Enabling Nucleophilic Substitution Reactions of Activated Alkyl Fluorides through Hydrogen Bonding

Abstract

It was discovered that the presence of water as a cosolvent enables the reaction of activated alkyl fluorides for bimolecular nucleophilic substitution reactions. DFT calculations show that activation proceeds through stabilization of the transition structure by a stronger F···H2O interaction and diminishing C-F bond elongation, and not simple transition state electrostatic stabilization. Overall, the findings put forward a distinct strategy for C-F bond activation through H-bonding.

Revised mechanistic explanation for the alcohol-promoted amination of benzylic fluorides under highly concentrated conditions: Computational and experimental evidence on a model substrate

“…We have recently published our findings that hydrogen-bond donation from water can activate C-F bonds allowing nucleophilic substitution of activated alkyl fluorides under neutral conditions [10]. During that study, DFT calculations suggested that three water molecules were involved at the transition state of the reaction (Scheme 1A).…”

Vessel Effect in C–F Bond Activation Prompts Revised Mechanism and Reveals an Autocatalytic Glycosylation

“…[11,12] Several other applications of C(sp 3 )-F bond activation have been developed, and significant highlights in this vast field of research have recently been reviewed in detail by Hamel and Paquin. Paquin and co-workers have developed methods for chemoselective benzylic-, [13][14][15][16][17] allylic- [13] and propargylic [18] C-F bond activation mediated through hydrogen bonding, reporting that the hydrogen fluoride developed during the reaction would function as an active catalyst, resulting in an autocatalytic kinetic profile. Paquin and co-workers have developed methods for chemoselective benzylic-, [13][14][15][16][17] allylic- [13] and propargylic [18] C-F bond activation mediated through hydrogen bonding, reporting that the hydrogen fluoride developed during the reaction would function as an active catalyst, resulting in an autocatalytic kinetic profile.…”

Triol-promoted activation of C–F bonds: Amination of benzylic fluorides under highly concentrated conditions mediated by 1,1,1-tris(hydroxymethyl)propane

“…In water or alcoholic solvent without added triol, low to moderate conversions were observed (12–26%). This was expected since these are all hydrogen bond-donor solvents [17,26]. A low but quantifiable increase in conversion is observed when 2 is added to these reactions, with the best result (35%) being obtained in water (Table 1, entries 1–3).…”

“…In summary, we have described that according to our previous proposed mechanism for the hydrogen bond-promoted C–F bond activation [17], simultaneous coordination of the three lone pairs of fluorine by a triol (e.g. 2 ) permits the nucleophilic substitution of benzylic fluorides by amines under neutral and solvent-free conditions.…”

“…Specifically for aliphatic monofluorides, a number of transition metal-catalyzed methods [1–9] and transition-metal-free methodologies [1,10–12] have been developed. In continuation with our interest in the activation of C–F bonds [13–16], we have recently reported that it was possible to enable the use of fluoride as a leaving group in nucleophilic substitution reactions of activated alkyl fluorides through hydrogen bonding [17]. Particularly, water was used as the hydrogen bond donor and co-solvent.…”