sign in sign up
<<
Home , Carbon tetrafluoride, Chlorodifluoromethane, Difluorocarbene, Fluoroform, Tetrafluoroethylene, Trifluoromethylation

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: ; HFC-23, , 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 , 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 , 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 tetrafluoride and hydrogen was the isolation of fluoroform, CHF3, the last member of the ... 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 or 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 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 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 (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 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 span a even at the , 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 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 , 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 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 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 , 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 2-pyrrolidonide as the base in stone” as the currently unwanted yet inevitably generated the presence of hexamethyldisilazane (HMDS). Using this material to be eliminated would find applications in the protocol, Shono prepared a series of trifluoromethylated production of highly useful chemicals. In particular, secondary alcohols from the corresponding aldehydes. trifluoromethylated building blocks and intermediates are in great and continuously growing demand from the Following Shono’s pioneering work (25), considerable progress agrochemical, pharmaceutical and specialty materials in the area was made in the late 1990s – early 2000s by four industries. Fluoroform would be by far the best CF3 source for groups of industrial and academic scientists in France (26-33). the synthesis of trifluoromethylated compounds from the Barhdadi, Troupel and Périchon (26) demonstrated that CHF3 perspective of not only availability and cost, but also ecology, can be efficiently deprotonated with the strong base safety and atom-economy (16). Fluoroform’s “exceptional generated from iodobenzene on a cathode plated with chemical inertness” (7), however, makes this goal exceedingly electrolytically deposited cadmium. Performing this challenging. Indeed, over two decades of intensive studies in transformation in DMF in the presence of an aldehyde gave

82 Chimica Oggi - Chemistry Today - vol. 32(3) May/June 2014 rise to the corresponding trifluoromethyl secondary alcohols in 3-acylenamines, disulfides and diselenides. The slow - 12-76 percent yield. Critical contributions to the area of generation of [(SiMe3)2N] under such conditions allowed to fluoroform activation via deprotonation under non- trifluoromethylate a few enolisable ketones, albeit in low to electrochemical conditions were made by Roques and moderate yield. Aldehydes and esters, however, could not be Russell (27, 28), Marek and Normant with co-workers (29, 30), trifluoromethylated under such conditions. Interestingly, in + - and Langlois’ group (31, 32). A summary of their work is certain cases [Me4N] F could be used in sub-stoichiometric presented in Scheme 1. It is worth to emphasize that it is quantities (20 percent). Deprotonation of CHF3 with N(SiMe3)3/ + - Folléas et al. who clearly underscored the importance of the [Me4N] F in the presence of N-formylmorpholine in THF gave need to develop trifluoromethylation methods using side- isolable (N-morpholinyl)C(H)(CF3)(OSiMe3) (32) that was used produced fluoroform as a CF3 source (29, 30). to trifluoromethylate ketones (32), aldehydes (32), and disulfides (33).

As described above and shown in Scheme 1, the trifluoromethylation reactions with fluoroform/base are conventionally performed in amide solvents in order to convert the - carbanionic “CF3 ” intermediate to the more stable hemiaminolate. The most widely used amide solvent for this purpose, DMF, is more costly than some other organic solvents such as toluene, ether, and THF. It is, therefore, desirable to replace DMF with a cheaper solvent for use

of CHF3 in trifluoromethylation reactions. As early as 2000, Large, Roques and Langlois (31) reported that benzophenone and fluorenone could be successfully trifluoromethylated in THF in the presence of only 0.3 equiv of DMF. Moreover, they also demonstrated that trifluoromethylation of dioctyl

