Chemistry:Radical fluorination

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Radical fluorination is a type of fluorination reaction, complementary to nucleophilic and electrophilic approaches.[1] It involves the reaction of an independently generated carbon-centered radical with an atomic fluorine source and yields an organofluorine compound.

File:Radical fluorination.tif

Historically, only three atomic fluorine sources were available for radical fluorination: Fluorine (F2), hypofluorites (O–F based reagents) and XeF2. Their high reactivity, and the difficult handling of F2 and the hypofluorites, limited the development of radical fluorination compared to electrophilic and nucleophilic methods.[2] The uncovering of the ability of electrophilic N–F fluorinating agents to act as an atomic fluorine source[3] led to a renaissance in radical fluorination.[2]

Various methodologies have since been developed for the radical formation of C–F bonds.[1] The radical intermediates have been generated from carboxylic acids and boronic acid derivatives, by radical addition to alkenes, or C–H and C–C bond activations. New sources of atomic fluorine are now emerging, such as metal fluoride complexes.

Sources of atomic fluorine

Fluorine gas

Fluorine gas (F2) can act both as an electrophilic and atomic source of fluorine.[4] The weak F–F bond strength (36 kcal/mol (150 kJ/mol)[5]) allows for homolytic cleavage. The reaction of F2 with organic compounds is, however, highly exothermic and can lead to non-selective fluorinations and C–C cleavage, as well as explosions.[6] Only a few selective radical fluorination methods have been reported.[7][8] The use of fluorine for radical fluorination is mainly limited to perfluorination reactions.[5]

O–F reagents

The O–F bond of hypofluorites is relatively weak. For trifluoromethyl hypofluorite (CF3OF), it has been estimated to be 43.5 kcal/mol (182 kJ/mol).[9] The ability of trifluoromethyl hypofluorite to transfer fluorine to alkyl radicals is notably demonstrated by reacting independently generated ethyl radicals from ethene and tritium in the presence of CF3OF.[10] The high reactivity of hypofluorites has limited their application to selective radical fluorination. They can, however, be used as radical initiators for polymerization.[11]

XeF2

Xenon difluoride (XeF2) has mainly been used for radical fluorination in radical decarboxylative fluorination reactions.[12] In this Hunsdiecker-type reaction, xenon difluoride is used to generate the radical intermediate, as well as the fluorine transfer source.[13]

File:Xe decarboxylation.tif

XeF2 can also be used to generate aryl radicals from arylsilanes, and act as an atomic fluorine source to furnish aryl fluorides.[14]

File:Xe silanes.tif

N–F reagents

Selectfluor and N-fluorobenzenesulfonimide (NFSI) are traditionally used as electrophilic sources of fluorine, but their ability to transfer fluorine to alkyl radicals has recently been demonstrated.[3] They are now commonly used as fluorine transfer agents to alkyl radicals.[1]

Others

Examples of radical fluorination using bromine trifluoride (BrF3)[15] and fluorinated solvents[16] have been reported. Recent examples in radical fluorination suggest that in-situ generated metal fluoride complexes can also act as fluorine transfer agents to alkyl radicals.[citation needed]

Radical fluorination methodologies

Decarboxylative fluorination

The thermolysis of t-butyl peresters has been used to generate alkyl radicals in presence of NFSI and Selectfluor.[3] The radicals' intermediates were efficiently fluorinated, demonstrating the ability of the two electrophilic fluorinating agents to transfer fluorine to alkyl radicals.

File:Perester.tif

Carboxylic acids can be used as radical precursors in radical fluorination methods. Metal catalysts such as silver[17] and manganese[18] have been used to induce the fluorodecarboxylation. The fluorodecarboxylation of carboxylic acids can also be triggered using photoredox catalysis.[19][20] More specifically, phenoxyacetic acid derivatives have been shown to undergo fluorodecarboxylation when directly exposed to ultraviolet irradiation[21] or via the use of a photosensitizer.[22]

File:Carboxylic acid.tif

Radical fluorination of alkenes

Alkyl radicals generated from radical additions to alkenes have also been fluorinated. Hydrides[23] and nitrogen-,[24] carbon-,[25] and phosphorus-centered[26] radicals have been employed, yielding a wide range of fluorinated difunctionalized compounds.

