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Unique properties of fluorine lead to a boundless potential when introducing it into or-ganic molecules. As evidenced by the widespread presence of fluorine atoms in modern pharmaceutic compounds, the interest in controlled introduction and modification of fluorine moieties is unlikely to fade away. This sparkled immense progress in the de-velopment of versatile organofluorine reagents and reaction techniques. Still, taming fluorine for a specific application often brings unexpected challenges.

In the past 100 years, the arsenal of fluorination methods has expanded from brutal


use of elemental fluorine or hydrofluoric acid to more refined and targeted techniques, such as electrophilic fluorination and the fluorinated synthons approach. Having full ac-cess to such a knowledge base, and commercial availability of a plethora of fluorination reagents with different mechanisms of action, allows chemists to achieve the synthesis of organofluorine compounds easier than ever before. Of course, there is always room for improvement, and with such trends, the development of cost-effective, predictable, selective, and functional group-tolerant reagents can serve as a beacon for future gener-ations of organofluorine chemists.

In our work, we focused on pursuing the synthesis of organic materials with high dielectric constant (as discussed in Chapter 1) by utilizing unique electronegativity of fluorine atoms and aligning them in pendant, polarizable chains. To achieve this, we aimed to synthesize short PVDF-like fragments, that can be coupled to the monomer of choice.

Based on our previous experience, as well as thorough subject study (which was briefly described in this chapter) and literature precedents, we chose direct nucleophilic fluorination as the most straightforward, cost-effective, and versatile approach to reach the desired goal. Results of our efforts are further elucidated in Chapter 3.



[1] M. G. García and L. Borgnino. Chapter 1. Fluoride in the context of the environment.

In Fluorine: Chemistry, Analysis, Function and Effects, pages 3–21. The Royal Society of Chemistry, 2015. ISBN 978-1-84973-888-0.

[2] K. Christe and S. Schneider. Fluorine. Encyclopædia Britannica. URLhttps://


[3] Mindat.org. Fluorine. URLhttps://www.mindat.org/min-5396.html.

[4] G. W. Gribble. Naturally occurring organofluorines. The Handbook of Environ-mental Chemistry, pages 121–136.

[5] H. Yamamoto, T. Hiyama, K. Kanie, T. Kusumoto, Y. Morizawa, and M. Shimzu. Or-ganofluorine Compounds: Chemistry and Applications. Springer Berlin Heidelberg, 2013. ISBN 9783662041642.

[6] F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G. Orpen, and R. Taylor. Tables of bond lengths determined by x-ray and neutron diffraction. part 1. bond lengths in organic compounds. Journal of the Chemical Society, Perkin Transactions 2, pages S1–S19, 1987.

[7] B. Baasner, J. L. Adcock, R. E. Banks, A. Bulan, and J. Burdon. Houben-Weyl Methods of Organic Chemistry Vol. E 10a, 4th Edition Supplement: Organo-Fluorine Com-pounds - Fluorinating Agents and Their Application in Organic Synthesis. Thieme, 2014. ISBN 9783131815446.

[8] R.D. Chambers. Fluorine in Organic Chemistry. Blackwell, 2004. ISBN 9780849317903.


[9] K. L. Kirk. Fluorination in medicinal chemistry: Methods, strategies, and recent developments. Organic Process Research & Development, 12(2):305–321, 2008.

[10] V. Ivasyshyn, H. Smit, and R. C. Chiechi. Synthesis of a hominal bis(difluoromethyl) fragment. ACS Omega, 4(9):14140–14150, 2019.

[11] C&EN. Drugs approved in 2021, . URLhttps://cen.acs.org/content/cen/


[12] C&EN. Drugs approved in 2020, . URLhttps://cen.acs.org/content/cen/


[13] T. Liang, C. N. Neumann, and T. Ritter. Introduction of fluorine and fluorine-containing functional groups. Angewandte Chemie International Edition, 52(32):

8214–8264, 2013.

[14] M. J. Tozer and T. F. Herpin. Methods for the synthesis of gem-difluoromethylene compounds. Tetrahedron, 52(26):8619–8683, 1996.