disulfide with CHF3/N(SiMe3)3/ + - [Me4N] F could be performed in pure THF, in the absence of DMF or any other amide solvent, to give Scheme 1. Trifluoromethylation of carbonyl and sulfur electrophiles with CHF3/base in DMF (27-31). C8H17SCF3 in 66 percent yield (31). Most recently, further progress was It was established (27-30) that DMF plays a dual role in the made toward the development of trifluoromethylation reactions (Scheme 1), both as a solvent and as an methods with CHF3 in non-amide solvents. For instance, Prakash - electrophile that adds the CF3 generated upon et al. (34) found that the treatment of Me3SiCl with CHF3/ - deprotonation of CHF3. The resultant hemiaminolate was KHMDS, a previously widely used (27, 28, 31) “CF3 ” source, in detected by NMR (28, 30) and shown to serve as a reservoir of toluene at -78°C produced Me3SiCF3 in 80 percent yield. Other the vastly less stable trifluoromethyl anion. Although this R3SiCl were converted to R3SiCF3 (42-78 percent yield) and hemiaminolate was found to decompose only slowly (hours) some non-enolisable ketones R(R’)CO to the corresponding at -20°C, instantaneous decomposition was observed at room tertiary alcohols R(R’)(CF3)COH (38-81 percent yield) with temperature (30). Therefore, the deprotonation of fluoroform CHF3/KHMDS in ether. Simultaneously, Shibata’s group (35) in DMF for trifluoromethylation reactions had to be conducted trifluoromethylated a series of non-enolisable aldehydes and at low temperatures, conventionally at -10 / -40°C. As shown ketones with CHF3 and Schwesinger’s phosphazene base in Scheme 1, quenching the hemiaminolate with a strong t-Bu-P4 in THF. The CHF3/t-Bu-P4 system was later also used by acid produced fluoral hydrate in high yield (27-30). Ring- others (36). Therefore, DMF can be replaced with lower cost substituted benzaldehydes (27-30), methyl benzoate (28), and solvents for certain trifluoromethylation reactions based on the benzophenone (31) gave the corresponding CHF3 deprotonation strategy. Ironically, however, this trifluoromethylated products. The bases efficiently used for replacement is a trade-off as it raises rather than lowers the these reactions were KN(SiMe3)2 (KHMDS) (27, 28, 31), cost because of the need for much more expensive bases, NaN(SiMe3)2 (NaHMDS) (27, 28, 31), MeSOCH2K (27-30), KHMDS (34) and t-Bu-P4 (35, 36), and lower temperatures (34). MeSOCH2Na (27, 28, 31), t-BuOK (27, 28, 31), and NaH (31). Furthermore, highly flammable ether as a replacement for DMF (34) is unlikely to be considered as a solvent in industrial settings Langlois and co-workers (31) found that fluoroform could be for safety reasons. - efficiently deprotonated with [(SiMe3)2N] generated in situ + - from N(SiMe3)3 and anhydrous [Me4N] F or RONa (R = Me, Et, Two recent papers (37, 38) on fluoroform activation with alkali i-Pr) in DMF for trifluoromethylation of carbonyl compounds, metal bases are worth discussing herein, despite the fact that

Chimica Oggi - Chemistry Today - vol. 32(3) May/June 2014 83 both deal with difluoromethylation, not trifluoromethylation of fluoroform in the “Latest Developments” section of a review (Scheme 2). Mikami and co-workers (37) difluoromethylated a article (16) that appeared on the Web on April Fool’s Day 2011. series of lithium enolates derived from lactones and protected As it turned out later in the same year (41), however, that was lactams as well as a few esters and one ketone. Thomoson not a joke. Two months after the disclosure (16), Popov, and Dolbier (38) most recently reported a simple and efficient Lindeman and Daugulis (39) reported the zincation reaction of method for the synthesis of difluoromethoxy and a series of 1H-perfluoroalkanes (RfH), CHF3 included, and the difluorothiomethoxy aromatic derivatives from CHF3/alkali use of this reaction for Cu-catalyzed fluoroalkylation of aryl and the corresponding phenols and thiophenols. The iodides (Scheme 3). This transformation readily occurs in mechanism of this reaction likely involves deprotonation of 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU) as a fluoroform by KOH, followed by fluoride elimination to solvent with bis-(2,2,6,6-tetramethylpiperidido)zinc and 10 produce (38). The latter might also mediate percent CuCl and 20 percent phenanthroline at 90°C to the difluoromethylation of the enolates, even though a furnish the corresponding fluoroalkylarenes. The reaction is different mechanism was proposed (37), albeit without efficient for the higher 1H-perfluoroalkanes but substantially unambiguous evidence. It is worth to note that CHF2 less so for fluoroform. Only one substrate, highly reactive ethyl derivatives are also used in the preparation of biologically 2-iodobenzoate, was trifluoromethylated in this way to give a active compounds. mixture of 2-CF3C6H4CO2Et (51 percent) and side-produced 2-C2F5C6H4CO2Et (ca. 10 percent) even in the presence of super-stoichiometric quantities of phenanthroline.

