CE07 - Chimie moléculaire

Synthesis of Fluorinated Ni(IV) Organometallics. – Ni4Rf

SYNTHESIS OF FLUORINATED Ni(IV) ORGANOMETALLICS

Organofluorine compounds are ubiquitous in medicinal chemistry and agrochemistry. However, the creation of C-CF3 bonds mediated by metals is very challenging due to the M-CF3 bond strength. An original strategy to enable an easier reductive elimination of aryl-CF3 derivatives from well-defined aryl-M-CF3 platforms resides in the preparation of high oxidation state organometallics, more prone to be reduced by 2 electrons. The Ni4Rf project seeks to explore this strategy using Ni(III) and Ni(IV).

The Ni4Rf project seeks to develop new strategies to favor the coupling of aromatics and trifluoromethyl groups involving high valent organometallics [mainly Ni(III) and Ni(IV) compounds].

Organofluorine compounds exhibit relevant biological properties and have important applications in many fields (pharmacy, agrochemicals and material science, among others). However, the introduction of fluorinated groups in organic backbones (especially in aromatic rings) is not an easy task and no (industrially) efficient methods are known for installing trifluoromethyl groups in a specific position. Over the last few years, many procedures to achieve the C-CF3 bond formation via cross-coupling reactions have been developed (typically promoted by palladium and copper complexes), but these methods are not suitable for industrial applications due to their low efficiency and high cost. The Ni4Rf project will seek to develop new alternatives of catalytic trifluoromethylation reactions. Our proposal will target the preparation of high-valent Ni(IV)Rf species to achieve the reductive elimination of Ar-CF3 coupled products under mild conditions. Three different approaches will be addressed: i) the use of solvent stabilized high-valent NiRf fragments (in both oxidation states +3 and +4; task 1); ii) the synthesis of NiRf clusters favored by the presence of diphosphine oxide ligands that will be used as promoters in aromatic trifluoromethylations (task 2); and iii) the formation of mononuclear Ni(IV)Rf complexes stabilized by N-donor ligands [particularly, to meet success in the isolation of the highly attractive Ni(IV)F species] and the study of their implications in C-CF3 bond forming reactions (task 2). The final goal of this proposal focuses in the development of catalytic procedures for C-CF3 bond formation reactions involving a Ni(II)/Ni(IV) redox scenario (task 3). To increase our chances of success, an original approach combining experimental/theoretical work will be performed.<br />Encouraged by the preliminary results carried out in our team, we plan to find a rational pathway to access different high-valent NiRf platforms, which will be reacted with a broad variety of organic substrates to afford the trifluoromethylation of many different scaffolds. This proposal focuses two long-term goals: i) the deep understanding about the nature of M-Rf bonds; and ii) the development of stoichiometric and catalytic processes for aromatic trifluoromethylations induced by Ni-complexes. Thus, our main goal addresses the isolation and full characterization of ArNi(IV)Rf species, and the study of their propensity to promote the reductive elimination of Ar-CF3 coupled products under mild conditions. The acquired information will be decisive in order to achieve the challenging task of developing the unprecedented Ni-catalyzed trifluoromethylation of aromatics via Ni(IV)-intermediates taking place in a SELECTIVE fashion.

The group takes advantage of the specific know-how gained over years working in the stabilization of highly reactive compounds and in the handling of fluorinated organometallics to accomplish the very complex task of isolating high-valent organometallics [mainly Ni(III)CF3, Ni(IV)CF3 and Ag(III)CF3]. To meet success, the use synthetic procedures will require the use of air and moisture free conditions (Schlenk techniques, glove box) and the strict control of reaction temperature. The reactions will be monitored by NMR (whenever possible) and the isolated compounds will be characterized using the excellent technological platform available at the “Institut de Chimie de Toulouse (ICT)” (mainly using NMR, EPR and x-ray services). With the desired [aryl-Ni-CF3] and [F-Ni-CF3] platforms in hand, the reactivity of these high oxidation state organometallics towards aryl-CF3 bond formation will be evaluated upon heating or irradiation. The role of plausible ancillary ligands that may favor the key reductive elimination step will be investigated as well.

- Finding a safe and efficient entry to Ag(III)CF3 chemistry from Ag(I)F and CF3SiMe3 using air as a mild and very convenient oxidant.
- Development of the first Ag mediated trifluoromethylation of arylboron derivatives enabled by Ag(I)/Ag(III) redox cycles.
- Preliminary results in the synthesis of novel «ligandless« Ni(III)CF3 and Ni(IV)CF3 platforms were acquired during the last 18 months. These results are being implemented now in the team, along wth the study of their reactivity.
- The electronic structures of high-valent Ni(IV) complexes were analyzed, including the Ni(IV) complex [(py)2Ni(F)2(CF3)2] previously prepared in the group (international collaboration led by Prof. Kyle Lancaster). The collected results point to an inverted ligand field configuration in these high-valent compounds

