Catalytic fluorination of chlorinated aromatic compounds : Synthesis of fluorinated building blocks for agrochemecal and pharmacochemical applications. – FLUORCAT
Catalysed synthesis of fluorinated building blocks for the pharmaceutical and agrochemical applications
This project concerns the search for new selective catalytic fluorination reactions and to propose original catalytic systems adapted to the chlorinated starting materials using HF as the fluorinating agent.
Background and objective of the project
This work deals with the gas phase catalysed fluorination of chloropyridines using metal fluorides as catalysts and HF as fluorination agent. Indeed, until now, these fluorinated molecules, used as building<br />blocks for the preparation of more complex molecules with therapeutic applications and / or plant health, are prepared in liquid phase in the presence of fluorinating agent such as KF. These processes lead to not recyclable product (KF). However, just few works, in the literature, describes such reactions. In this context, from fundamental aspect of research, this work aims to establish a database from relationships between the properties of the catalyst and the reactivity of chlorinated substrate. This is neceesary to develop new fluorination reactions by aromatic nucleophilic substitution under selective conditions. Therefore, it is necessary to establish the basic rules in order to determine the operating<br />conditions and the catalytic system depending on the reactivity of chlorinated substrates
Monometallic different fluorides based on aluminum, calcium, magnesium, strontium, lanthanum and barium having a variable acidity-basicity scale were prepared. The synthesis methods were chosen in order to obtain materials with the largest possible surface areas. Physicochemical properties of these materials were characterized at each stage of their development in order to have a good understanding. The catalytic performance of these materials were measured initially for the fluorination of 2-chloropyridine (simple model molecule). A parametric study temperature, working time, contact time, ...) was performed to identify the active sites and the mechanisms involved. Finally, the conditions have
been generalized to the transformation of other chloropyridines : monosubstituted (3-chloropyridine and 4-chloropyridine), disubstituted (2,3-dichloropyridine and 2,4-dichloropyridine), and trisubstituted (2,3,5-trichloropyridine and 2,3-dichloro-5- (trifluoromethyl) pyridine). The goal is to determine, on one hand, the reactivity of chloropyridines depending on the position of the chlorine atom (ortho, meta or para with respect to the nitrogen atom), and on the other hand, the influence of the presence of electron-attracting groups (-Cl, -CF3) on the reactivity of these positions.
BaF2 is the most active material at 300 ° C and MgF2 becomes the most powerful catalyst at 350 ° C. A reaction mechanism has been proposed considering the adsorption of the molecule through the nitrogen atom and / or chlorine for materials containing barium followed by a Cl / F exchange via an aromatic nucleophilic substitution. Finally, the use of these metal fluorides has been generalized to the fluorination of other substituted chloropyridines. In all cases the main compound corresponds to the
formation of substituted 2-fluoropyridines. Finally, it is important to note that a techno-economic study showed that this new approach was 1.5 times cheaper than that the one currently used for the production of 1,000 tons of 2-fluoropyridine.
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This work allowed the defense of the thesis of Arnaud Astruc (15 December 2015) and the publication
of one article in an international journal and 1 communication in a French congress and 3 in international
congresses.
1 - Ba1-xLaxF2+x as catalyst for the gas phase fluorination of 2-chloropyridine by HF
A. Astruc, S. Célérier, E. Pavon, A-S. Mamede, L. Delevoye and S. Brunet
2 – Reactivity of various substituted chloropyridines over metallic fluorides.
A. Astruc, S. Célérier, F. Metz and S. Brunet
3 – Local Structural Characterisation of Aluminum Hydroxyl-fluorides by 19F MAS NMR and
correlation sequences.
A. Astruc, S. Célérier, E. Pavon, D. Grekov, A-S. Mamede, S. Brunet and L. Delevoye
The presence of the fluorine atom in molecules increases their biological activity .This represents a significant interest for applications in medicinal chemistry and agrochemical industries. Given the growing interest to introduce an atom or atom (s) of fluoride in an organic molecule, it is essential to develop new methods for selective fluorination. A new way is the preparation of fluorinated building blocks by nucleophilic aromatic substitution from the chlorinated starting materials in the presence of a catalyst and hydrogen fluoride as the fluorinating agent. The objective of this work is to establish firstly the feasibility of such reactions and secondly the rules determining the operating conditions and the formulation of catalysts. This will thus adapt the catalyst as a function of the reactivity of chlorinated substrates. The project partners are complementary and have a proven ability to work together.
Project coordination
Sylvette Brunet (CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE POITOU-CHARENTES)
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.
Partnership
LACCO CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE POITOU-CHARENTES
UCCS ECOLE NATIONALE SUPERIEURE DE CHIMIE DE LILLE
RHODIA OPERATIONS
Help of the ANR 363,000 euros
Beginning and duration of the scientific project:
February 2012
- 36 Months
