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 [ 18 F]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 [ 18 F]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 -CH 2 OMs and -CH 2 CH 2 CH 2 OMs 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 00 -bis-Boc protected guanidine compound being much more reactive than the N, N 0 -bis-Boc protected guanidine compound.

Hydrogen Bonding in SN2 Reactions Promoted or Inhibited by Ionic Liquids: Effects of Side Chain

“…Locating the nucleophile near at or far from the reaction site in prereaction complexes as the results of ionic interactions and/or hydrogen bonding, either for promotion or prohibition of chemical transformation, seems to be a new feature in reaction dynamics, as discussed in previous studies for S N Ar reactions of diaryliodonium salts 34–35 . To our best knowledge, our present analysis is the first such case for S N 2 process.…”

Synthesis and preliminary evaluation of benzylaminoimidazoline derivatives as novel norepinephrine transporter ligands

“…Currently reported molecular probes targeting NET are mostly non‐substituted guanidine, which have encountered some difficulties in preparation. For the radiolabeling of NET‐targeted probes containing guanidine groups, due to the effect of the hydrogen bonds and Coulomb interactions between the unprotected N‐H, BOC and halogen ions (F − , I + ), the yield of nucleophilic reaction or electrophilic reaction of bis‐BOC protected guanidine precursors is relatively low, or even not proceed at all in some cases (Lee et al, 2019). In order to solve the problem, the preparation of many NET‐targeting radiotracers with favorable properties had to adopt a complex multi‐step radiolabeling route (Jang et al, 2013; Li et al, 2021; Vaidyanathan et al, 1994; Zhang, Huang, Pillarsetty, et al, 2014), or challenge the more difficult synthesis strategy of fully protected guanidine labeling precursors, which hindered their further clinical translation (Chen et al, 2020; Jung et al, 2017; Yamaguchi et al, 2018).…”

Novel [18F]-Labeled Meta-Bromobenzylguanidine Derivatives: Potential Positron Emission Tomography Imaging Probes for the Norepinephrine Transporter

“…This was probably due to the two unprotected protons of the guanidinyl group, which might interfere with the nucleophilic process of 18 F radiofluorination. The unprotected −NH of the guanidine group may form hydrogen bonds with fluorine ions, which could significantly affect the nucleophilic reactivity of [ 18 F – ] with the -OTs group . Recently, strategies that fully protect the guanidine group, such as the tetrakis-Boc protecting group and triazinanone protecting structure, have been used for 18 F radiolabeling of benzylguanidine ([ 18 F]­FIBG; [ 18 F]­MFBG) or phenethylguanidine ([ 18 F]­4F-MHPG/3F-PHPG; [ 18 F]­AF78) analogues. ,,, Thus, to shorten the radiosynthetic time and improve the radiochemical yield of 18 F-12 , the synthesis of a fully protected benzylguanidine precursor for 18 F radiofluorination is warranted.…”