Evidence for Ionic Intermediates in Fluorination of Alkenes with N–F Type of Reagents

Zupan, Marko; Škulj, Primož; Stavber, Stojan

doi:10.1246/cl.1998.641

Cited by 13 publications

(9 citation statements)

References 12 publications

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“…These mechanistic experiments conclude that Selectfluor proceeds via a two-electron mechanism in reaction with vinyl ethers, which may be extrapolated to reaction with glycals. Although these findings support previous conclusions, these are the first examples of using a hypersensitive vinyligous ether radical probe to study fluorination, and they are of particular importance to the use of Selectfluor in glycal chemistry.…”

Section: Resultssupporting

confidence: 86%

“…Several recent mechanistic studies have attempted to determine the mechanism of N−F fluorinating reagents. − ,− These studies based on kinetics, electrochemistry, or radical trapping inspired our synthesis of more sensitive molecules based on the hypersensitive radical probes containing a phenyl-cyclopropyl moiety. , Radicals formed on these molecules trigger the opening of a cyclopropyl ring at a rate of 10 11 sec -1 . , We reasoned that if a SET occurs during the reaction between Selectfluor and a glycal the radical cation formed would rearrange into a noncyclic olefin.…”

Section: Resultsmentioning

confidence: 99%

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Electrophilic Fluorination−Nucleophilic Addition Reaction Mediated by Selectfluor: Mechanistic Studies and New Applications

et al. 1999

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The electrophilic fluorination−nucleophilic addition reaction with Selectfluor-type reagents upon glycals has been studied and optimized. This reaction leads to selective fluorination at the 2-position with concomitant nucleophilic addition to the anomeric center. To understand the stereochemical outcome of this process, a mechanistic study has led to the discovery that, in the fucose series, Selectfluor adds specifically in a syn manner, yielding a 1-[TEDA-CH2Cl]-2-fluoro saccharide that anomerizes slowly to a more stable intermediate. The anomeric α/β distribution was studied as a function of reactants and conditions, and it was found that a judicious choice of protective group strategy can improve the stereoselectivity of both fluorination and nucleophilic addition. Furthermore, a hypersensitive radical probe was used to probe the reaction, and no product characteristic of a radical process was isolated, suggesting that no single electron transfer occurs during the attack of the glycal on Selectfluor. The importance of solvent effect, Selectfluor counterion, and stepwise procedure has also been discussed. This study has brought an important improvement of yields and a broader range of allowed nucleophiles such as secondary alcohols of carbohydrates, amino acids, phosphates, or phosphonates. This optimized process was further applied to the modification of important bioactive molecules, including the synthesis of fluorinated daunomycin and oleandrin analogues and the oxidation of thioglycosides to the corresponding sulfoxides.

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Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Electrophilic Fluorination−Nucleophilic Addition Reaction Mediated by Selectfluor: Mechanistic Studies and New Applications

et al. 1999

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“…An additional argument for the opened structure of the β-fluorocarbonium intermediate has also been presented in one of our previous studies, 27 where the formation of fluoroacetamides from alkenes and phenyl-substituted alkenes, which give less stable intermediates with NFTh in acetonitrile, was reported. We also observed recently that in the reaction of F-TEDA {F-TEDA = 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)} with norbornene rearranged products were formed, suggesting the carbonium ion nature of the intermediate, 35 while a photochemically generated norbornene ion-radical reacted with a nucleophile forming a radical intermediate and no rearranged products were observed. 36 However, the discussion of the possible mechanisms of fluorination of organic compounds with "electrophilic" fluorinating agent is still far from closed, as we are not able to clearly discriminate between two possible pathways of formation of the intermediate, namely direct fluorine transfer and a two-step pathway with cation-radical intermediates, which has been suggested many times in the case of the mild introduction of fluorine into phenyl-substituted alkenes with the N-F type of reagents to be the main reaction path.…”

Section: Resultssupporting

confidence: 51%

Effect of reaction conditions on the kinetic and activation parameters for the mild introduction of fluorine into α-substituted styrenes with AccufluorTM NFTh