[15] K. D. Dykstra, N. Ichiishi, S. W. Krska, and P. F. Richardson. Emerging fluorina-tion methods in organic chemistry relevant for life science applicafluorina-tion. In G. Haufe and F. R. Leroux, editors, Fluorine in Life Sciences: Pharmaceuticals, Medicinal Dia-gnostics, and Agrochemicals, Progress in Fluorine Science, pages 1–90. Academic Press, 2019.

[16] O. A. Tomashenko and V. V. Grushin. Aromatic trifluoromethylation with metal complexes. Chemical Reviews, 111(8):4475–4521, 2011.

[17] T. Furuya, A. S. Kamlet, and T. Ritter. Catalysis for fluorination and trifluoromethyl-ation. Nature, 473(7348):470–477, 2011.

[18] T. Besset, C. Schneider, and D. Cahard. Tamed arene and heteroarene trifluoro-methylation. Angewandte Chemie International Edition, 51(21):5048–5050, 2012.

[19] F. Swarts. Étude sur le fluo chloroforme [a study on fluorinated chloroform].

Académie Royale de Belgique, 24:474, 1892.

[20] G. Balz and G. Schiemann. Über aromatische fluorverbindungen, I.: Ein neues ver-fahren zu ihrer darstellung. Berichte der deutschen chemischen Gesellschaft (A and B Series), 60(5):1186–1190, 1927.

[21] G. A. Olah, J. T. Welch, Y. D. Vankar, M. Nojima, I. Kerekes, and J. A. Olah. Synthetic Methods and Reactions. 63. Pyridinium Poly(Hydrogen Fluoride)(30% Pyridine–

70% Hydrogen Fluoride): A Convenient Reagent for Organic Fluorination Reac-tions. The Journal of Organic Chemistry, 44(22):3872–3881, 1979.

[22] D. Bello and D. O’Hagan. Lewis acid-promoted hydrofluorination of alkynyl sulfides to generateα-fluorovinyl thioethers. Beilstein Journal of Organic Chemistry, 11:

1902–1909, 2015.


[23] J. A. Akana, K. X. Bhattacharyya, P. Müller, and J. P. Sadighi. Reversible C-F bond formation and the Au-catalyzed hydrofluorination of alkynes. Journal of the Amer-ican Chemical Society, 129(25):7736–7737, 2007.

[24] F. Nahra, S. R. Patrick, D. Bello, M. Brill, A. Obled, D. B. Cordes, A. M. Z. Slawin, D. O’Hagan, and S. P. Nolan. Hydrofluorination of alkynes catalysed by gold biflu-orides. ChemCatChem, 7(2):240–244, 2015.

[25] B. C. Gorske, C. T. Mbofana, and S. J. Miller. Regio- and stereoselective synthesis of fluoroalkenes by directed Au(I) catalysis. Organic Letters, 11(19):4318–4321, 2009.

[26] O. E. Okoromoba, J. Han, G. B. Hammond, and B. Xu. Designer HF-based fluorination reagent: Highly regioselective synthesis of fluoroalkenes and gem-difluoromethylene compounds from alkynes. Journal of the American Chemical Society, 136(41):14381–14384, 2014.

[27] S. C. Sondej and J. A. Katzenellenbogen. gem-Difluoro Compounds: A Convenient Preparation From Ketones and Aldehydes by Halogen Fluoride Treatment of 1,3-Dithiolanes. The Journal of Organic Chemistry, 51(18):3508–3513, 1986.

[28] J. Newton, D. Driedger, M. B. Nodwell, P. Schaffer, R. E. Martin, R. Britton, and C. M.

Friesen. A convenient synthesis of difluoroalkyl ethers from thionoesters using sil-ver(I) fluoride. Chemistry - A European Journal, 25(70):15993–15997, 2019.

[29] C. W. Tullock, F. S. Fawcett, W. C. Smith, and D. D. Coffman. The chemistry of sulfur tetrafluoride. I. the synthesis of sulfur tetrafluoride. Journal of the American Chem-ical Society, 82(3):539–542, 1960.

[30] P. Kirsch. Modern fluoroorganic chemistry: synthesis, reactivity, applications. John Wiley & Sons, 2013.