As the CF3 and C2F5 derivatives could not be separated by conventional means, preparative HPLC was used to isolate the desired trifluoromethylated product in Scheme 2. Difluoromethylation reactions with CHF3/base (37, 38). pure form. The side formation

of C2F5 and sometimes higher Rf derivatives in Cu-mediated trifluoromethylation reactions is ACTIVATION OF FLUOROFORM WITH TRANSITION METALS: THE a frequently encountered, serious problem (16). α-Elimination

NOVEL ORGANOMETALLIC APPROACH of fluoride from CuCF3, followed by migratory insertion of the resultant CF2 species into the as yet unreacted Cu-CF3 bond The major problem with the fluoroform deprotonation gives rise to CuC2F5, which then pentafluoroethylates the - methodology (see above) is the low stability of the CF3 substrate. As a result, the desired trifluoromethylated product equivalents that easily eliminate fluoride to produce is contaminated with its C2F5 counterpart, which is difficult if difluorocarbene. To avoid the formation of CF2, deprotonation not impossible to separate. of CHF3 must be conducted at low temperatures, which is uneconomical. Moreover, many types of important electrophiles, such as organic halides, cannot be efficiently trifluoromethylated using the deprotonation methodology. A Scheme 3. Cu-catalyzed fluoroalkylation of aryl iodides via zincation of 1H-perfluoroalkanes (39). potentially more industrially feasible alternative would be direct metalation of the H-CF3 bond to produce a trifluoromethyl organometallic compound that is stable yet capable of transferring the CF3 Less than one month after the communication by the group to organic substrates. In the late 1990s, a number of Daugulis group appeared on the Web (39), an article by attempts were made to prepare CuCF3 and ZnCF3 derivatives Goldman et al. came out (40), reporting a novel reaction of in one step from fluoroform and various organocopper and H-CF3 oxidative addition to a pincer Ir(I) complex (Scheme 4). -zinc compounds (30). Although brilliantly conceived, this idea The highly reactive [(PCP)Ir] species generated upon loss of was not fulfilled back then. It took over 10 years before the first norbornene from the Ir centre oxidatively added the C-H reports on CHF3 activation with transition metals appeared in bond of fluoroform at as low as -10°C. At room temperature, the literature. In 2011, three different groups independently the resultant trifluoromethyl Ir(III) hydride underwent α-F- reported reactions of fluoroform leading directly to the elimination, followed by reductive elimination of HF. formation of CF3 derivatives of Zn (39), Ir (40) and Cu (41).

The first mentioning of fluoroform activation with a transition metal complex was the public disclosure Scheme 4. Activation of fluoroform via oxidative addition to an Ir(I) pincer complex (40). of the cupration reaction

84 Chimica Oggi - Chemistry Today - vol. 32(3) May/June 2014 The most synthetically significant reaction of fluoroform not only by means of expected O···HCF3 hydrogen bonding, activation with a transition metal complex is the but also via K···F contacts involving two of the three F atoms aforementioned cupration (41). We have found that CuCl of the CHF3 molecule. The total of eight acidic (H, Cu, K) and reacts with 2 equiv of t-BuOM (M = K, Na) in DMF to give basic (O, O, C, F, F) centres interacting with one another quantitatively novel ate complexes [M(DMF)n][Cu(OBu-t)2] (n provide a low-energy reaction pathway for the synchronous = 1 for M = K; n = 2 for M = Na). Both the Na and K H-CF3 bond breakage and Cu-CF3 bond formation with ≠ -1 dialkoxycuprates have been isolated and structurally ΔG 298K = 21.5 kcal mol calculated for the gas phase. characterized. Pre-isolated or generated in situ, these complexes readily cuprate CHF3 at room temperature and As seen from the above, the plays a peculiar atmospheric pressure to give CuCF3 in over 90 percent yield dual role in the cupration of fluoroform. After the reaction, the within minutes (Scheme 5). Isolation of the immediate product potassium cation slowly decomposes the CuCF3 product and should therefore be sequestered with TREAT HF in order to avoid yield losses (41). During the reaction, however, the presence of the K+ is key to lowering the activation barrier to the transformation. Both effects originate from electrophilic interactions Scheme 5. Direct cupration of fluoroform (41, 42). of the alkali metal cation with the fluorine

atoms of the CF3 group. of the cupration reaction is highly challenging because of Indeed, both the cupration reaction of fluoroform with its slow decay via α-F-elimination. This undesired reaction is [M(DMF)n][Cu(OBu-t)2] and the decomposition of its CuCF3 prompted by electrophilic attack of the potassium cations product are faster for M = Na than for M = K, as the former is present in the reaction solution on the fluorine atoms of the more electrophilic than the latter (41). Consequently, the use

