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Contemporary synthetic strategies in organofluorine chemistry

Nature Reviews Methods Primers volume 1, Article number: 47 (2021) Cite this article

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Abstract

Fluorinated molecules have a wide range of applications and are used as medicines, agrochemicals and refrigerants and in smartphone liquid crystal displays, photovoltaic solar cells, Teflon tapes and the coatings of textiles and buildings. Fluorination and fluoroalkylation — incorporation of a trifluoromethyl, difluoromethyl or monofluoromethyl group — are the major strategies used for the construction of carbon–fluorine bonds and fluorinated carbon–carbon bonds, respectively. The past two decades have witnessed a rapid growth in fluorination and fluoroalkylation methods thanks to the development of new reagents and catalysts. This Primer aims to provide an overview of state-of-the-art strategies in fluorination, trifluoromethylation, difluoromethylation and monofluoromethylation, with an emphasis on using C–H functionalization, although other strategies for fluorination and fluoroalkylation are also discussed. Further landmark achievements are expected in the fields of fluorination and fluoroalkylation as organofluorine compounds are used increasingly in everyday applications.

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Fig. 1: Outline of synthetic organofluorine chemistry.
Fig. 2: Incorporation of fluorine via C–H activation.
Fig. 3: Main palladium-catalysed and copper-catalysed C–H fluorination protocols.
Fig. 4: Main C–H fluorination protocols via carbon-centred radical intermediates.
Fig. 5: General overview of trifluoromethylation methods.
Fig. 6: Example trifluoromethylation protocols.
Fig. 7: Main protocols of introducing CF2H at sp3 carbon centres.
Fig. 8: Main protocols of introducing CF2H at (hetero)aromatic carbons and heteroatoms.
Fig. 9: Monofluoromethylating reagents and their use in C–H monofluoromethylation reactions.
Fig. 10: Applications of synthetic organofluorine chemistry in life sciences.

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Acknowledgements

This work is partially supported by the National Key Research and Development Program of China (2016YFB0101200), the National Natural Science Foundation of China (21632009, 21421002, 21672242, 21971252 and 21991122), Key Programs of the Chinese Academy of Sciences (KGZD-EW-T08), the Key Research Program of Frontier Sciences of CAS (QYZDJ-SSW-SLH049), Shanghai Science and Technology Program (18JC1410601) and the Youth Innovation Promotion Association CAS (2019256). R.B. acknowledges support from a Natural Sciences and Engineering Research Council (NSERC) of Canada Discovery Grant (2019-06368) and M.M. was supported by a NSERC CGSM award. The authors also thank the European Research Council (grant agreements 832994 and 789553) for financial support.

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Authors and Affiliations

  1. Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada

    Robert Britton & Michael Meanwell

  2. Chemistry Research Laboratory, University of Oxford, Oxford, UK

    Veronique Gouverneur & Gabriele Pupo

  3. Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Jin-Hong Lin, Chuanfa Ni, Ji-Chang Xiao & Jinbo Hu

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  1. Robert Britton
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Contributions

Introduction (J.H.); Experimentation, Applications, Reproducibility and data deposition, Limitations and optimizations: Fluorination (G.P. and V.G.), Trifluoromethylation (J.-H.L. and J.-C.X.), Difluoromethylation (C.N. and J.H.), Monofluoromethylation (M.M. and R.B.); Outlook (J.H.); Overview of Primer (all authors).

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Correspondence to Jinbo Hu.

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Nature Reviews Methods Primers thanks L. Hunter, N. Shibata and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Heteroelement

Any element in the periodic table that is not carbon or hydrogen.

Positron emission tomography

(PET). A functional imaging technique that uses radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities.

Swarts reaction

A fluorination method used to prepare alkyl fluorides from alkyl chlorides or bromides. The typical fluorination reagent is antimony(III) trifluoride in the presence of a catalytic amount of antimony(V) salts.

Balz–Schiemann reaction

A method for the production of aryl fluorides from primary aromatic amine via a diazonium tetrafluoroborate intermediate.

Halex reaction

The nucleophilic substitution reaction between an aryl or alkyl halide and the other halide ions.

Phase transfer catalysis

A process in which the rate of a reaction in a heterogeneous two-phase system is enhanced by the addition of a substance that transfers one of the reactants across the interface between the two phases.

C–H bond dissociation energies

Measures of the strength of C–H bonds, which can be defined as the standard enthalpy change when C–H is cleaved by homolysis to give a carbon radical and a hydrogen atom.

Density functional theory

A computational quantum mechanical modelling method to investigate the electronic structure or nuclear structure of atoms, molecules and the condensed phases.

Heteroatom

Any atom that is not a carbon atom or a hydrogen atom, similar to heteroelement.

Bioisosteres

Chemical substituents or groups with similar physical or chemical properties.

Minisci reaction

A nucleophilic radical substitution to an electron-deficient aromatic compound, most commonly involving the introduction of an alkyl group to a nitrogen-containing aromatic heterocycle.

Cryptand

A family of synthetic bicyclic and polycyclic multidentate ligands for a range of cations.

Atom economy

The conversion efficiency of a chemical process in terms of all atoms involved and the desired products produced.

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Britton, R., Gouverneur, V., Lin, JH. et al. Contemporary synthetic strategies in organofluorine chemistry. Nat Rev Methods Primers 1, 47 (2021). https://doi.org/10.1038/s43586-021-00042-1

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