Origin of Difference in the Reactivity of Aliphatic and Aromatic Guanidine‐containing Pharmaceuticals Toward [18F]Fluorination: Coulombic Forces and Hydrogen Bonding

Abstract

Quantum chemical analysis is presented to elucidate the origin of difference in the reactivity of aliphatic vs. aromatic guanidine‐containing pharmaceuticals toward [18F]fluorination. We focus on the position (near to or far away from the site of reaction) of F− nucleophile in pre‐reaction complexes, as determined by intricate interplay of the Coulombic forces between the ionic species and hydrogen bonding with the –Boc protected guanidine. In [18F]fluorination of aliphatic guanidine compounds, the freely moving nucleophile F− is positioned close to the site of fluorination irrespective of the length of side chain, in agreement with the observed similar reaction yields for –CH2OMs and –CH2CH2CH2OMs side chains. As for the effects of positions of –Boc protection, we predict that the effects would to be contrary to the corresponding aromatic case, with the N, N″‐bis‐Boc protected guanidine compound being much more reactive than the N, N′‐bis‐Boc protected guanidine compound.