[31] G. S. Lal, G. P. Pez, R. J. Pesaresi, and F. M. Prozonic. Bis(2-methoxyethyl)aminosulfur trifluoride: a new broad-spectrum deoxofluorinating agent with enhanced thermal stability. Chemical Communications, pages 215–216, 1999.

[32] L. M. Yagupolskii, K. I. Petko, A. N. Retchitsky, and I. I. Maletina. The interaction of 2,6-dimethyl-3,5-dicarboxy-4-phenylpyridine with SF4in HF solution. Journal of Fluorine Chemistry, 67(1):5–6, 1994.

[33] M. Bugera, S. Trofymchuk, K. Tarasenko, O. Zaporozhets, Y. Pustovit, and P. K. Mykhailiuk. Deoxofluorination of aliphatic carboxylic acids: A route to trifluoromethyl-substituted derivatives. The Journal of Organic Chemistry, 84(24):

16105–16115, 2019.

[34] S. Trofymchuk, M. Bugera, A. A. Klipkov, V. Ahunovych, B. Razhyk, S. Semenov, A. Boretskyi, K. Tarasenko, and P. K. Mykhailiuk. Scalable approach to fluorinated heterocycles with sulfur tetrafluoride (SF4). The Journal of Organic Chemistry, 86 (17):12181–12198, 2021.


[35] S. Trofymchuk, M. Y. Bugera, A. A. Klipkov, B. Razhyk, S. Semenov, K. Tarasenko, V. S. Starova, O. A. Zaporozhets, O. Y. Tananaiko, A. N. Alekseenko, Y. Pustovit, O. Kiriakov, I. I. Gerus, A. A. Tolmachev, and P. K. Mykhailiuk. Deoxofluorination of (hetero)aromatic acids. The Journal of Organic Chemistry, 85(5):3110–3124, 2020.

[36] W. J. Middleton. New Fluorinating Reagents. Dialkylaminosulfur Fluorides. The Journal of Organic Chemistry, 40(5):574–578, 1975.

[37] K. C. Mange and W. J. Middleton. Fluorination of Cyclohexanols With 4-Morpholinosulfur Trifluoride [1]. Journal of Fluorine Chemistry, 43(3):405–413, 1989.

[38] R. P. Singh, U. Majumder, and J. M. Shreeve. Nucleophilic di- and tetrafluorination of dicarbonyl compounds. The Journal of Organic Chemistry, 66(19):6263–6267, 2001.

[39] F. Beaulieu, L.-P. Beauregard, G. Courchesne, M. Couturier, F. LaFlamme, and A. L’Heureux. Aminodifluorosulfinium tetrafluoroborate salts as stable and crys-talline deoxofluorinating reagents. Organic Letters, 11(21):5050–5053, 2009.

[40] S. Lepri, F. Buonerba, P. Maccaroni, L. Goracci, and R. Ruzziconi. Are carboxylic esters really refractory to DAST? on the fluorination ofα-hydroxyesters with DAST.

Journal of Fluorine Chemistry, 171:82–91, 2015.

[41] T. Umemoto, R. P. Singh, Y. Xu, and N. Saito. Discovery of 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride as a deoxofluorinating agent with high thermal stability as well as unusual resistance to aqueous hydrolysis, and its diverse fluorin-ation capabilities including deoxofluoro-arylsulfinylfluorin-ation with high stereoselectiv-ity. Journal of the American Chemical Society, 132(51):18199–18205, 2010.

[42] H. Hayashi, H. Sonoda, K. Fukumura, and T. Nagata. 2,2-Difluoro-1,3-dimethylimidazolidine (DFI). A new fluorinating agent. Chemical Communica-tions, pages 1618–1619, 2002.

[43] M. K. Nielsen, C. R. Ugaz, W. Li, and A. G. Doyle. PyFluor: A low-cost, stable, and selective deoxyfluorination reagent. Journal of the American Chemical Society, 137 (30):9571–9574, 2015.

[44] N. N. Yarovenko and M. A. Raksha. Fluorination with α-fluorinated amines.