CuCF3. There are two ways to avoid this decomposition. of [Na(DMF)2][Cu(OBu-t)2] for the cupration of fluoroform is + One is to remove the K from the system altogether. disadvantageous because of the lower stability of the CuCF3 This can be efficiently done by sequestering the potassium product toward Na+. cations in the form of poorly DMF-soluble KF upon addition of a source of HF, such as Et3N(HF)3 (TREAT HF) or Py(HF)n. The cupration of fluoroform, followed by stabilization with As a result, a solution of “ligandless” CuCF3 is produced TREAT HF furnishes DMF solutions of “ligandless” CuCF3 in ≥ 90 that is stable for days at ambient temperature (41), yet percent overall yield (see above and Scheme 5). This low-cost highly reactive toward a variety of substrates (see below). reagent that is stable for a few days at room temperature, The other way to suppress the K+-induced decomposition exhibits a remarkable ability to efficiently trifluoromethylate a of the CuCF3 is to diminish the electrophilicity of the variety of substrates, both inorganic and organic (Scheme 7). potassium ion. This has been achieved by complexation Special attention has been paid to aromatic with 18-crown-6 (Scheme 5) to give stable [K(18-crown-6)] trifluoromethylation with the fluoroform-derived CuCF3 [(t-BuO)Cu(CF3)] that has been isolated and structurally because of the particular importance of building blocks and characterized (42). intermediates bearing a CF3 substituent on the ring (16). Trifluoromethylated aromatic compounds are currently - The cupration of fluoroform does not involve CF3 or CF2 manufactured mainly via a two-step process that involves intermediates (41) but rather is governed by a unique exhaustive chlorination of a methyl group on the aromatic mechanism where the alkali metal cation plays a crucial role ring and subsequent Swarts-type fluorination of the CCl3 (42). It has been found that [K(L)][Cu(OBu-t)2] (L = 18-crown-6, group with HF. This process generates large quantities of crypt-222) and [Me4N][Cu(OBu-t)2] are much less reactive chlorine waste, exhibits exceedingly low functional group toward CHF3 than [K(DMF)][Cu(OBu-t)2]. This low reactivity tolerance because of the involvement of highly reactive stems from the diminished Lewis acidity of the counter-cation materials (Cl2, HCl, HF) and is inapplicable to the vast majority that is needed to provide electrophilic assistance to the of heterocyclic substrates. cupration. Scheme 6 shows a striking transition state for the reaction, where fluoroform and [K(DMF)][Cu(OBu-t)2] interact A total of over 80 various aromatic substrates, both nucleophilic (aryl boronic acids) and electrophilic (haloarenes), have been trifluoromethylated to the corresponding benzotrifluorides with fluoroform-derived

CuCF3 (43, 44). The oxidative trifluoromethylation of aryl boronic acids readily occurs at room temperature or below in air as the oxidant, with high Scheme 6. Cupration of fluoroform via a transition state stabilized by multiple acidic (a) and basic (b) centre interactions (42). selectivity and yield of 67-99 percent (43). The most reactive haloarenes, aryl iodides,

Chimica Oggi - Chemistry Today - vol. 32(3) May/June 2014 85 trifluoromethyl derivatives

RC(O)CH2CF3 in 57-98 percent yield upon treatment with the ligandless

CuCF3 (45). The reaction occurs within 15 min – 2 h at room temperature and exhibits excellent selectivity. Applications of the fluoroform-derived reagent in inorganic synthesis are exemplified by the preparation of

[(IPr)Cu(CF3)] and [(tmeda)Pd(Ph)(CF3)] in quantitative yield (41), as shown in Scheme 7.

