Nucleophilic Fluorination with KF Catalyzed by 18-Crown-6 and Bulky Diols: A Theoretical and Experimental Study

Abstract

The activation of potassium fluoride for nucleophilic fluorination of alkyl halides is an important challenge because of the high lattice energy of this salt and its low solubility in many polar aprotic solvents. Crown ethers have been used for increasing the solubilization of KF during several decades. Nevertheless, these macrocycles are not enough to produce a high reaction rate. In this work, theoretical methods were used for designing a synergic combination of bulky diols with crown ethers able to accelerate this kind of reaction. The calculations have predicted that the bulky diol 1,4-Bis­(2-hydroxy-2-propyl)­benzene, which has distant hydroxyl groups, is able to catalyze nucleophilic fluorination in combination with 18-crown-6 via two hydrogen bonds to the SN2 transition state. Experimental studies following the theoretical predictions have confirmed the catalytic effect and the estimated kinetic data point out that the bulky diol at 1 mol L–1 in combination with 18-crown-6 is able to produce an 18-fold increase in the reaction rate in relation to crown ether catalysis only. The reaction produces 46% yield of fluorination after 24 h at moderate temperature of 82 °C, with minimal formation of the side elimination product. Thus, this work presents an improved method for fluorination with KF salt.

Hydrogen Bonding Phase-Transfer Catalysis with Alkali Metal Fluorides and Beyond

“…More recently, Pliego and co-workers disclosed an alternative synergistic approach in which an 18-crown-6 and a bulky diol (BDMB = 1,4-bis(2-hydroxy-2-propyl)benzene) were combined for the phase-transfer fluorination of alkyl bromides in acetonitrile with solid KF. 35 In a complementary approach, Kim, Lee, and co-workers reported that crown-ether-strapped calix[4]arenes 14 – 18 can facilitate nucleophilic fluorination with CsF and KF ( Scheme 5 ). 36 BACCA (bis- tert -alcohol-functionalized crown-6-calix[4]arene, 14 ) enabled the fluorination of alkyl mesylate 19 , a substrate prone to elimination, with S N 2:E2 ratios higher than 10:1 when tert -amyl alcohol was employed as solvent ( Scheme 5 ).…”

Kinetics and Quantum Chemical Analysis of Intramolecular SN2 Reactions by Using Metal Salts and Promoted by Crown Ethers: Contact Ion Pair vs. Separated Nucleophile Mechanism

“…In this latter mechanism, the electronegative atoms (usually O atoms) or negative ions in a promoter bind to the counter‐cation (such as Cs + , K + ), essentially obliterating the influence of the positive charge of the counter‐cation on the nucleophile, thereby allowing the latter to behave as if the counter‐cation were not present in the vicinity. Along this line of reasoning for the mechanism of S N 2 rate enhancement by Lewis bases, crown ethers may also be a good promoter/catalyst, as recently exemplified in an excellent experimental/theoretical work by Pliego and co‐workers for S N 2 fluorination using KF facilitated by (18‐Crown‐6) in bulky diol [29] …”

Nucleophilic Radiofluorination Using Tri-tert-Butanol Ammonium as a Bifunctional Organocatalyst: Mechanism and Energetics

“…Generally, this is undesirable for radiofluorination, as 18 F possesses a relatively short half-life of 109.77 min. Various non-radioactive nucleophilic fluorination methods [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ] have been developed using various phase-transfer catalysts (PTCs) for their application in radiopharmaceutical chemistry in which hydrogen bonding between protic PTC and nucleophile [ 18 F]fluoride enhances the reaction and selectivity [ 36 , 37 ]. The recent development of tri-( tert -butanol)-methylammonium [ 18 F]fluoride (TBMA- 18 F) [ 13 ] as a promoter for radiofluorination demonstrated an excellent [ 18 F]fluoride elution efficiency under the reduced basicity of [ 18 F]fluoride, with moderate to good obtained RCYs.…”

“…Shinde and co-workers proposed that these excellent organocatalytic properties of the counter-cation may be attributed to the coordinating capacity of the two functional groups (ammonium and hydroxyl) in TBMA + . This rate enhancement, promoted by the counter-cation, which would be the first such example for 18 F-fluorination, exhibits significant advantages over more conventional methods using alkali metal cations, M + (M = K, Rb, Cs), because in the latter case the Lewis base promoters such as bulky alcohols [ 8 , 32 ], oligoethylene glycols [ 8 , 31 , 32 ], ionic liquids [ 8 , 33 ], or crown ethers [ 34 , 35 ] are required to suppress the harmful Coulomb forces of the counter-cation on the nucleophile.…”