Photoelectrochemical Iron(III) Catalysis for Late-Stage C─H Fluoroalkylations

Abstract

Chemo- and site-selective functionalization of complex molecules poses a fundamental challenge. Herein, we introduce a resource-economic photoelectrocatalysis strategy to enable versatile direct fluoroalkylations catalyzed by Earth-abundant iron and paired with the hydrogen evolution reaction (HER). Notably, the devised approach proved amenable to versatile late-stage C─H fluoroalkylations of bio-relevant heterocycles, such as xanthines, nucleobases, and nucleosides. Mechanistic studies supported a ligand-to-metal charge transfer-induced formation of the fluoroalkyl radical.

Keywords: C─H Functionalization; Electrophotochemistry; Fluoroalkylation; Iron catalysis; Sustainable chemistry.

Figure 1

Motivation and strategy for the late‐stage C─H fluoroalkylation. a) Natural abundance of iron and other transition metals in comparison. b) Representative fluoroalkyl‐containing compounds with pharmaceutical relevance. c) Beneficial effects of fluoroalkyl‐substitution on pharmacological properties. d) Lipophilicity indexes log P(o/w) for selected fluoroalkyl radicals. Calculations were performed at the ωB97X‐D + SMD(Octanol or Water)/def2‐QZVPP//ωB97X‐D/def2‐TZVPP level of theory (top) and calculated relative nucleophilicity of different fluoroalkyl radicals at the ωB97X‐D + SMD(Acetonitrile)/def2‐QZVPP//ωB97X‐D/def2‐TZVPP level of theory. Values take the malononitrile radical as reference (bottom). e) Electrochemical approaches to C─H fluoroalkylation using sulfinate and carboxylic acid reagents, and this work: Late‐stage C─H fluoroalkylations of complex biomolecules and drug compounds enabled by photoelectrochemical iron(III)‐catalysis. PC = photocatalyst, R_F = fluoroalkyl group ‐CF₂Alk, FTO = fluorine‐doped tin oxide glass. CCE = constant current electrolysis.

Figure 2

Conceptualization and development of ferra‐photoelectrocatalysis. a) Mechanism manifold for homogenous photoelectrochemical C─H fluoroalkylation. b) Model reaction and control experiments. Reaction conditions: Undivided cell, heteroarene 1a (0.30 mmol), fluorinated carboxylic acid 2a (0.90 mmol), Fe(ClO₄)₃•10H₂O (0.06 mmol), LiClO₄ (0.067 M), MeCN (3 mL), glassy carbon anode (GC) and platinum plate cathode (Pt), CCE at 4.0 mA, 390 nm light irradiation, 1000 rpm stirring rate. [a] Yields were determined by ¹⁹F NMR with PhCF₃ as internal standard; isolated yields are shown in parenthesis. c) Detection of molecular hydrogen via GC‐TCD headspace analysis (top) and quantitative monitoring of gas evolution (bottom). d) Kinetic analysis with substrate 1a and 2a revealing the current as rate limiting factor.

Figure 3

Studies of the LMCT process. a) Cyclic voltammetry curves of a model reaction under standard conditions (left) and CV studies on complexation of Fe(III) salt with carboxylic acid: Undivided cell, caffeine 1a (0.30 mmol), fluorinated carboxylic acid 2a (0.90 mmol), Fe(ClO₄)₃•10H₂O (0.06 mmol), LiClO₄ (0.067 M), MeCN (3 mL). b) UV/Vis spectra of the model reaction. c) Radical trap experiments.

Figure 4

Robustness of homogenous ferra‐photoelectrocatalysis. a) Fluoroalkyl versatility. b) Assessment of chemo‐ and site‐selectivity. Reaction conditions: Undivided cell, heteroarene 1 (0.30 mmol), fluorinated carboxylic acid 2 (0.90 mmol), Fe(ClO₄)₃•10H₂O (0.06 mmol), LiClO₄ (0.067 M), MeCN (3 mL), glassy carbon anode (GC) and platinum plate cathode (Pt), 6–12 h. CCE at 4.0 mA, 390 nm light irradiation, 1000 rpm stirring rate. Isolated yields. [a] n‐Bu₄NBF₄ (0.1 M) as supporting electrolyte, 36 h. [b] GF anode. [c] Reaction time 18 h. [d] DMSO/H₂O (2:1) as a solvent. [e] CPE at 1.5 V; reaction time 30 h.

Figure 5

Late‐stage C─H fluoroalkylation. a) Compatibility with diverse nucleosides und nucleoside analogs. b) Selective direct fluoroalkylation of unprotected uridine‐5′‐monophosphate (UMP). Reaction conditions: Undivided cell, heteroarene 1 (0.30 mmol), fluorinated carboxylic acid 2 (0.90–1.20 mmol), Fe(ClO₄)₃•10H₂O (0.06 mmol), LiClO₄ (0.20–0.30 mmol), DMSO/H₂O (2:1 v/v, 3 mL), glassy carbon anode (GC) and platinum plate cathode (Pt), 6–12 h. CCE at 4.0 mA, 390 nm light irradiation, 1000 rpm stirring rate. Isolated yields. [a] n‐Bu₄NBF₄ (0.1 M) as supporting electrolyte, 36 h. [b] ¹⁹F NMR yield with PhCF₃ as internal standard in parenthesis.