertise in catalysis, who join forces to take the challenge of noble metal replacement in cross-coupling reactions – a class of transformations of high industrial importance to produce fine chemicals and active pharmaceutical ingredients. Synergies and complementary types of expertise within the Doctoral Network are exploited (i) to harness the reactivity of 1st row transition metals for several types of cross-coupling, which will be also applied to industrially relevant targets, and (ii) to train outstanding PhD students aware of the importance of sustainability issues and expert in the use and combination of different catalytic methodologies.
NextBase is an intersectoral consortium of research groups with a strong expertise in catalysis, who join forces to take the challenge of noble metal replacement in cross-coupling reactions – a class of transformations of high industrial importance to produce fine chemicals and active pharmaceutical ingredients. Synergies and complementary types of expertise within the Doctoral Network are exploited (i) to harness the reactivity of 1st row transition metals for several types of cross-coupling, which will be also applied to industrially relevant targets, and (ii) to train outstanding PhD students aware of the importance of sustainability issues and expert in the use and combination of different catalytic methodologies.
NextBase is committed to advance the field of base metal catalytic cross-couplings along the following general directions, which correspond to the research Work Packages of the Network:
C-C bond formation by redox-neutral cross-coupling (Work Package 1), involving both classical reagents (e.g. boronic acids/esters and organomagnesium compounds) and unfunctionalized C-H groups as nucleophiles.
C-C bond formation by deoxygenative cross-coupling (Work Package 2), allowing formation of single and multiple C-C bonds from oxygenated substrates (e.g. phenols, aryl ethers, carbonyl compounds) traditionally underexploited but very common, for example, in bio-derived building blocks.
C-heteroatom bond formation by cross-coupling (Work Package 3), providing access to very important classes of compounds such as phenols, ethers, amines, amides, esters, thiols.
Application of the new methodologies to the synthesis of industrial targets (Work Package 4), which will be selected based on the input received from the industrial beneficiaries (Fabbrica Italiana Sintetici and Johnson&Johnson Innovative Medicine), both active in the manufacture of active pharmaceutical ingredients.
Implementation of Work Package 1-3 is being performed by the six Doctoral Candidates of the Network, who were recruited in April-June 2024. The research activity is devoted to the following objectives:
1) Visible light-promoted C-heteroatom and C-C couplings in the presence of bifunctional Ni-, Co-, Cu- and Fe-catalysts (Università degli Studi di Milano – Doctoral Candidate 1).
2) C-C or C-N coupling of lignin-derived aromatics promoted by bimetallic base metal-nanoparticle catalysts in alternative reaction media (Universität Graz – Doctoral Candidate 2).
3) Cross-coupling by C(sp2) or C(sp3)-H activation promoted by heterosubstituted cyclopentadienyl Co- and Fe-complexes (Université de Caen Normandie – Doctoral Candidate 3).
4) Deoxygenative coupling of carbonyl compounds promoted by homogeneous and heterogeneous (Fe, Mn, Co, Ni, Cu) catalysts (Leibniz Institut für Katalyse – Doctoral Candidate 4).
5) Fe-catalytic Kumada-type cross-coupling to forge C(sp2)-C(sp2) bonds (Fabbrica Italiana Sintetici – Doctoral Candidate 5).
6) Mn-, Fe- and Cu-catalytic arylation by Suzuki-type coupling and C-H activation (Johnson&Johnson Innovative Medicine – Doctoral Candidate 6).
7) Synthesis of industrial targets – APIs and API intermediates (all beneficiaries – Doctoral Candidate 1-6).
C-C bond formation by redox-neutral cross-coupling (Work Package 1), involving both classical reagents (e.g. boronic acids/esters and organomagnesium compounds) and unfunctionalized C-H groups as nucleophiles.
C-C bond formation by deoxygenative cross-coupling (Work Package 2), allowing formation of single and multiple C-C bonds from oxygenated substrates (e.g. phenols, aryl ethers, carbonyl compounds) traditionally underexploited but very common, for example, in bio-derived building blocks.
