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

Champagne, Pier Alexandre; Drouin, Mélina; Legault, Claude Y.; Audubert, Clément; Paquin, Jean‐François

doi:10.1016/j.jfluchem.2014.08.018

Cited by 26 publications

(16 citation statements)

References 24 publications

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“…The weak HB interactions observed in the X‐ray structure are believed to play an important role in the transition state, resulting in a weakening of the C−F bond. It is interesting to note that the number of putative HB donors in close proximity to the fluorine atom is three, that is, the same number of HB donors as computed by Paquin to describe the nucleophilic substitution reactions of benzyl fluoride . This high number of HB donors in close proximity to the fluorine atom of the CH 2 F moiety is probably required for enzymatic and chemical nucleophilic reactions due to the weakness of the HBs involving fluorine.…”

Section: Resultsmentioning

confidence: 81%

Weak Intermolecular Hydrogen Bonds with Fluorine: Detection and Implications for Enzymatic/Chemical Reactions, Chemical Properties, and Ligand/Protein Fluorine NMR Screening

Dalvit

Vulpetti

2016

Chemistry A European J

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It is known that strong hydrogen-bonding interactions play an important role in many chemical and biological systems. However, weak or very weak hydrogen bonds, which are often difficult to detect and characterize, may also be relevant in many recognition and reaction processes. Fluorine serving as a hydrogen-bond acceptor has been the subject of many controversial discussions and there are different opinions about it. It now appears that there is compelling experimental evidence for the involvement of fluorine in weak intramolecular or intermolecular hydrogen bonds. Using established NMR methods, we have previously characterized and measured the strengths of intermolecular hydrogen-bond complexes involving the fluorine moieties CH2 F, CHF2 , and CF3 , and have compared them with the well-known hydrogen-bond complex formed between acetophenone and the strong hydrogen-bond donor p-fluorophenol. We now report evidence for the formation of hydrogen bonds involving fluorine with significantly weaker donors, namely 5-fluoroindole and water. A simple NMR method is proposed for the simultaneous measurement of the strengths of hydrogen bonds between an acceptor and a donor or water. Important implications of these results for enzymatic/chemical reactions involving fluorine, for chemical and physical properties, and for ligand/protein (19) F NMR screening are analyzed through experiments and theoretical simulations.

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Section: Resultsmentioning

confidence: 81%

Weak Intermolecular Hydrogen Bonds with Fluorine: Detection and Implications for Enzymatic/Chemical Reactions, Chemical Properties, and Ligand/Protein Fluorine NMR Screening

Dalvit

Vulpetti

2016

Chemistry A European J

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“…Such ar esult,s imilart ot he one in absence of Ti(OiPr) 4 ( Table 1, entry 22), suggests that TiF 4 plays no role in the reaction. Finally,c onsidering that variousa lcohols are known to promote CÀ Fb ond activation of benzylic fluorides, [7] and that isopropanol is generatedi nt he reaction mixture, we set up experiments to verify the potential role of iPrOH with or withoutt he thiourea catalyst. The results obtained (Table 1, entries [24][25] showed that iPrOH does not act as ap romoter for the CÀFb ond activation reactionw hen only present in stoichiometric amounts.…”

Section: Resultsmentioning

confidence: 99%

“…[4] Although this interaction is not particularly strong, our grouph as demonstrated that the hydrogen bonding interaction is sufficient to activate ab enzylic CÀFb ond towardS N 2u sing varioush ydrogen-bond donors( HBDs) such as water, [5] 1,1,1-tris(hydroxymethyl)propane [6] andv ariousa lcohols under neutralc onditions. [7,8] In all cases, the HBD was used as the solvent or in a stoichiometric fashion (Scheme 1a). We also demonstrated that using as tronger HBD such as hexafluoroisopropanol (HFIP), this time as the co-solvent( typically aC H 2 Cl 2 /HFIP (9:1) mixture), resultedi naS N 1p athway (Scheme 1b).…”

Section: Introductionmentioning

confidence: 99%

Thiourea‐Catalyzed C−F Bond Activation: Amination of Benzylic Fluorides

Houle

Savoie

Davies

et al. 2020

Chemistry A European J

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We describe the first thiourea‐catalyzed C−F bond activation. The use of a thiourea catalyst and Ti(OiPr)4 as a fluoride scavenger allows the amination of benzylic fluorides to proceed in moderate to excellent yields. Preliminary results with S‐ and O‐based nucleophiles are also presented. DFT calculations reveal the importance of hydrogen bonds between the catalyst and the fluorine atom of the substrate to lower the activation energy during the transition state.

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“…Hydrogen-bonding with a suitably situated proton donor is supported by computational 28 and experimental findings 24,29 . There is general agreement that, as pointed out long ago by Pauling 30 and utilized in recent development of catalytic reactions 31,32 , fluoride ions are effective H-bonding acceptors. There is nevertheless evidence 2,33 that, because of fluorine's exceptional electronegativity and low polarizability, a C–F bond may not participate in strong hydrogen-bonding 34 ; fluorocarbons are after all more hydrophobic than even hydrocarbons.…”

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confidence: 75%

Catalytic enantioselective addition of organoboron reagents to fluoroketones controlled by electrostatic interactions

et al. 2016

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Organofluorine compounds are central to modern chemistry, and broadly applicable transformations that generate them efficiently and enantioselectively are in much demand. Here we introduce efficient catalytic methods for additions of allyl and allenyl organoboron reagents to fluorine-substituted ketones. These reactions are facilitated by readily and inexpensively available catalysts and deliver versatile and otherwise difficult-to-access tertiary homoallylic alcohols in up to 98% yield and >99:1 enantiomeric ratio. Utility is highlighted by a concise enantioselective approach to synthesis of anti-parasitic drug Bravecto™ (presently sold as the racemate). Different forms of ammonium-organofluorine interactions play a key role in controlling enantioselectivity. The greater understanding of various non-bonding interactions afforded by these studies should facilitate future development of transformations involving fluoro-organic entities.

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

Cited by 26 publications

References 24 publications

Weak Intermolecular Hydrogen Bonds with Fluorine: Detection and Implications for Enzymatic/Chemical Reactions, Chemical Properties, and Ligand/Protein Fluorine NMR Screening

Weak Intermolecular Hydrogen Bonds with Fluorine: Detection and Implications for Enzymatic/Chemical Reactions, Chemical Properties, and Ligand/Protein Fluorine NMR Screening

Thiourea‐Catalyzed C−F Bond Activation: Amination of Benzylic Fluorides

Catalytic enantioselective addition of organoboron reagents to fluoroketones controlled by electrostatic interactions

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