Zhurnal Obshchei Khimii, 29:2159–2163, 1959.

[45] A. Takaoka, H. Iwakiri, and N. Ishikawa. F-propene-dialkylamine reaction products as fluorinating agents. Bulletin of the Chemical Society of Japan, 52(11):3377–3380, 1979.

[46] D.C. England, L.R. Melby, M.A. Dietrich, and R.V. Lindsey Jr. Nucleophilic reactions of fluoroolefins. Journal of the American Chemical Society, 82(19):5116–5122, 1960.


[47] I. I. Gerus, R. V. Mironets, E. N. Shaitanova, and V. P. Kukhar. Synthesis of new β-trifluoromethyl containing GABA and β-fluoromethyl containing N-benzylpyrrolidinones. Journal of Fluorine Chemistry, 131(2):224–228, 2010.

[48] M. A. Tius. Xenon difluoride in synthesis. Tetrahedron, 51(24):6605–6634, 1995.

[49] R. I. Troup, B. Jeffries, R. E. Saudain, E. Georgiou, J. Fish, J. S. Scott, E. Chiarparin, C. Fallan, and B. Linclau. Skipped fluorination motifs: Synthesis of building blocks and comparison of lipophilicity trends with vicinal and isolated fluorination motifs.

The Journal of Organic Chemistry, 86(2):1882–1900, 2021.

[50] S. Barata-Vallejo, B. Lantaño, and A. Postigo. Recent advances in trifluoromethyl-ation reactions with electrophilic trifluoromethylating reagents. Chemistry - A European Journal, 20(51):16806–16829, 2014.

[51] J. B. I. Sap, C. F. Meyer, N. J. W. Straathof, N. Iwumene, C. W. am Ende, A. A. Trabanco, and V. Gouverneur. Late-stage difluoromethylation: concepts, developments and perspective. Chemical Society Reviews, 50:8214–8247, 2021.

[52] B. R. Langlois, T. Billard, and S. Roussel. Nucleophilic trifluoromethylation: Some recent reagents and their stereoselective aspects. Journal of Fluorine Chemistry, 126 (2):173–179, 2005.

[53] E. T. McBee, Robert D. Battershell, and H. P. Braendlin. A new synthesis of per-fluoroalkylmagnesium halides. The Journal of Organic Chemistry, 28(4):1131–1133, 1963.

[54] O. R. Pierce, E. T. McBee, and G. F. Judd. Preparation and reactions of perfluoroal-kyllithiums1. Journal of the American Chemical Society, 76(2):474–478, 1954.

[55] A. Zanardi, M. A. Novikov, E. Martin, J. Benet-Buchholz, and V. V. Grushin. Direct cupration of fluoroform. Journal of the American Chemical Society, 133(51):20901–

20913, 2011.

[56] I. Ruppert, K. Schlich, and W. Volbach. Die ersten CF3-substituierten or-ganyl(chlor)silane. Tetrahedron Letters, 25(21):2195–2198, 1984.

[57] J. Wiedemann, T. Heiner, G. Mloston, G. K. Surya Prakash, and G. A. Olah. Direct preparation of trifluoromethyl ketones from carboxylic esters: Trifluoromethyla-tion with (trifluoromethyl)trimethylsilane. Angewandte Chemie InternaTrifluoromethyla-tional Edi-tion, 37(6):820–821, 1998.

[58] G. K. Surya Prakash and A. K. Yudin. Perfluoroalkylation with organosilicon re-agents. Chemical Reviews, 97(3):757–786, 1997.

[59] L. M. Yagupolskii, N. V. Kondratenko, and G. N. Timofeeva. Zhurnal Organicheskoi Khimii, 20:103–106, 1984.


[60] T. Umemoto and S. Ishihara. Power-variable electrophilic trifluoromethylating agents. S, Se, and Te(trifluoromethyl)dibenzothio, seleno, and -tellurophenium salt system. Journal of the American Chemical Society, 115(6):2156–

2164, 1993.

[61] T. Umemoto. Electrophilic perfluoroalkylating agents. Chemical Reviews, 96(5):

1757–1778, 1996.

