Very Efficient Nucleophilic Aromatic Fluorination Reaction in Molten Salts: A Mechanistic Study

Abstract

We report a quantum chemical study of an extremely efficient nucleophilic aromatic fluorination in molten salts. We describe that the mechanism involves solvent anion interacting with the ion pair nucleophile M + F − (M = Na, K, Rb, Cs) to accelerate the reaction. We show that our proposed mechanism may well explain the excellent efficiency of molten salts for S N Ar reactions, the relative efficacy of the metal cations, and also the observed large difference in rate constants in two molten salts (n-C 4 H 9 ) 4 N + CX 3 SO 3 − , (X=H, F) with slightly different sidechain (-CH 3 vs. -CF 3 ).

18F-Labeling of Arenes and Heteroarenes for Applications in Positron Emission Tomography

“…Molten salts have been used as reaction solvents as an alternative to the more conventional polar aprotic solvents used for nucleophilic aromatic fluorination reactions. 143 With favorable substitution patterns, the reactions can occur under very mild conditions. A rare example of a room temperature S N Ar reaction is the radiosynthesis of 2-chloro-1-[ 18 F]fluoro-4-nitrobenzene, which can be prepared in 71−76% RCY in MeCN with a reaction time of 25 min from the corresponding aryltrimethylammonium triflate.…”

“…Halides have also been used as leaving groups for the introduction of [ 18 F]­fluoride via halogen exchange but are typically not as effective. − Reaction conditions used for S N Ar commonly require heating to high temperatures in polar aprotic solvents. Molten salts have been used as reaction solvents as an alternative to the more conventional polar aprotic solvents used for nucleophilic aromatic fluorination reactions . With favorable substitution patterns, the reactions can occur under very mild conditions.…”

Modern Carbon–Fluorine Bond Forming Reactions for Aryl Fluoride Synthesis

“…Displacement of the chloride in electron-poor aryl chlorides under forcing conditions with anhydrous potassium fluoride (the halogen exchange, or “Halex” process) was developed in 1936, followed by the fluorodenitration of arenes by ipso attack at the carbon atom bearing the nitro group (Figure ) . Increased efficiency for arene fluorodenitration has also been reported by performing the reaction in a molten salt as solvent . Aryl chlorides and nitroarenes are more suitable substrates for nucleophilic fluorination reactions than aryl bromides and iodides because the rate-limiting step in S N Ar fluorination reactions is the addition of fluoride to form a Meisenheimer complex; therefore, more electron-withdrawing leaving groups accelerate the substitution by fluoride.…”

Nucleophilic substitution reactions promoted by oligoethylene glycols: a mechanistic study of ion‐pair SN2 processes facilitated by Lewis base

“…This puzzle is now well resolved by invoking a new type of S N 2 reactions in which the nucleophile reacts as an ion‐pair, and the protic solvent acts as a Lewis base on the metal cation M + (rather than as a Lewis acid on the nucleophile) to reduce its retarding Coulombic influence on M + . This new concept has also been instrumental for elucidating the promoting effects of ionic liquids and molten salts in S N 2 and S N Ar reactions. In this work, we provide a systematic analysis of the mechanism of S N 2 reactions in various n ‐oligoethylene glycols (oligoEGs) such as triethylene glycol (triEG), tetraethylene glycol (tetraEG), and pentaethylene glycol (pentaEG) (see Scheme ).…”