Fluorination of boronic acid derivatives

Alkyl fluorides have been synthesized via radicals generated from boronic acid derivatives using silver.[27]

File:Radical fluorination of boronates.tif

C(sp3)–H fluorination

One major advantage of radical fluorination is that it allows the direct fluorination of remote C–H bonds. Metal catalysts such as manganese,[28] copper,[29] and tungsten[30] have been used to promote the reaction. Metal-free C(sp3)–H fluorinations rely on the use of radical initiators (triethylborane,[31] persulfates[32] or N-oxyl radicals[33]) or organic photocatalysts.[33]

Some methods have also been developed to selectively fluorinate benzylic C–H bonds.[34]

C–C bond activation

Cyclobutanols and cyclopropanols have been used as radical precursors for the synthesis of β- or γ-fluoroketones. The strained rings undergo C–C bond cleavage in presence of a silver[35][36] or an iron catalyst[36] or when exposed to ultraviolet light in presence of a photosensitizer.[37]

File:C—C bond activation.tif

Potential applications

One potential application of radical fluorination is for efficiently accessing novel moieties to serve as building blocks in medicinal chemistry.[38] Derivatives of propellane with reactive functional groups, such as the hydrochloride salt of 3-fluorobicyclo[1.1.1]pentan-1-amine, are accessible by this approach.[38]