Stavber

Pecan

Zupan

2000

J. Chem. Soc., Perkin Trans. 2

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Kinetic studies on fluorination of α-substituted styrenes with 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Accufluor TM NFTh) in acetonitrile or in acetonitrile in the presence of methanol or water as nucleophiles were carried out. These reactions exhibited overall second-order kinetics and formed Markovnikov type products. The corresponding second-order rate constants for fluorination of the studied substrates in the presence of methanol at 38.8 ЊC are: k 2 = 1.1 × 10 Ϫ3 M Ϫ1 s Ϫ1 for styrene (1a), 3.3 × 10 Ϫ2 M Ϫ1 s Ϫ1 for α-methylstyrene (1b) and 3.4 × 10 Ϫ2 M Ϫ1 s Ϫ1 for 1,1-diphenylethene (1c). The substitution of methanol as nucleophile by water had very little effect on the rate of the process. Solvent polarity variation (Grunwald-Winstein Y benzyl ) showed a similar small effect, too, indicating negligible change in the polarity of the rate-determining transition state in comparison with the reactants. Activation enthalpies (between 62 and 80 kJ mol Ϫ1 ) and activation entropies (between Ϫ74 and Ϫ32 J mol Ϫ1 K Ϫ1 ) were determined for fluorination of α-substituted styrenes with NFTh in acetonitrile in the presence of methanol and water as nucleophiles. Hammett correlation analysis of the reaction of substituted styrenes with NFTh in MeCN, MeCN-H 2 O and MeCN-MeOH gave reaction constants ρ ϩ of Ϫ1.48, Ϫ1.52 and Ϫ1.80, respectively, which support our belief in the mainly non-polar character of the rate-determining transition state of the studied reactions.

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“…7,8 Halogen transfer from the N type of reagents is very sensitive to reaction conditions, especially in the case of fluorine transfer where acetonitrile as solvent affects the reactions to form Ritter type fluoroamides, whereas in the presence of a nucleophile vicinal fluoro-hydroxy or fluoro-alkoxy products are formed. [25][26][27][28] In order to obtain kinetic and thermodynamic activation information comparable to that on fluorine transfer, 29 we decided first to investigate the products formed in bromination of norbornene with NBS in acetonitrile in the presence of water. From the crude reaction mixture, three main products were isolated by preparative GC, and their structure confirmed by comparison of the spectroscopic data with the literature.…”

Section: Resultsmentioning

confidence: 99%

The chemistry of organohalogenic molecules. Part 172. Kinetic studies of bromine transfer from N-bromo-succinimide to norbornene under protic conditions

Zupan¹,

Škulj²,

Stavber³

2002

Arkivoc

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Kinetic studies of bromofunctionalisation of cycloalkenes with N-bromosuccinimide (NBS) in acetonitrile-water under various conditions were carried out. Reaction with bicyclo[2,2,1]heptene (norbornene) in acetonitrile-water solution gave three main products: 2-exo-hydroxy-7-synbromo norbornane, 2-exo-hydroxy-7-anti-bromo norbornane and bromonortricyclane in 5:1:1 ratio. The course of the reaction obeys a simple rate equation:with k 2 = 0.35 M -1 s -1 at 10°C. In order to obtain further insight into the nature of the transition state during the bromine transfer from NBS, the effect of cycloalkene ring size was investigated and the following relative values were determined: 9.7 for the norbornene/cyclohexene pair, while a lower structural effect was found for the cyclopentene/cyclohexene pair, i.e. 1.2. For the bromination of norbornene the following activation parameters were determined: ∆H ‡ = 6.1 kcal mol -1 , ∆S ‡ = -38 cal mol -1 K -1 . The solvent polarity variation (Grunwald -Winstein Y) was used to obtain information about the nature of the rate determining step in bromine transfer from NBS to norbornene and m = 0.8 was determined, indicating a large change in the polarity of the transition state as compared to the reactants. The observed kinetic data suggests that the rate determining transition state in bromofunctionalisation of cyclic alkenes has a three-centered cyclic structure, the nucleophile also playing an important role.

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Evidence for Ionic Intermediates in Fluorination of Alkenes with N–F Type of Reagents

Cited by 13 publications

References 12 publications

Electrophilic Fluorination−Nucleophilic Addition Reaction Mediated by Selectfluor: Mechanistic Studies and New Applications

Electrophilic Fluorination−Nucleophilic Addition Reaction Mediated by Selectfluor: Mechanistic Studies and New Applications

Effect of reaction conditions on the kinetic and activation parameters for the mild introduction of fluorine into α-substituted styrenes with AccufluorTM NFTh

The chemistry of organohalogenic molecules. Part 172. Kinetic studies of bromine transfer from N-bromo-succinimide to norbornene under protic conditions

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