[62] P. Eisenberger, S. Gischig, and A. Togni. Novel 10-I-3 hypervalent iodine-based com-pounds for electrophilic trifluoromethylation. Chemistry - A European Journal, 12 (9):2579–2586, 2006.

[63] J. Charpentier, N. Früh, and A. Togni. Electrophilic trifluoromethylation by use of hypervalent iodine reagents. Chemical Reviews, 115(2):650–682, 2015.

[64] I. Kieltsch, P. Eisenberger, and A. Togni. Mild electrophilic trifluoromethylation of carbon- and sulfur-centered nucleophiles by a hypervalent iodine(III)-CF3reagent.

Angewandte Chemie International Edition, 46(5):754–757.

[65] K. Stanek, R. Koller, and A. Togni. Reactivity of a 10-I-3 hypervalent iodine trifluoro-methylation reagent with phenols. The Journal of Organic Chemistry, 73(19):7678–

7685, 2008.

[66] A. T. Parsons and S. L. Buchwald. Copper-catalyzed trifluoromethylation of unac-tivated olefins. Angewandte Chemie International Edition, 50(39):9120–9123, 2011.

[67] Z. He, T. Luo, M. Hu, Y. Cao, and J. Hu. Copper-catalyzed di- and trifluoromethyl-ation ofα,β-unsaturated carboxylic acids: A protocol for vinylic fluoroalkylations.

Angewandte Chemie International Edition, 51(16):3944–3947.

[68] A. Studer. A “renaissance” in radical trifluoromethylation. Angewandte Chemie In-ternational Edition, 51(36):8950–8958, 2012.

[69] G. H. Rasmusson, R. D. Brown, and G. E. Arth. Photocatalyzed reaction of trifluoro-methyl iodide with steroidal dienones. The Journal of Organic Chemistry, 40(6):

672–675, 1975.

[70] R. N. Haszeldine. 603. the reactions of fluorocarbon radicals. part I. the reaction of iodotrifluoromethane with ethylene and tetrafluoroethylene. Journal of the Chem-ical Society, pages 2856–2861, 1949.

[71] V.C.R. Mcloughlin and J. Thrower. A route to fluoroalkyl-substituted aromatic com-pounds involving fluoroalkylcopper intermediates. Tetrahedron, 25(24):5921–5940, 1969.

[72] Y. Kobayashi and I. Kumadaki. Trifluoromethylation of aromatic compounds. Tet-rahedron Letters, 10(47):4095–4096, 1969.

[73] B. Folléas, I. Marek, J.-F. Normant, and L. Saint-Jalmes. Fluoroform: an efficient precursor for the trifluoromethylation of aldehydes. Tetrahedron, 56(2):275–283, 2000.


[74] T. Kitazume and N. Ishikawa. Palladium-catalyzed cross-coupling reactions between allyl, vinyl or aryl halide and perfluoroalkyl iodide with zinc and ultrasonic irradiation. Chemistry Letters, 11(1):137–140, 1982.

[75] M. Oishi, H. Kondo, and H. Amii. Aromatic trifluoromethylation catalytic in copper.

Chemical Communications, pages 1909–1911, 2009.

[76] T. Knauber, F. Arikan, G.-V. Röschenthaler, and L. J. Gooßen. Copper-catalyzed trifluoromethylation of aryl iodides with potassium (trifluoro-methyl)trimethoxyborate. Chemistry - A European Journal, 17(9):2689–2697, 2011.

[77] L. Chu and F.-L. Qing. Copper-mediated oxidative trifluoromethylation of boronic acids. Organic Letters, 12(21):5060–5063, 2010.

[78] C.-P. Zhang, Z.-L. Wang, Q.-Y. Chen, C.-T. Zhang, Y.-C. Gu, and J.-C. Xiao. Copper-mediated trifluoromethylation of heteroaromatic compounds by trifluoromethyl sulfonium salts. Angewandte Chemie International Edition, 50(8):1896–1900, 2011.

[79] H. Morimoto, T. Tsubogo, N. D. Litvinas, and J. F. Hartwig. A broadly applicable copper reagent for trifluoromethylations and perfluoroalkylations of aryl iodides and bromides. Angewandte Chemie International Edition, 50(16):3793–3798, 2011.

