Ligand-Free Cerium-Catalyzed Decarboxylative Fluorination of Aliphatic Carboxylic Acids

Photoinduced LMCT Catalysis for Efficient C(sp³)–F Bond Construction

A Sustainable Approach via Earth-Abundant Lanthanide Photocatalysis

Abstract and Synthetic Significance

The incorporation of fluorine into organic molecules is a transformative strategy in medicinal chemistry, as it significantly modulates metabolic stability and lipophilicity. However, conventional fluorination methods often necessitate specialized reagents or expensive noble-metal catalysts. Recent research published in ACS Organic & Inorganic Au by Azhar, Peng, and El-Sepelgy introduces a ligand-free, cerium-catalyzed protocol for the decarboxylative fluorination of carboxylic acids. By leveraging photoinduced Ligand-to-Metal Charge Transfer (LMCT), this method converts readily available aliphatic carboxylic acids into high-value alkyl fluorides under remarkably mild, oxidant-free conditions.

Experimental Parameters and Optimization

The reaction utilizes the unique redox properties of Cerium (Ce^III/Ce^IV) to facilitate radical generation without the need for exogenous ligands or stoichiometric oxidants.

Standard Reaction Conditions

R–COOH + Selectfluor → [CeCl₃·7H₂O (10 mol%)] → R–F + CO₂

• Light Source: 390 nm LEDs (Purple Light)
• Fluorinating Reagent: Selectfluor (1.5–2.0 equivalents)
• Solvent: Acetonitrile/Water (MeCN/H₂O) mixture
• Atmosphere: Inert Argon (Ar)

Substrate Versatility

The protocol demonstrates an expansive scope, tolerating various sensitive functional groups:

Primary, Secondary, and Tertiary Acids: All undergo efficient conversion to corresponding fluorides.
Bioactive Derivatives: Successful fluorination of complex molecules such as Gemfibrozil and Dehydrocholic acid.
Functional Tolerance: Compatible with ketones, esters, amides, and phthalimides.

Proposed Mechanistic Pathway

The reaction mechanism is centered on the generation of alkyl radicals via the excitation of a Cerium(IV)-carboxylate species. Unlike traditional photoredox catalysis, this relies on direct LMCT excitation.

Catalyst Activation: The Cerium(III) salt is oxidized to a Cerium(IV) species by the fluorinating agent (Selectfluor).
Complex Formation: The aliphatic carboxylic acid undergoes ligand exchange with the Ce(IV) center to form a Cerium-carboxylate complex.
LMCT Excitation: Irradiation with 390 nm light induces Ligand-to-Metal Charge Transfer (LMCT), promoting an electron from the carboxylate oxygen to the Ce(IV) center.
Decarboxylation: Homolytic cleavage of the O–Ce bond produces a carboxyl radical, which rapidly extrudes CO₂ to generate an alkyl radical (R•).
Fluorine Atom Transfer (FAT): The alkyl radical abstracts a fluorine atom from Selectfluor, yielding the final alkyl fluoride and regenerating the Cerium catalyst.

Conclusion and Academic Merit

This methodology represents a significant advancement in lanthanide catalysis, providing a "ligand-free" alternative to established photoredox systems. By eliminating the need for expensive iridium or ruthenium sensitizers, this cerium-based approach offers a cost-effective and scalable solution for late-stage fluorination. The reliance on LMCT rather than external oxidants further enhances the atom economy and sustainability of the transformation.