The Nucleophilicity of Persistent α‐Monofluoromethide Anions

Zhang, Zhe; Puente, Ángel; Wang, Fang; Rahm, Martin; Mei, Yuncai; Mayr, Herbert; Prakash, G. K. Surya

doi:10.1002/ange.201605616

Angewandte Chemie

2016

DOI: 10.1002/ange.201605616

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The Nucleophilicity of Persistent α‐Monofluoromethide Anions

Zhe Zhang

Ángel Puente

Fang Wang

et al.

Abstract: a-Fluorocarbanions are key intermediates in nucleophilic fluoroalkylation reactions.A lthough frequently discussed, the origin of the fluorine effect on the reactivity of afluorinated CH acids has remained largely unexplored. We have nowinvestigated the kinetics of aseries of reactions of asubstituted carbanions with reference electrophiles to elucidate the effects of a-F, a-Cl, and a-OMe substituents on the nucleophilic reactivities of carbanions.

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Cited by 6 publications

References 65 publications

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Reagenzien für die selektive Fluormethylierung: Herausforderungen der Organofluorchemie

Reichel

Karaghiosoff

2020

Angewandte Chemie

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Die Einführung einer CH2F‐Gruppe in organische Moleküle ist in den letzten Jahren zweifellos zu einem sehr wichtigen Forschungsgebiet geworden. Aufgrund der vorteilhaften Eigenschaften von Organofluorverbindungen – wie ihre metabolische Stabilität – ist der Einbau der CH2F‐Gruppe als bioisosterer Ersatz für verschiedene funktionelle Gruppen eine attraktive Strategie, um z. B. neue Medikamente zu entwickeln. Darüber hinaus findet die Monofluormethyleinheit auch in der Agrochemie, in der pharmazeutischen Chemie und in der Feinchemie einen breiten Einsatz. Aufgrund des menschengemachten Klimawandels und des wachsenden Bedarfs an umweltfreundlichen industriellen Prozessen sind Alternativen zu den häufig verwendeten Fluormethylierungsmitteln auf FCKW‐ und HFBKW‐Basis (CH2FCl und CH2FBr) dringend erforderlich und im Montrealer Protokoll auch gefordert. Dies hat in letzter Zeit viele Forscher dazu veranlasst, die Entwicklung umweltfreundlicher Fluormethylierungsmittel zu entwickeln. Dieser Kurzaufsatz umfasst sowohl die klassischen als auch die neue Generation von Fluormethylierungsmitteln. Es werden Reagenzien und deren Vorläuferverbindungen diskutiert, die sowohl direkt als auch indirekt über elektrophile und nukleophile als auch radikalische Wege reagieren.

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Reagenzien für die selektive Fluormethylierung: Herausforderungen der Organofluorchemie

Reichel

Karaghiosoff

2020

Angewandte Chemie

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The Acidities of Nucleophilic Monofluoromethylation Reagents: An Anomalous α‐Fluorine Effect

Zheng

Jing

et al. 2021

Angewandte Chemie

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Fluorine incorporation into organic molecules is expected to lower the pKa of neighboring functionality via its strong electron‐withdrawing effect, and this strategy has been widely exploited in diverse disciplines. Herein, we report a striking anomalous α‐fluorine substitution effect on the α‐Csp3‐H acidity. We have experimentally measured the pKa values of a series of popular nucleophilic monofluoromethylating reagents α‐fluoro(phenylsulfonyl)methane derivatives as well as their C‐H analogues by Bordwell's overlapping indicator method in dimethyl sulfoxide solution. Contrary to expectations, we found that α‐fluorine substituent does not generally enhance but rather weaken the α‐Csp3‐H acidity of most (phenylsulfonyl)methane derivatives. DFT computations reproduce and provide insight into the anomalous α‐fluorine effect. A correlation was identified between the C‐H pKa of (phenylsulfonyl)methane derivatives and Mayr's nucleophilicity parameter (N) of the corresponding carbanions.

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Reagents for Selective Fluoromethylation: A Challenge in Organofluorine Chemistry

2020

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The introduction of a monofluoromethyl moiety has undoubtedly become a very important area of research in recent years. Owing to the beneficial properties of organofluorine compounds, such as their metabolic stability, the incorporation of the CH2F group as a bioisosteric substitute for various functional groups is an attractive strategy for the discovery of new pharmaceuticals. Furthermore, the monofluoromethyl unit is also widely used in agrochemistry, in pharmaceutical chemistry, and in fine chemicals. The problems associated with climate change and the growing need for environmentally friendly industrial processes mean that alternatives to the frequently used CFC and HFBC fluoromethylating agents (CH2FCl and CH2FBr) are urgently needed and also required by the Montreal Protocol. This has recently prompted many researchers to develop alternative fluoromethylation agents. This Minireview summarizes both the classical and new generation of fluoromethylating agents. Reagents that act via electrophilic, nucleophilic, and radical pathways are discussed, in addition to their precursors.

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The Nucleophilicity of Persistent α‐Monofluoromethide Anions

Cited by 6 publications

References 65 publications

Reagenzien für die selektive Fluormethylierung: Herausforderungen der Organofluorchemie

Reagenzien für die selektive Fluormethylierung: Herausforderungen der Organofluorchemie

The Acidities of Nucleophilic Monofluoromethylation Reagents: An Anomalous α‐Fluorine Effect

Reagents for Selective Fluoromethylation: A Challenge in Organofluorine Chemistry

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