FLUORINE CHEMISTRY VLADIMIR V. GRUSHIN Institute of Chemical Research of Catalonia (ICIQ - Institut Català d'Investigació Química) Avgda. Països Catalans 16, 43007, Tarragona, Spain Fluoroform as a feedstock for high-value fluorochemicals: novel trends and recent developments KEYWORDS: fluoroform; HFC-23, trifluoromethylation, transition metal reagents and catalysts, organofluorine compounds. Trifluoromethylated building blocks and intermediates are in exceptionally high demand for the synthesis of Abstractagrochemicals, pharmaceuticals, and specialty materials. Readily available, nontoxic and ozone-friendly fluoroform (CHF3, trifluoromethane, HFC-23), a side-product of Teflon manufacturing and a potent greenhouse gas, would be by far the best CF3 source for a variety of trifluoromethylation reactions. Chemoselective activation of fluoroform, however, is highly challenging. This article provides an overview of synthetic methods employing fluoroform with emphasis on new trends and most recent, promising developments in the area. INTRODUCTION acids are not effective. Even in bright sunlight, there is no reaction with bromine; with chlorine, in bright sunlight, and in In its April 3, 1890 issue, the Nature magazine highlighted (1) a quartz vessel, the hydrogen is replaced slowly to yield CF3Cl. two papers on the same subject presented at the then most With fluorine a vigorous reaction occurs, but without recent meeting of the Chemical Society of Paris. The topic carbonization, and yields carbon tetrafluoride and hydrogen was the isolation of fluoroform, CHF3, the last member of the fluoride... With regard to the physiological effect, it is sufficient haloform family to be discovered, by Chabrié and Meslans. to state that exposure of a guinea pig for one hour to a Both scientists had prepared and isolated fluoroform from the 50-50% mixture of CHF3 and air by volume caused no effect reactions of chloroform or iodoform with silver fluoride, whatsoever. The animal was not apparently aware of the determined its density, and probed its alkaline hydrolysis (1-4). presence of the gas. In a second experiment, a guinea pig Since then, however, fluoroform had remained an exotic and was maintained in an “artificial atmosphere” of 80 volumes of virtually unstudied compound for over 40 years (5) until in the fluoroform and 20 volumes of oxygen for one hour, and again mid-1930s Ruff (6) and Henne (7) developed the synthesis of did not exhibit any symptoms of discomfort, though it was fluoroform from HgF and CHI3 or CHF2Br, respectively. These patiently aware of unusual conditions, at the start of the methods enabled, for the first time, the preparation of pure experiment” (7). fluoroform in sufficient quantities for thorough reactivity and biological activity studies. The results of those studies by In April 1938, one year after Henne’s report (7) on fluoroform Henne led him to identify fluoroform as a “substance from the Ohio State University, a recent PhD graduate of the characterized by exceptional physiological and chemical same university, 27-year-old Roy Plunkett, made one of the inertness” (7). In his 1937 report, Henne wrote: most important and fascinating discoveries of the 20th century. While researching new refrigerants at Kinetic “Fluoroform is characterized by its great stability, and almost Chemicals Inc., a joint venture between DuPont and Frigidaire complete chemical as well as physiological inertness. White (General Motors), Plunkett and his technician J. Rebok hot silica decomposes it very slowly, though completely, thus accidentally discovered polytetrafluoroethylene (8, 9), making it possible to analyze it by means of the method currently widely known under the DuPont trademark of previously recommended, and determining its molecular Teflon®. This groundbreaking finding marked the birth of weight at the same time (assuming that it behaves as a fluoropolymer chemistry (10), a new field of science that, in 75 perfect gas). Decomposition by calcium oxide is also slow, years of its existence, has brought numerous previously and proceeds only at elevated temperature (red hot), where unimaginable benefits into almost all aspects of human life. it is complete. Metals are indifferent to it. Caustic solutions, Applications of Teflon® and other fluoropolymers span a even at the boiling point, are without effect. Concentrated broad range from high-performance materials for the nuclear Chimica Oggi - Chemistry Today - vol. 32(3) May/June 2014 81 power, automotive, aviation and electronic industries to non- both academia and industry toward use of fluoroform as a stick cookware and unique all-weather apparel. As it is hard CF3 source have not produced a practicable process. In the to imagine modern life without fluoropolymers, their