[80] M. Reichel and K. Karaghiosoff. Reagents for selective fluoromethylation: A chal-lenge in organofluorine chemistry. Angewandte Chemie International Edition, 59 (30):12268–12281, 2020.

[81] Y. Fujiwara, J. A. Dixon, R. A. Rodriguez, R. D. Baxter, D. D. Dixon, M. R. Collins, D. G.

Blackmond, and P. S. Baran. A new reagent for direct difluoromethylation. Journal of the American Chemical Society, 134(3):1494–1497, 2012.

[82] S.-Q. Zhu, Y.-L. Liu, H. Li, X.-H. Xu, and F.-L. Qing. Direct and regioselective C-H oxidative difluoromethylation of heteroarenes. Journal of the American Chemical Society, 140(37):11613–11617, 2018.

[83] T. T. Tung, S. B. Christensen, and J. Nielsen. Difluoroacetic acid as a new reagent for direct C-H difluoromethylation of heteroaromatic compounds. Chemistry - A European Journal, 23(72):18125–18128, 2017.

[84] W. Zhang, X.-X. Xiang, J. Chen, C. Yang, Y.-L. Pan, J.-P. Cheng, Q. Meng, and X. Li.

Direct C-H difluoromethylation of heterocycles via organic photoredox catalysis.

Nature Communications, 11(1):1–10, 2020.

[85] P. Kirsch, M. Lenges, A. Ruhl, D. V. Sevenard, and G.-V. Röschenthaler. Reductive di-merization of dithianylium salts and fluorodesulfuration: a new synthetic approach to tetrafluoroethylene substructures. Journal of Fluorine Chemistry, 125(6):1025–

1029, 2004.


[86] D. V. Sevenard, P. Kirsch, E. Lork, and G.-V. Röschenthaler. 2-Trifluoromethyl-1,3-dithianylium triflate: a convenient ‘masked’ electrophilic pentafluoroethylation re-agent. Tetrahedron Letters, 44(32):5995–5998, 2003.

[87] P. Kirsch, A. Ruhl, G.-V. Röschenthaler, and D. Sevenard. Bis(alkylthio)carbenium salts, (Merck KGaA), WO 02064583 (A3), 2002.

[88] V. A. Soloshonok. Fluorine-containing synthons. ACS Publications, 2005.

[89] S. Z. Zhu, Y. L. Wang, W. M. Peng, L. P. Song, and G. F. Jin. Synthesis of fluoroalkyl substituted heterocycles using fluorinecontaining building blocks. Current Organic Chemistry, 6(12):1057–1096, 2002.

[90] I. I. Gerus, O. A. Balabon, S. V. Pazenok, N. Lui, I. S. Kondratov, K. V. Tarasenko, E. N. Shaitanova, V. E. Ivasyshyn, and V. P. Kukhar. Synthesis and Properties of Polyfunctional Cyclicβ-Alkoxy-α,β-Unsaturated Ketones Based on 4-Methylene-1,3-Dioxolanes. European Journal of Organic Chemistry, 2018(27-28):3853–3861, 2018.

[91] E. N. Shaitanova, I. I. Gerus, O. A. Balabon, V. E. Ivasyshyn, K. V. Tarasenko, C. G.

Daniliuc, and G. Haufe. Synthesis of fluorine-containing 3-aminocyclopent-2-enones via intramolecular cyclization. European Journal of Organic Chemistry, 2020(46):7156–7163, 2020.

[92] M. Y. Bugera, K. V. Tarasenko, I. S. Kondratov, I. I. Gerus, B. V. Vashchenko, V. E. Ivasy-shyn, and O. O. Grygorenko. (Het)aryl difluoromethyl-substitutedβ-alkoxyenones:

Synthesis and heterocyclizations. European Journal of Organic Chemistry, 2020(9):

1069–1077, 2020.




Abstract: This chapter describes the synthesis of a discrete unit of hominal bis(gem-CF2).