C-heteroatom bond formation by cross-coupling (Work Package 3), providing access to very important classes of compounds such as phenols, ethers, amines, amides, esters, thiols.
Application of the new methodologies to the synthesis of industrial targets (Work Package 4), which will be selected based on the input received from the industrial beneficiaries (Fabbrica Italiana Sintetici and Johnson&Johnson Innovative Medicine), both active in the manufacture of active pharmaceutical ingredients.
Implementation of Work Package 1-3 is being performed by the six Doctoral Candidates of the Network, who were recruited in April-June 2024. The research activity is devoted to the following objectives:
1) Visible light-promoted C-heteroatom and C-C couplings in the presence of bifunctional Ni-, Co-, Cu- and Fe-catalysts (Università degli Studi di Milano – Doctoral Candidate 1).
2) C-C or C-N coupling of lignin-derived aromatics promoted by bimetallic base metal-nanoparticle catalysts in alternative reaction media (Universität Graz – Doctoral Candidate 2).
3) Cross-coupling by C(sp2) or C(sp3)-H activation promoted by heterosubstituted cyclopentadienyl Co- and Fe-complexes (Université de Caen Normandie – Doctoral Candidate 3).
4) Deoxygenative coupling of carbonyl compounds promoted by homogeneous and heterogeneous (Fe, Mn, Co, Ni, Cu) catalysts (Leibniz Institut für Katalyse – Doctoral Candidate 4).
5) Fe-catalytic Kumada-type cross-coupling to forge C(sp2)-C(sp2) bonds (Fabbrica Italiana Sintetici – Doctoral Candidate 5).
6) Mn-, Fe- and Cu-catalytic arylation by Suzuki-type coupling and C-H activation (Johnson&Johnson Innovative Medicine – Doctoral Candidate 6).
7) Synthesis of industrial targets – APIs and API intermediates (all beneficiaries – Doctoral Candidate 1-6).
Cross-coupling reactions are a vast research area which is still quite far from being ‘conquered’ by base metals. The scientific impact of the project consists in taking the challenge of noble metal replacement in cross-coupling chemistry with some highly innovative approaches that have not been yet fully exploited for this reactivity, such as i) use of ‘non-innocent’ ligands to modulate the metal reactivity; ii) use of photoredox catalysis to trigger and control the SET pathways typical of these metals; iii) heterogeneous catalytic approaches involving bimetallic base metal-nanoparticle catalysts in alternative reaction media.
The project has already delivered significant scientific advances towards its goals:
1) Development of highly innovative bifunctional photocatalysts enabling efficient Ni-photoredox C–O cross-coupling.
2) Synthesis and evaluation of novel Fe and Co heterosubstituted Cp complexes, and first catalytic hit for isoquinoline formation using an Fe(II) complex.
3) Identification of active homogeneous and heterogeneous base metal-catalysts for deoxygenative C–C coupling of carbonyl compounds.
4) Discovery of a robust Fe-based Kumada coupling suitable for industrially relevant intermediates.
5) Development of a Ni-catalyzed addition of boronic acids to nitriles for the synthesis of ketones and tertiary amines.
6) Discovery of a metal-free C–N coupling methodology promoted by trioctylphosphine oxide.
The project has already delivered significant scientific advances towards its goals:
1) Development of highly innovative bifunctional photocatalysts enabling efficient Ni-photoredox C–O cross-coupling.
2) Synthesis and evaluation of novel Fe and Co heterosubstituted Cp complexes, and first catalytic hit for isoquinoline formation using an Fe(II) complex.
3) Identification of active homogeneous and heterogeneous base metal-catalysts for deoxygenative C–C coupling of carbonyl compounds.
4) Discovery of a robust Fe-based Kumada coupling suitable for industrially relevant intermediates.
5) Development of a Ni-catalyzed addition of boronic acids to nitriles for the synthesis of ketones and tertiary amines.
6) Discovery of a metal-free C–N coupling methodology promoted by trioctylphosphine oxide.