The cupration methodology has been extended to pentafluoroethylation reactions with readily available and inexpensive

C2F5H (46). Surprisingly, higher H-perfluoroalkanes CF3(CF2)nH (n = 2, 5, 7), HCF2(CF2)4CF2H and (CF3)2CFH do not give rise to RfCu under the conditions leading to the highly selective cupration of fluoroform; complex mixtures of organofluorine products and KF/

Scheme 7. Trifluoromethylation reactions with fluoroform-derived “ligandless” CuCF3 (41, 43-45). KHF2 are produced instead. In sharp contrast, however, a C2F5Cu derivative is formed in nearly quantitative yield upon treatment of are trifluoromethylated with fluoroform-derived CuCF3 in C2F5H with [K(DMF)][Cu(OBu-t)2]. The resultant complex nearly quantitative yield at 23-50°C (44). Although [K(DMF)2][(t-BuO)Cu(C2F5)] is stable and has been isolated bromoarenes are intrinsically much less reactive than and structurally characterized. Acidolysis of the Cu-O bond iodoarenes, a large series of bromo derivatives of , with TREAT HF produces “ligandless” CuC2F5 that has been pyrimidine, pyrazine, and thiazole as well as more electron- used to pentafluoroethylate a broad variety of substrates deficient or ortho-substituted aryl bromides have been (Scheme 8). Since the subject of the current article is successfully trifluoromethylated (44). Only the most reactive chloro substrates such as 2-chloronicotinic acid can be converted to the corresponding CF3 compounds. Importantly, these reactions of aryl halides readily occur in the absence of any added ligands and exhibit exceptionally high chemoselectivity as no side-formation of arenes, biaryls and C2F5 derivatives (see above) is observed. All in all, the trifluoromethylation reactions of haloarenes with fluoroform-derived ligandless CuCF3 (Scheme 7) provide an unmatched combination of high yield, selectivity and low cost (44).

Another important transformation that cannot be effected by previously known synthetic means but is easily achieved with fluoroform-derived

CuCF3 is the nucleophilic trifluoromethylation of α-haloketones (Scheme 7). A broad variety of haloketones of the type RC(O)CH2X (R Scheme 8. Pentafluoroethylation reactions with C F -derived CuC F (46). = aryl, heteroaryl, alkyl; X = Br, Cl) have 2 5 2 5 been converted to the corresponding

86 Chimica Oggi - Chemistry Today - vol. 32(3) May/June 2014 fluoroform activation, the pentafluoroethylation methods are accordingly. Of the two obvious options available, utilization not discussed in detail herein. A few important points are of fluoroform as a chemical feedstock for high-value noteworthy, however. First, the reliably established structure of fluorinated building blocks and intermediates is vastly

[K(DMF)2][(t-BuO)Cu(C2F5)], along with the aforementioned preferred over its destruction. However, chemoselective mechanistic study (42) strongly suggest that the insufficiently activation of inert fluoroform under industrially feasible stable for isolation primary product of the cupration of conditions represents a considerable challenge. The older fluoroform is a similar mixed cuprate [K(DMF)n][(t-BuO)Cu(CF3)]. methodology of deprotonation of fluoroform with strong alkali Second, the enhanced thermal stability of the CuC2F5 metal bases might not be able to deliver a solution to the reagent (owing to the less facile α-F-elimination) allows for fluoroform problem for a number of reasons, including both pentafluoroethylation of not only iodoarenes but also energy and reagent cost issues. unactivated aryl bromides. Finally, the cupration method advances considerably the area of pentafluoroethylation In recent three years, a new approach to activation of that is underdeveloped despite the fact that in certain fluoroform has emerged, which is based on metalation with instances C2F5 derivatives exhibit properties that are superior transition metal compounds. Thus far, four transition metals have to those of their CF3 analogues (46). been demonstrated to activate and cleave the C-H bond of fluoroform to give rise to the corresponding M-CF3 derivatives. Most recently, one more element, , was added to These metals are copper, zinc, iridium and palladium. The the tiny family of the transition metals that can activate and cupration method and its demonstrated applications seem to cleave the C-H bond of fluoroform. It has been found (47) hold particular promise, especially for the preparation of highly that [(dppp)Pd(Ph)(OH)] readily reacts with CHF3 in the sought-after trifluoromethylated aromatic and heteroaromatic presence of a Lewis base promoter (Bu3P, dppp) in DMF to compounds. The fluoroform cupration technology is not only give [(dppp)Pd(Ph)(CF3)] (Scheme 9). The reaction cleanly novel but also distinctly different from the older deprotonation occurs at room temperature and is governed by a methods. First, the mechanism of the reaction of fluoroform with - remarkable push-pull mechanism that involves cooperative strong alkali metal bases leads to CF3 carbanionic equivalents H-bonding of CHF3 to the OH ligand and Lewis base that are unstable, easily eliminating fluoride to give coordination to the Pd centre. The promoter is released after difluorocarbene. Low temperatures must be used to minimize the Pd-CF3 bond formation and thus can be used in catalytic this decomposition. In contrast, the cupration of fluoroform is not - quantities. Interestingly, this fluoroform activation with Pd is mediated by CF3 but rather leads directly to the covalent nucleophile-assisted, whereas the cupration (see above) Cu-CF3 bond and thus can be performed at ambient involves electrophilic assistance from the alkali metal cation temperature without risking the formation of CF2. Second, the interacting with fluorine atoms of the CHF3 molecule. It is reactivity patterns characteristic of fluoroform-derived CuCF3 - noteworthy that the product of the palladation reaction of are completely different from those of the CF3 carbanionic fluoroform, [(dppp)Pd(Ph)(CF3)], was earlier prepared by species produced upon deprotonation of CHF3. For instance, - another route and found to reductively eliminate PhCF3, CF3 readily adds across the C=O bond but cannot albeit under drastic conditions (48). Chemoselective C-CF3 trifluoromethylate aryl halides, whereas the CuCF3 smoothly bond formation at Pd(II) under mild conditions is highly converts haloarenes to the corresponding benzotrifluorides while challenging (16, 49) but possible, as was demonstrated for the being totally unreactive toward carbonyl functionalities. Finally, it first time only in 2006 (50). is worth to re-emphasize that with potassium t-butoxide being the most expensive material employed in the entire cupration process and the lack of need to use low temperatures, fluoroform-derived

