Hydrogen Bonding: Regulator for Nucleophilic Fluorination

Abstract

The recent advances in nucleophilic fluorination, regulated through hydrogen bonding interactions are summarized. Two main categories of fluorine nucleophiles are discussed. Alkali-metal fluorides are widely used in various fluorination transformations because they are inexpensive and safe nucleophilic fluorine sources. But the non-controllable nucleophilicity and strong basicity of some of them cause undesired side reactions, which led to the introduction of hydrogen bonding to fine tune their nucleophilicity and basicity. In contrast, an HF-based fluorine nucleophile, HF/DMPU, is in some aspects superior to the conventional HF/pyridine (Olah's reagent) or HF/Et N because of the higher hydrogen bond basicity of DMPU. It has been used in several nucleophilic fluorinations such as fluorination of alkynes, fluoro-Prins reaction and fluorination of aziridines.

Enantioselective, Catalytic Vicinal Difluorination of Alkenes

“…Brønsted acidity is a critical parameter in diverting the established geminal pathway to favour formation of the desired vicinal product. Understanding this phenomenon will be the focus of future research efforts . CCorrelations of enantioselectivity with the log (e.r.)…”

Anion coordination chemistry using O–H groups

“…Nucleophilic fluorination is an important transformation particularly given the importance of organofluorines in pharmaceuticals and the use of 18 F tracers for positron emission tomography. 113 Reactions such as those shown in Scheme 1 are of interest as a method for late-stage installation of fluorine groups, although such reactions are prone to several side reactions, most notably elimination caused by basic fluoride. Some work has investigated methods to control the reactivity of fluoride using hydrogen bonding.…”

Fluorine effect in nucleophilic fluorination at C4 of 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-D-hexopyranose

“…At this point, it became obvious to us that it would be difficult to selectively prepare 1,6-anhydro-2,3,4-trideoxy-2,3,4-trifluorohexopyranose analogues using DAST-mediated deoxyfluorination. Consequently, we turned our attention towards activation of the C4 hydroxy group as a triflate followed by exposure to a fluorine nucleophile [ 31 ]. We selected Et 3 N·3HF as a simple, stable, and versatile nucleophilic reagent since it would be possible to modulate the nucleophilicity/basicity with addition of Et 3 N [ 32 ].…”