last few years, however, novel reactivity patterns for CHF3 production is fully expected to continue on an increasingly have been discovered, which hold promise for use of large scale. fluoroform as a raw material for the synthesis of trifluoromethylated compounds on a larger scale. This article is What is the connection between fluoroform and aimed at providing an overview and analysis of recent fluoropolymers? Fluoroform is a side-product of the process to progress in the area of fluoroform activation toward the manufacture chlorodifluoromethane CHClF2 (HCFC-22; R-22) development of new trifluoromethylation and related that is used in refrigeration and air-conditioning but largely methods. pyrolyzed to make tetrafluoroethylene, the monomer of Teflon®. The industrially employed Swarts reaction of chloroform CHCl3 with HF to produce CHClF2 inevitably gives BASIC PROPERTIES OF FLUOROFORM rise to small quantities of fluoroform CHF3 (HFC-23; R-23) as a result of overfluorination. Although the thus side-generated Fluoroform (MW = 70.0; CAS number 75-46-7) is a nontoxic, CHF3 accounts for only a few percent of the targeted non-flammable, odourless, and colourless gas (b.p. = -82°C) compound, HCFC-22, the massive worldwide production of that is slightly soluble in water and soluble in many organic the latter currently yields around 20,000 metric tons of solvents. The high thermodynamic stability of fluoroform fluoroform annually (11-13). follows from the C-H and C-F bond dissociation energies of 106 and 127 kcal mol-1, respectively (17,18). The lack of The side-generated fluoroform lacks industrial applications on reactive sites on the CHF3 molecule makes it kinetically inert. a scale commensurate with that of its production. As a result, Fluoroform is a weak C-H acid (pKa = 27 in water), orders of large quantities of the unavoidably generated chemically magnitude less acidic than chloroform CHCl3 (19). Numerous inert, nontoxic, non-flammable, and ozone-friendly fluoroform reports have been published on hydrogen bonding of are conventionally released into the atmosphere (11). In fluoroform to various H-bond acceptors. Only strong bases, recent 15 years, however, there has been growing serious however, can deprotonate fluoroform quite efficiently to - concern over this simplest and cheapest way of disposal of produce CF3 equivalents. The latter is highly unstable but HFC-23 waste-streams (11-14). Fluoroform has a formidable under certain conditions may be used to trifluoromethylate 4 global warming potential of >10 that of CO2 (second only to some electrophiles, such as non-enolisable carbonyl SF6) and a long, >250-year atmospheric lifetime. The compounds. These transformations have been reviewed (20- continuing release of fluoroform into the atmosphere would 23) and therefore will be summarized here only briefly (in the likely lead to an ecological disaster, the so-called “climate following section). bomb”, the risk of which is currently higher because of the recent ending of the carbon credit trading program (15). DEPROTONATION OF FLUOROFORM: THE TRADITIONAL Two obvious solutions are available to the HFC-23 problem ORGANIC APPROACH (14). One is to treat the side-produced fluoroform as a chemical waste to be eliminated by means of thermal In the mid-1950s, Hine and co-workers (24) found that of a oxidation, catalytic hydrolysis, or plasma destruction. None of series of trihalomethanes CHX3, where X = F, Cl, Br in various these methods is without significant problems that include combinations, fluoroform was by far the least susceptible to high energy consumption required to burn flame-retarding basic hydrolysis. Kinetic data were successfully obtained for CHF3, the need for special materials for an incinerator that the reactions of all of the trihalomethanes with NaOH in should operate at 1200°C in the presence of strongly corrosive aqueous dioxane, except for fluoroform, whose hydrolysis was HF, costly catalysts and the potential generation of highly “too slow to measure”. toxic substances such as dioxins and fluorophosgene. Furthermore, neutralization of the HF produced results in large In 1991, Shono’s group (25) reported that fluoroform could be quantities of inorganic fluorides, which raises environmental deprotonated with strong bases such as NaH and t-BuOK in - concerns. DMF. The CF3 equivalent produced in this way was shown to add across the C=O bond of benzaldehyde to furnish The vastly preferred alternative to the destruction of the side- α-(trifluoromethyl)benzyl alcohol in 28-40 percent yield. Much produced fluoroform would be its utilization as a feedstock for better yields of up to 92 percent were achieved with valuable fluorochemicals. That would “kill two birds with one electrochemically generated