Control of reactivity and selectivity of guanidinyliodonium salts toward ¹⁸F-Labeling by monitoring of protecting groups: Experiment and theory

We analyze the effects of protecting group(s) on the efficiency of aromatic ¹⁸F-labeling of guanidine-containing radiopharmaceuticals by quantum chemical methods. We elucidate the origin of experimental observations: The fully protected N,N’,N’’,N’’-tetrakis-Boc guanidine group exhibits remarkably enhanced reactivity and improved selectivity in contrast to both N,N’-bis-Boc protected guanidine and its isomer in the absence of hydrogen bonding with fluoride ion. We find that this very intriguing observation of reaction rates highly depending on the position of protection by –Boc is due to the effects of strong Coulombic interactions among the ionic species, which allow an optimal position (just above the electropositive carbon and the leaving group) of F⁻ in the reaction involving the fully protected N,N’,N’’,N’’-tetrakis-Boc guanidine group.