CuCF3 enables a variety of Scheme 9. Nucleophile- trifluoromethylation catalyzed activation of reactions not only with fluoroform with Pd(II) (47). excellent selectivity and in high yield, but also at a low cost.

CONCLUSIONS ACKNOWLEDGEMENT

In this article, we have traced the history of fluoroform from its I am most grateful to my co-workers, students and discovery at the end of the 19th century, through many collaborators who have contributed to the fluoroform decades of remaining a rather unremarkable, barely noticed activation and trifluoromethylation projects and whose compound, to finally becoming a center of attention in names are on the papers cited in the References and recent years. Nontoxic, ozone-friendly and otherwise Notes section. The ICIQ Foundation, Consolider Ingenio seemingly harmless fluoroform is now recognized as a sinister 2010 (Grant CSD2006-0003), and the Spanish Government greenhouse gas that is side-produced in large quantities by (Grant CTQ2011-25418) are acknowledged for support of the fluoropolymer industry and must be dealt with our research.

Chimica Oggi - Chemistry Today - vol. 32(3) May/June 2014 87 REFERENCES AND NOTES 27. Roques N., Russell J., PCT Int. Appl. WO 97/19038 (1997). 28. Russell J., Roques N., , 54, 13771-13782 (1998). 29. Folléas B., Marek I., Normant J.-F., et al., Tetrahedron Lett., 39, 1. Anonymous, Nature, 41, 521 (1890). 2973-2976 (1998). 2. Meslans, M., C. R. Acad. Sc. (Paris), 110, 717-719 (1890). 30. Folléas B., Marek I., Normant J.-F., et al., Tetrahedron, 56, 275-283 (2000). 3. Chabrié M. C., Bull. Soc. Chim. Fr. 3, 7, 18-31 (1892). 31. Large S., Roques N., Langlois B. R., J. Org. Chem., 65, 8848-8856 4. Viel C., Labrude P., Revue d’Histoire de la Pharmacie, 356, 473- (2000). 484 (2007). 32. Billard T., Bruns S., Langlois B. R., Org. Lett., 2, 2101-2103 (2000). 5. Booth H. S., Bixby E. M., Ind. Eng. Chem., 24, 637-641 (1932). 33. Blond G., Billard T., Langlois B. R., Tetrahedron Lett., 42, 2473-2475 6. Ruff O., Bretschneider O., Luchsinger W., et al., Ber. Dtsch. Chem. (2001). Ges., 69B, 299-308 (1936). 34. Prakash G. K. S., Jog, P. V., Batamack P. T. D., et al., Science, 338, 7. Henne A. L., J. Am. Chem. Soc., 59, 1200-1202 (1937). 1324-1327 (2012). 8. Plunkett R. J., U.S. Patent 2,230,654 (1939). 35. Kawai H., Yuan Z., Tokunaga E., et al., Org. Biomol. Chem., 11, 9. Banks R. E., Tatlow J. C., J. Fluorine Chem., 33, 71-108 (1986). 1 1446-1450 (2013). 10. Fluoropolymers, Edited by Hougham G. G., Cassidy P. E., Johns K., 36. Zhang Y., Fujiu M., Serizawa H., et al., J. Fluorine Chem., 156, 367- et al., Kluwer Academic / Plenum Publishers, New York, USA (1999). 