The controlled introduction of fluorine atoms is a powerful synthetic tool to introduce di-pole moments with minimal impact to sterics. Polyvinylidene fluoride (PVDF) is a striking example of the influence of fluorine atoms, which impart ferroelectric behavior from the alignment of the dipole moments of CF2units, however, it is prepared via direct polymer-ization of vinylidene difluoride. Thus, a different synthetic pathway is required to pro-duce synthons containing discrete numbers of CF2groups in a hominal relation to each other. We found out that, in the case of short chains, the consecutive deoxofluorination of sequentially-introduced keto groups is inefficient, as it requires harsh conditions and decreasing yields at each step. To solve this problem, we combined the selective desulfur-ative fluorination of dithiolanes with pyridinium fluoride and the deoxofluorination of keto groups with morpholinosulfur trifluoride. This strategy is highly reproducible and scalable, allowing the synthesis of the hominal bis(gem-CF2) fragment as a shelf-stable tosylate, which can be used to install discrete chains of hominal bis(gem-CF2) on a variety of synthons and monomers.

The contents of this chapter were published in ACS Omega, American Chemical Society (10.1021/acso-mega.9b02131). I would like to thank Hans Smit for his contribution to this work.

3.1. I


The introduction of fluorine atoms into organic compounds has established itself as a powerful tool for tuning their chemical and physical properties with minimal impact on sterics. Fluorination often improves chemical resistance, thermal stability, biological and optical activity.[1] As a result, C-F bonds can be found in a wide variety of pharma-ceuticals, [2,3] agrochemicals, surfactants, dyes, and polymeric materials.[4,5]

The unique properties of the fluorine atom have drawn increasing attention to its potential application in the field of organic photovoltaics (OPV), where the introduc-tion of C-F bonds into the monomers of conjugated polymers can significantly improve their performance.[6,7] The systematic introduction of C-F bonds into the backbones of benzoditiophene-[8,9] and thiophene-containing[10–13] conjugated (co)polymers leads to an increase in power conversion efficiencies (PCEs) through a combination of subtle effects.[6] The utility of this approach is evident in the work of Zhao et al., where the combination of fluorinated donor and non-fullerene acceptors gave rise to OPV devi-ces with PCEs over 13 %.[14] In addition to direct backbone fluorination, several studies have explored the effects of introducing fluorinated pendant groups of semi-fluorinated alkyl chains.[15,16] Such modifications lead to favorable microstructural ordering and remarkably high electron mobilities. There is a growing focus on the electrostatics of pendant groups (i.e., permanent dipoles) in organic materials, from enhancing the dielec-tric constant of OPV materials[17,18] to stabilizing dopants in thermoelectrics.[19] A striking instance of the strong dipole moment created by C-F bonds is ferroelectricity in polyvinylidene difluoride (PVDF), which arises from the alignment of CF2groups en-abled by the – CH2CF2– repeating unit.[20–23]

We are interested in synthesizing discrete chains containing these hominal bis(gem-CF2) (i.e., CF2CH2CF2[24]) units that can be attached to small molecules and monomers to tailor their electrostatic properties. However, the synthesis of hominal CF2units has not been widely reported. Typically, such compounds are obtained in the mixture of telomers, as illustrated in Figure3.1.

Rf X

Haupschein et al. [25, 26] and other works [29, 31-35]


Terjeson et al. [28]

5 days at 90 °C

Figure 3.1 Background for this study: telomerization approach


Haupschein et al. accomplished the telomerization of 1,1-difluoroethylene under thermal conditions, yielding telomer iodides and bromides containing the hominal bis-(gem-CF2) fragment.[25] In later work, they prepared fluorocarbon halosulfates, acids, and derivatives that also contained such units [26]. However, in both cases, the hom-inal bis(gem-CF2) fragment is formed in a mixture with perfluorinated moieties. The synthesis also required large autoclaves and long, extensive heating followed by difficult fractional distillations. Similar difficulties were observed by others, via a variety of syn-thetic approaches: photochemically initiated reactions of bistrifluoromethyl disulphide with olefins,[27] thermal polymerization of SF5Br with fluoroolefins,[28] modification of other telomers,[29] telomerization of VDF withα,ω-diiodoperfluoroalkanes[30] and iodoperfluoroalkanes.[31–35]