References

  1. ↑ 1.0 1.1 1.2 Paquin, Jean-François; Sammis, Glenn; Chatalova-Sazepin, Claire; Hemelaere, Rémy (Aug 2015). "Recent Advances in Radical Fluorination". Synthesis 47 (17): 2554–2569. doi:10.1055/s-0034-1378824. 
  2. ↑ 2.0 2.1 Sibi, Mukund P.; Landais, Yannick (Feb 2013). "Csp3–F Bond Formation: A Free-Radical Approach". Angewandte Chemie International Edition 52 (13): 3570–3572. doi:10.1002/anie.201209583. PMID 23441011. 
  3. ↑ 3.0 3.1 3.2 Rueda-Becerril, Montserrat; Chatalova-Sazepin, Claire; Leung, Joe C. T.; Okbinoglu, Tulin; Kennepohl, Pierre; Paquin, Jean-François; Sammis, Glenn M. (Mar 2012). "Fluorine Transfer to Alkyl Radicals". Journal of the American Chemical Society 134 (9): 4026–4029. doi:10.1021/ja211679v. ISSN 0002-7863. PMID 22320293. 
  4. ↑ Bigelow, Lucius A. (Feb 1947). "The Action of Elementary Fluorine upon Organic Compounds". Chemical Reviews 40 (1): 51–115. doi:10.1021/cr60125a004. ISSN 0009-2665. PMID 20287884. 
  5. ↑ 5.0 5.1 Hutchinson, John; Sandford, Graham (1997). Chambers, Richard D.. ed. Elemental Fluorine in Organic Chemistry. Topics in Current Chemistry. Berlin, Heidelberg: Springer. pp. 1–43. doi:10.1007/3-540-69197-9_1. ISBN 978-3-540-63170-5. 
  6. ↑ Simons, J. H.; Block, L. P. (Oct 1939). "Fluorocarbons. The Reaction of Fluorine with Carbon". Journal of the American Chemical Society 61 (10): 2962–2966. doi:10.1021/ja01265a111. ISSN 0002-7863. 
  7. ↑ Grakauskas, Vytautas (Aug 1969). "Aqueous fluorination of carboxylic acid salts". The Journal of Organic Chemistry 34 (8): 2446–2450. doi:10.1021/jo01260a040. ISSN 0022-3263. 
  8. ↑ Bockemüller, Wilhelm (Jan 1933). "Versuche zur Fluorierung organischer Verbindungen. III. Über die Einwirkung von Fluor auf organische Verbindungen" (in German). Justus Liebigs Annalen der Chemie 506 (1): 20–59. doi:10.1002/jlac.19335060103. ISSN 1099-0690. 
  9. ↑ Czarnowski, J.; Castellano, E.; Schumacher, H. J. (Jan 1968). "The energy of the O–F bond in trifluoromethyl hypofluorite". Chemical Communications (20): 1255. doi:10.1039/c19680001255. 
  10. ↑ Wang, Nunyii; Rowland, F. S. (Nov 1985). "Trifluoromethyl hypofluorite: a fluorine-donating radical scavenger". The Journal of Physical Chemistry 89 (24): 5154–5155. doi:10.1021/j100270a006. ISSN 0022-3654. 
  11. ↑ Francesco, Venturini; Sansotera, Maurizio; Navarrini, Walter (November 2013). "Recent developments in the chemistry of organic perfluoro hypofluorites". Journal of Fluorine Chemistry. 2013 ACS Fluorine Award Issue: Professor Iwao Ojima 155: 2–20. doi:10.1016/j.jfluchem.2013.07.005. 
  12. ↑ Tius, Marcus A. (Jun 1995). "Xenon difluoride in synthesis". Tetrahedron 51 (24): 6605–6634. doi:10.1016/0040-4020(95)00362-C. 
  13. ↑ Patrick, Timothy B.; Darling, Diana L. (Aug 1986). "Fluorination of activated aromatic systems with cesium fluoroxysulfate". The Journal of Organic Chemistry 51 (16): 3242–3244. doi:10.1021/jo00366a044. ISSN 0022-3263. 
  14. ↑ Lothian, Aileen P.; Ramsden, Christopher A. (Jan 1993). "Rapid Fluorodesilylation of Aryltrimethylsilanes Using Xenon Difuoride: An Efficient New Route to Aromatic Fluorides". Synlett 1993 (10): 753–755. doi:10.1055/s-1993-22596. 
  15. ↑ Sasson, Revital; Rozen, Shlomo (Jan 2005). "Constructing the CF3 group; unique trifluorodecarboxylation induced by BrF3". Tetrahedron 61 (5): 1083–1086. doi:10.1016/j.tet.2004.11.063. 
  16. ↑ Yamada, Shigeyuki; Gavryushin, Andrei; Knochel, Paul (March 2010). "Convenient Electrophilic Fluorination of Functionalized Aryl and Heteroaryl Magnesium Reagents". Angewandte Chemie International Edition 49 (12): 2215–2218. doi:10.1002/anie.200905052. PMID 20162637. 
  17. ↑ Yin, Feng; Wang, Zhentao; Li, Zhaodong; Li, Chaozhong (Jun 2012). "Silver-Catalyzed Decarboxylative Fluorination of Aliphatic Carboxylic Acids in Aqueous Solution". Journal of the American Chemical Society 134 (25): 10401–10404. doi:10.1021/ja3048255. ISSN 0002-7863. PMID 22694301. 
  18. ↑ Huang, Xiongyi; Liu, Wei; Hooker, Jacob M.; Groves, John T. (Apr 2015). "Targeted Fluorination with the Fluoride Ion by Manganese-Catalyzed Decarboxylation". Angewandte Chemie International Edition 54 (17): 5241–5245. doi:10.1002/anie.201500399. ISSN 1521-3773. PMID 25736895. 
  19. ↑ Rueda Becerril, Montserrat; Mahé, Olivier; Drouin, Myriam; Majewski, Marek B.; West, Julian G.; Wolf, Michael O.; Sammis, Glenn M.; Paquin, Jean-François (Jan 2014). "Direct C–F Bond Formation Using Photoredox Catalysis". Journal of the American Chemical Society 136 (6): 2637–2641. doi:10.1021/ja412083f. PMID 24437369. 
  20. ↑ Ventre, Sandrine; Petronijević, Filip R.; MacMillan, David W. C. (Apr 2015). "Decarboxylative Fluorination of Aliphatic Carboxylic Acids via Photoredox Catalysis". Journal of the American Chemical Society 137 (17): 5654–5657. doi:10.1021/jacs.5b02244. PMID 25881929. 
