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Review
. 2020 Feb 7;25(3):721.
doi: 10.3390/molecules25030721.

Harnessing Ionic Interactions and Hydrogen Bonding for Nucleophilic Fluorination

Affiliations
Review

Harnessing Ionic Interactions and Hydrogen Bonding for Nucleophilic Fluorination

Young-Ho Oh et al. Molecules. .

Abstract

We review recent works for nucleophilic fluorination of organic compounds in which the Coulombic interactions between ionic species and/or hydrogen bonding affect the outcome of the reaction. SN2 fluorination of aliphatic compounds promoted by ionic liquids is first discussed, focusing on the mechanistic features for reaction using alkali metal fluorides. The influence of the interplay of ionic liquid cation, anion, nucleophile and counter-cation is treated in detail. The role of ionic liquid as bifunctional (both electrophilic and nucleophilic) activator is envisaged. We also review the SNAr fluorination of diaryliodonium salts from the same perspective. Nucleophilic fluorination of guanidine-containing of diaryliodonium salts, which are capable of forming hydrogen bonds with the nucleophile, is exemplified as an excellent case where ionic interactions and hydrogen bonding significantly affect the efficiency of reaction. The origin of experimental observation for the strong dependence of fluorination yields on the positions of -Boc protection is understood in terms of the location of the nucleophile with respect to the reaction center, being either close to far from it. Recent advances in the synthesis of [18F]F-dopa are also cited in relation to SNAr fluorination of diaryliodonium salts. Discussions are made with a focus on tailor-making promoters and solvent engineering based on ionic interactions and hydrogen bonding.

Keywords: hydrogen bonding; ionic interactions; nucleophilic fluorination.

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Conflict of interest statement

The authors declare no conflict of interest

Figures

Scheme 1
Scheme 1
Sc(OTf)3-catalyzed Friedel-Crafts alkylation of benzene with 1-hexene in various solvents.
Figure 1
Figure 1
Transition state for SN2 fluorination using CsF in [bmim][OMs]. MPW1K/6-311G ** method for C, H, O, N, F, S atoms, Hay-Wadt VDZ (n + 1) basis set with relevant effective core potential for alkali metal elements Cs, using Gaussian 03 set of programs.
Figure 2
Figure 2
Pre-reaction complexes of SN2 fluorination in [bmim][F]. (a) equivalent of IL = 1 (b) equivalent of IL = 2. M06-2X/6-311G ** method for C, H, O, N, S, F atoms, using Gaussian 09 set of programs.
Figure 3
Figure 3
Promotion of SN2 fluorination by oligoethylene glycol substituted imidazolium salts.
Figure 4
Figure 4
SN2 fluorination in pyrene-tagged IL.
Figure 5
Figure 5
Mechanism of SN2 fluorination catalyzed by pyrene-tagged IL. M06-2X/6-311G ** method for C, H, O, N, S atoms, LANL2DZ24 basis set with relevant effective core potential for alkali metal elements (Cs, K). Gaussian 09 set of programs.
Scheme 2
Scheme 2
[18F]Fluorination of SNAr fluorination of diaryliodonium salts containing the 2-thienyl group.
Scheme 3
Scheme 3
Chemoselective radiosynthesis of [18F]fluoroarenes using an aryl(2,4,6-trimethoxyphenyl)iodonium tosylate as a precursor for 18F-incorporation on electron-rich aryl rings.
Scheme 4
Scheme 4
Dependence of 18F-labeling of guanidine-containing radiopharmaceutical on the positions of -Boc protection.
Figure 6
Figure 6
Pre-reaction complexes for reactions listed in Scheme 2. In (a) the absence of hydrogen bonding positions F favorable for fluorination, whereas in (b) hydrogen bonding with -NHR moves F far off the reaction center. M06-2X/6-311G ** method for C, H, O, N, F, S atoms, LANL2DZ basis set with relevant effective core potential for alkali metal elements (I, Br, Cs), using Gaussian 09 set of programs.
Scheme 5
Scheme 5
Nickel-mediated preparation of [18F]fluoroarenes.
Scheme 6
Scheme 6
Cold fluorination of tri-Boc protected iodonium salts with tetramethylammonium fluoride (TMAF).
Scheme 7
Scheme 7
Proposed processes for Wirth and co-workers. Model I process (SNAr bromination) is predicted to be dominant over Model II process (SNAr fluorination).
Scheme 8
Scheme 8
Preparation of [18F]F-dopa from tert-butyl ester precursor.

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References

    1. Vaillancourt F.H., Yeh E., Vosburg D.A., Garneau-Tsodikova S., Walsh C.T. Nature’s inventory of halogenation catalysts: Oxidative strategies predominate. Chem. Rev. 2006;106:3364–3378. doi: 10.1021/cr050313i. - DOI - PubMed
    1. Champagne P.A., Desroches J., Hamel J.D., Vandamme M., Paquin J.F. Monofluorination of Organic Compounds: 10 Years of Innovation. Chem. Rev. 2015;115:9073–9174. doi: 10.1021/cr500706a. - DOI - PubMed
    1. Mascaretti O.A. Modern methods for the monofluorination of aliphatic organic compounds. Aldrichim. Acta. 1993;26:47–58.
    1. Lee J.W., Oliveira M.T., Jang H.B., Lee S., Chi D.Y., Kim D.W., Song C.E. Hydrogen-bond promoted nucleophilic fluorination: Concept, mechanism and applications in positron emission tomography. Chem. Soc. Rev. 2016;45:4638–4650. doi: 10.1039/C6CS00286B. - DOI - PubMed
    1. Liang T., Neumann C.N., Ritter T. Introduction of fluorine and fluorine-containing functional groups. Angew. Chem. Int. Ed. 2013;52:8214–8264. doi: 10.1002/anie.201206566. - DOI - PubMed