3 371 (2013). 11. Oram D. E., Sturges W. T., Penkett S. A., et al., Geophys. Res. Lett., 37. Iida T, Hashimoto R., Aikawa K., et al., Angew. Chem. Int. Ed., 51, 25, 35-38 (1998). 9535-9538 (2012). 12. McCulloch A., Lindley A. A., Atmos. Environ., 41, 1560–1566 (2007). 38. Thomoson C. S., Dolbier W. R., Jr., J. Org. Chem., 78, 8904-8908 ( 13. Miller B. R., Rigby M., Kuijpers L. J. M., et al., Atmos. Chem. Phys., 2 (2013). 10, 7875–7890 (2010). 39. Popov I., Lindeman S., Daugulis O., J. Am. Chem. Soc., 133, 9286- 14. Han W., Li Y., Tang H., Liu H., J. Fluorine Chem., 140, 7-16 (2012). 92 9289 (2011). 40. Choi J., Wang D. Y., Kundu S., et al., Science, 332, 1545-1548 (2011). 15. Bomgardner M. M., Chem. Eng. News, 91, 6 (2013). 41. Zanardi A., Novikov M. A., Martin E., et al., J. Am. Chem. Soc., 133, 16. Tomashenko O. A., Grushin V. V., Chem. Rev., 111, 4475-4521 2 20901-20913 (2011). (2011). 42. Konovalov A. I., Benet-Buchholz J., Martin E., Grushin V. V., Angew. Chem. 17. Amphlett J. C., Coomber J. W., Whittle E., J. Phys. Chem., 70, In Int. Ed., 52, 11637-11641 (2013). 593-594 (1966). 43. Novák P., Lishchynskyi A., Grushin V. V., Angew. Chem. Int. Ed., 51, 18. Shia J., Hea J., Wang H.-J., J. Phys. Org. Chem., 24, 65-73 (2011). 7 7767-7770 (2012). 19. Symons E. A., Clermont M. J., J. Am. Chem. Soc., 103, 3127-3130 (1981). 44. Lishchynskyi A., Novikov M. A., Martin E., et al., J. Org. Chem., 78, 20. Rozen S., Hagooly, A., Fluoroform in e-EROS Encyclopedia of 1 11126-11146 (2013). Reagents for Organic Synthesis, Wiley, Chichester, United 45. Novák P., Lishchynskyi A., Grushin V. V., J. Am. Chem. Soc., 134, Kingdom, 5110-5112 (2001). 161 16167-16170 (2012). 21. Langlois B. R., Billard T., Synthesis, 185-194 (2003). 46. Lishchynskyi A., Grushin V. V., J. Am. Chem. Soc., 135, 12584-12587 (2013). 22. Langlois B. R., Billard T., ACS Symp. Ser., 911, 57-86 (2005). 47. Takemoto S., Grushin V. V., J. Am. Chem. Soc., 135, 16837-16840 23. Jog P. V., Prakash G. K. S., J. Postdoc. Res., 1, 1-13 (2013). ( (2013). 24. Hine J., Dowell A. M., Jr., Singley J. E., Jr., J. Am. Chem. Soc., 78, 48. Grushin V. V., Marshall W. J., J. Am. Chem. Soc., 128, 4632-4641 (2006). 479-482 (1956). 49. Grushin V. V., Acc. Chem. Res., 43, 160-171 (2010). 25. Shono T., Ishifune M., Okada T., et al., J. Org. Chem., 56, 2-4 (1991). 50. Grushin V. V., Marshall W. J., J. Am. Chem. Soc., 128, 12644-12645 26. Barhdadi R., Troupel M., Périchon M., Chem. Commun., 1251-1252 (1998). ( (2006).