The Ni4Rf proposal aims to prepare high oxidation state organonickel complexes that are stabilized by perfluorinated groups such as fluoride (F) itself or the trifluoromethyl group (CF3). In the second part of the project we will focus our efforts towards the following goals:
- the synthesis and characterization of [aryl–Ni(IV)–CF3] and [F–Ni(IV)–CF3] platforms;
- the use of these [aryl–Ni(IV)–CF3] and [F–Ni(IV)–CF3] platforms as novel trifluoromethylating agents of a diverse variety of organic scaffolds (mainly aromatics). To do so, the reactivity of the isolated Ni(III)CF3 and Ni(IV)CF3 complexes towards organic substrates must be evaluated. In particular, key information regarding the ability of Ni(III) and Ni(IV) to undergo reductive elimination from the putative [aryl–Ni(IV)–CF3] or [aryl–Ni(III)–CF3] platforms must be acquired through stoichiometric investigations;
- the deep understanding of the bonding situation and the reasons behind the remarkable stability of Ni–CF3 bonds, with special focus on high valent Ni(III)CF3 and Ni(IV)CF3 species;
- the development of a catalytic version for aromatic trifluoromethylation via unusual Ni(II)CF3/Ni(IV)CF3 redox cycles; and in a more general sense
- to explore the chemistry of high oxidation state of MCF3 compounds with the aim of developing novel methodologies for trifluoromethylation. In particular, the of unprecedented Ag(III)CF3 compounds recently reported in the group will be studied in parallel to the Ni(IV) chemistry.

Articles:

1. “Cross-Coupling Through Ag(I)/Ag(III) RedOx Manifold”. L. Demonti, N. Saffon-Merceron, N. Mézailles, N. Nebra,* Chem. Eur. J. 2021, 27, 15396-15405.
(Hot Paper). (Cover Feature).
Press release by L’Actualité Scientifique (CNRS Journal).
Press release by L’Actualité Chimique (Journal of the SCF).
Highlighted in ChemDigest blog.

2. “Compuestos Organometálicos en Estado de Oxidación Inusualmente Elevado. Utilización en la Trifluorometilación Oxidativa de Derivados Arilboro”. L. Demonti, N. Nebra,* An. Quím. 2022, 118, 16-24.

3. “Scrutinizing Formally Ni(IV) Centers through the Lenses of Core Spectroscopy, Molecular Orbital Theory, and Valence Bond Theory”. I. DiMucci, C. Titus, D. Nordlund, J. Bour, E. Chong, M. Kosobokov, C. Martin, N. Nebra, D. Vicic, S. Yruegas, S. MacMillan, J. Shearer,* K. Lancaster,* 2022, submitted for publication.

Organofluorine compounds exhibit relevant biological properties and have important applications in many fields (pharmacy, agrochemicals and material science, among others). However, the introduction of fluorinated groups in organic backbones (especially in aromatic rings) is not an easy task and no (industrially) efficient methods are known for installing trifluoromethyl groups in a specific position. Over the last few years, many procedures to achieve the C-CF3 bond formation via cross-coupling reactions have been developed (typically promoted by palladium and copper complexes), but these methods are not suitable for industrial applications due to their low efficiency and high cost. The Ni4Rf project will seek to develop new alternatives of catalytic trifluoromethylation reactions. Our proposal will target the preparation of high-valent Ni(IV)Rf species to achieve the reductive elimination of Ar-CF3 coupled products under mild conditions. Three different approaches will be addressed: i) the use of solvent stabilized high-valent NiRf fragments (in both oxidation states +3 and +4; task 1); ii) the synthesis of NiRf clusters favored by the presence of diphosphine oxide ligands that will be used as promoters in aromatic trifluoromethylations (task 2); and iii) the formation of mononuclear Ni(IV)Rf complexes stabilized by N-donor ligands [particularly, to meet success in the isolation of the highly attractive Ni(IV)F species] and the study of their implications in C-CF3 bond forming reactions (task 2). The final goal of this proposal focuses in the development of catalytic procedures for C-CF3 bond formation reactions involving a Ni(II)/Ni(IV) redox scenario (task 3). To increase our chances of success, an original approach combining experimental/theoretical work will be performed.
Encouraged by the preliminary results carried out in our team, we plan to find a rational pathway to access different high-valent NiRf platforms, which will be reacted with a broad variety of organic substrates to afford the trifluoromethylation of many different scaffolds. This proposal focuses two long-term goals: i) the deep understanding about the nature of M-Rf bonds; and ii) the development of stoichiometric and catalytic processes for aromatic trifluoromethylations induced by Ni-complexes. Thus, our main goal addresses the isolation and full characterization of ArNi(IV)Rf species, and the study of their propensity to promote the reductive elimination of Ar-CF3 coupled products under mild conditions. The acquired information will be decisive in order to achieve the challenging task of developing the unprecedented Ni-catalyzed trifluoromethylation of aromatics via Ni(IV)-intermediates taking place in a SELECTIVE fashion.

Project coordination

Noel NEBRA-MUNIZ (LABORATOIRE HETEROCHIMIE FONDAMENTALE ET APPLIQUEE)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

LHFA LABORATOIRE HETEROCHIMIE FONDAMENTALE ET APPLIQUEE

Help of the ANR 279,612 euros
Beginning and duration of the scientific project: October 2020 - 48 Months

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