  21. ↑ Leung, Joe C. T.; Chatalova-Sazepin, Claire; West, Julian G.; Rueda Becerril, Montserrat; Paquin, Jean-François; Sammis, Glenn M. (Oct 2012). "Photo-fluorodecarboxylation of 2-Aryloxy and 2-Aryl Carboxylic Acids". Angewandte Chemie International Edition 51 (43): 10804–10807. doi:10.1002/anie.201206352. ISSN 1521-3773. PMID 23023887. 
  22. ↑ Leung, Joe C. T.; Sammis, Glenn M. (Apr 2015). "Radical Decarboxylative Fluorination of Aryloxyacetic Acids Using N-Fluorobenzenesulfonimide and a Photosensitizer". European Journal of Organic Chemistry 2015 (10): 2197–2204. doi:10.1002/ejoc.201500038. ISSN 1099-0690. 
  23. ↑ Barker, Timothy J.; Boger, Dale L. (Aug 2012). "Fe(III)/NaBH4-Mediated Free Radical Hydrofluorination of Unactivated Alkenes". Journal of the American Chemical Society 134 (33): 13588–13591. doi:10.1021/ja3063716. PMID 22860624. 
  24. ↑ Li, Zhaodong; Zhang, Chengwei; Zhu, Lin; Liu, Chao; Li, Chaozhong (Feb 2014). "Transition-metal-free, room-temperature radical azidofluorination of unactivated alkenes in aqueous solution". Organic Chemistry Frontiers 1 (1): 100–104. doi:10.1039/c3qo00037k. 
  25. ↑ Kindt, Stephanie; Heinrich, Markus R. (Nov 2014). "Intermolecular Radical Carbofluorination of Non-activated Alkenes". Chemistry: A European Journal 20 (47): 15344–15348. doi:10.1002/chem.201405229. ISSN 1521-3765. PMID 25303212. 
  26. ↑ Zhang, Chengwei; Li, Zhaodong; Zhu, Lin; Yu, Limei; Wang, Zhentao; Li, Chaozhong (Sep 2013). "Silver-Catalyzed Radical Phosphonofluorination of Unactivated Alkenes". Journal of the American Chemical Society 135 (38): 14082–14085. doi:10.1021/ja408031s. PMID 24025164. 
  27. ↑ Li, Zhaodong; Wang, Zhentao; Zhu, Lin; Tan, Xinqiang; Li, Chaozhong (Nov 2014). "Silver-Catalyzed Radical Fluorination of Alkylboronates in Aqueous Solution". Journal of the American Chemical Society 136 (46): 16439–16443. doi:10.1021/ja509548z. PMID 25350556. 
  28. ↑ Liu, Wei; Huang, Xiongyi; Cheng, Mu-Jeng; Nielsen, Robert J.; Goddard, William A.; Groves, John T. (Sep 2012). "Oxidative Aliphatic C–H Fluorination with Fluoride Ion Catalyzed by a Manganese Porphyrin". Science 337 (6100): 1322–1325. doi:10.1126/science.1222327. ISSN 0036-8075. PMID 22984066. Bibcode: 2012Sci...337.1322L. https://authors.library.caltech.edu/35682/2/Liu.W.SM.pdf. 
  29. ↑ Bloom, Steven; Pitts, Cody Ross; Miller, David Curtin; Haselton, Nathan; Holl, Maxwell Gargiulo; Urheim, Ellen; Lectka, Thomas (Oct 2012). "A Polycomponent Metal-Catalyzed Aliphatic, Allylic, and Benzylic Fluorination". Angewandte Chemie International Edition 51 (42): 10580–10583. doi:10.1002/anie.201203642. ISSN 1521-3773. PMID 22976771. 
  30. ↑ Halperin, Shira D.; Fan, Hope; Chang, Stanley; Martin, Rainer E.; Britton, Robert (Mar 2014). "A Convenient Photocatalytic Fluorination of Unactivated C–H Bonds". Angewandte Chemie International Edition 53 (18): 4690–4693. doi:10.1002/anie.201400420. PMID 24668727. 
  31. ↑ Pitts, Cody Ross; Ling, Bill; Woltornist, Ryan; Liu, Ran; Lectka, Thomas (Oct 2014). "Triethylborane-Initiated Radical Chain Fluorination: A Synthetic Method Derived from Mechanistic Insight". The Journal of Organic Chemistry 79 (18): 8895–8899. doi:10.1021/jo501520e. PMID 25137438. 
  32. ↑ Zhang, Xiaofei; Guo, Shuo; Tang, Pingping (Jun 2015). "Transition-metal free oxidative aliphatic C–H fluorination". Organic Chemistry Frontiers 2 (7): 806–810. doi:10.1039/c5qo00095e. 
  33. ↑ 33.0 33.1 Amaoka, Yuuki; Nagatomo, Masanori; Inoue, Masayuki (Apr 2013). "Metal-Free Fluorination of C(sp3)–H Bonds Using a Catalytic N-Oxyl Radical". Organic Letters 15 (9): 2160–2163. doi:10.1021/ol4006757. PMID 23600550. 
  34. ↑ Koperniku, Ana; Liu, Hongqiang; Hurley, Paul B. (Jan 2016). "Mono- and Difluorination of Benzylic Carbon Atoms". European Journal of Organic Chemistry 2016 (5): 871–886. doi:10.1002/ejoc.201501329. ISSN 1099-0690. 
  35. ↑ Ishida, Naoki; Okumura, Shintaro; Nakanishi, Yuuta; Murakami, Masahiro (Jan 2015). "Ring-opening Fluorination of Cyclobutanols and Cyclopropanols Catalyzed by Silver". Chemistry Letters 44 (6): 821–823. doi:10.1246/cl.150138. https://www.jstage.jst.go.jp/article/cl/44/6/44_150138/_article. 
  36. ↑ 36.0 36.1 Ren, Shichao; Feng, Chao; Loh, Teck-Peng (Apr 2015). "Iron- or silver-catalyzed oxidative fluorination of cyclopropanols for the synthesis of β-fluoroketones". Organic & Biomolecular Chemistry 13 (18): 5105–5109. doi:10.1039/c5ob00632e. PMID 25866198. 
  37. ↑ Bloom, Steven; Bume, Desta Doro; Pitts, Cody Ross; Lectka, Thomas (May 2015). "Site-Selective Approach to β-Fluorination: Photocatalyzed Ring Opening of Cyclopropanols". Chemistry: A European Journal 21 (22): 8060–8063. doi:10.1002/chem.201501081. ISSN 1521-3765. PMID 25877004. 
  38. ↑ 38.0 38.1 Goh, Y. L.; Adsool, V. A. (Dec 2015). "Radical fluorination powered expedient synthesis of 3-fluorobicyclo[1.1.1]pentan-1-amine". Organic & Biomolecular Chemistry 13 (48): 11597–11601. doi:10.1039/C5OB02066B. PMID 26553141. 



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