It is apparently impossible to control the number of CH2CF2units by means of telo-merization; a fully synthetic and controllable approach that does not require harsh con-ditions, achievable in a typical laboratory environment, and is easily reproduced would be ideal. As discussed in Chapter 2, there are numerous methods of introducing fluorine atoms into organic molecules. Their development over the years has built up an array of tools, each with its pros and cons. For our research, we chose several criteria that will dictate our choice of strategy: synthetic availability, substrate scope, ease of labor-atory handling, scalability, cost-effectiveness, and the number of literature precedents (depicted in Figure3.2). Based on these parameters, we chose deoxofluorination with dialkylaminosulfur trifluorides (see Scheme2.6) as a primary approach.

SF4 , HF

Stepanov et al. [36]


... chain extension ...


R 2) acidic treatment

Hamel et al. [43]

Figure 3.2 Background for this study: synthetic approaches


Stepanov et al. demonstrated one of the first examples of synthetically-feasible com-pounds containing hominal bis(gem-CF2) fragment.[36] By treating pentane-2,4-dione with SF4for 3 h at 20C they managed to obtain a mixture that contained 8 % of 2,2,4,4-tetrafluoropentane and 70 % of 4,4-difluoropentan-2-one among other fluorinated prod-ucts. With increased reaction time (up to 40 h) and the addition of HF, they observed a shift toward the formation of 2,2,4,4-tetrafluoropentane as a predominant product. The same behavior was observed in the case of 2,2,4,4-tetrafluorohexane from hexane-2,4-dione. Even though this approach seems straightforward, reacting SF4 and HF in an autoclave is so dangerous that is forbidden nowadays in many (academic) laborator-ies (such as our own). As a result, more convenient and user-friendly reagents of in-troducing CF2groups have been developed,[37] largely as a class of dialkylaminosulfur tetrafluorides[38] and pyridinium poly(hydrogen fluoride) (PPHF, 70 % hydrogen fluor-ide, 30 % pyridine, also known as Olah reagent).[39]

Significant progress toward the user-friendly synthesis of hominal bis(gem-CF2 )-con-taining compounds using these methods has been done by O’Hagan and co-workers.

For example, Wang et al. introduced CF2groups into a palmitic acid analog by sequen-tial preparation of appropriate precursor ketones followed by deoxofluorination using diethylaminosulfur trifluoride (DAST).[40] The conversion to the CF2group occurred in modest yields and required neat DAST at elevated temperature. Jones et al. synthes-ized 2,2-dimethyl-5-phenyl-1,1,3,3-tetrafluorocyclohexane by means of the direct deox-ofluorination of a diketone precursor. [41] Attempts to use the same approach in the case of diketones, which did not have dimethyl-substituted methylene between keto groups were unsuccessful, yielding only complex and intractable products, which could be at-tributed to the high degree of enolization of such diketones. This behavior of diketones was also noted previously in the work by Singh et al.. [42] In both works by Stepanov et al.[36] and Wang et al.,[40] the route to compounds containing the hominal bis(gem-CF2) fragment included the formation of 3,3-difluoroketones as intermediates. 3,3-diflu-oroketones themselves are attractive building blocks, but are difficult to synthesize; how-ever, recent work by Hamel et al. demonstrated that the synthesis of 3,3-difluoroketones via a regioselective gold-catalyzed formal hydration of propargylic gem-difluorides.[43]

Given the relative scarcity of examples of the successful isolation of compounds con-taining hominal bis(gem-CF2) units, there does not appear to be any reasonable syn-thetic route to realizing our goal of incorporating them into pendant chains. In this work, we demonstrate an approachable, reproducible, and reliable strategy for synthes-izing compounds containing the hominal bis(gem-CF2) fragment from the precursor

Given the relative scarcity of examples of the successful isolation of compounds con-taining hominal bis(gem-CF2) units, there does not appear to be any reasonable syn-thetic route to realizing our goal of incorporating them into pendant chains. In this work, we demonstrate an approachable, reproducible, and reliable strategy for synthes-izing compounds containing the hominal bis(gem-CF2) fragment from the precursor