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

We present a quantum chemical analysis of the (18)F-fluorination of 1,3-ditosylpropane, promoted by a quaternary ammonium salt (tri-(tert-butanol)-methylammonium iodide (TBMA-I) with moderate to good radiochemical yields (RCYs), experimentally observed by Shinde et al. We obtained the mechanism of the S(N)2 process, focusing on the role of the –OH functional groups facilitating the reactions. We found that the counter-cation TBMA(+) acts as a bifunctional promoter: the –OH groups function as a bidentate ‘anchor’ bridging the nucleophile [(18)F]F(−) and the –OTs leaving group or the third –OH. These electrostatic interactions cooperate for the formation of the transition states of a very compact configuration for facile S(N)2 (18)F-fluorination.