Alkylation of in situ generated fluorinated alkoxides: novel synthesis of partially fluorinated ethers

Fluorinated ethers R f CF 2 OR were prepared from acyl chlorides R f COCl, alkylating agents (such as dimethyl sulfate, alkyl triflates, alkyl mesylates and tosylates, etc.) and potassium fluoride in diglyme at 80~100 o C. The success and the efficiency of the reaction are affected by two factors: the stability and nucleophilicity of the fluorinated alkoxide generated in situ ; and the other is the electrophilicity of the alkylating agents used.


Introduction
In general, carbon-fluorine bonds (C-F, ~116 kcal/mol) are stronger than carbon-hydrogen bonds (C-H, ~99 kcal/mol). 1However, not all organofluorine compounds are more stable than their non-fluorinated analogs, and sometimes they are even less stable.For instance, if a partially or fully fluorinated organic compounds contains an acidic hydrogen at the β position, HF elimination is observed.This is the main reason that α-fluoro alcohols are thermally unstable and difficult to be synthesized or isolated. 2Formation of fluoromethanol (FCH 2 OH) from ethyl fluoroformate and from formyl fluoride was first reported by Olah and Pavlath 3 in 1953, and Weinmayer 4 in 1963 claimed the formation of fluoromethanol (25-30% in equilibrium) from a solution of paraformaldehyde in excess hydrogen fluoride.But both research groups were unable to isolate and characterize the pure compound.Trifluoromethanol (CF 3 OH) has been prepared, purified and characterized from trifluoromethyl hypochlorite and hydrogen chloride by Kloter and Seppelt 5 in 1979, but it decomposes readily above -20 o C. Stable protonated α-fluoro alcohols in condensed state or in crystalline state have been known, such as protonated fluoromethanol (FCH 2 OH 2 + ) by Olah and Mateescu, 6 protonated heptafluoroisopropanol {(CF 3 ) 2 C(F)OH 2 + } by Minkwitz and Reinemann, 7 and protonated trifluoromethanol (CF 3 OH 2 + ) by Christe and co-workers. 8However, to our knowledge, the only reported α-fluoro alcohol stable in the pure state at ambient temperature is heptafluorocyclobutanol (C 4 F 7 OH), which was prepared from hexafluorocyclobutanone and hydrogen fluoride by Andreades and England 9 in 1961.All these difficulties in the preparation and isolation of α-fluoro alcohols make them not practical as reagents for organic synthesis, especially for the generation of α-fluoro alkoxide (R f O -) synthon.
α-Fluoroalkoxides, particularly perfluoroalkoxides, have been reported for more than thirty years.The first preparations of reasonably stable, crystalline perfluoroalkoxides of alkali metals, i.e.R f OM (R f = CF 3, M = K, Rb or Cs; R f = CF 3 , C 2 F 5 , C 3 F 7 or perfluoroisopropyl group, M=Cs or Rb), were reported by Redwood and Willis 10 in 1965 and 1966.Pittman, 11 Evans 12 and their coworkers also reported the formation of adducts between fluorinated ketones and metal fluorides in 1965 and 1968, respectively.Above room temperature (20 o C), these metal perfluoroalkoxides decompose into metal fluorides and acyl fluorides or ketones, 10 which indicates their relatively lower nucleophilicity compared with their non-fluorinated alkoxide analogs.And in the following twenty years, only few synthetic applications of these perfluoroalkoxides have been explored, such as reactions with unsaturated acyl chloride, 13 with allyl bromide, 10b with olefin in the presence of a halogen, 14 with epibromohydrin 11 and fluoroolefin epoxides. 15Tris(dimethylamino)sulfonium trifluoromethoxide (TAS + CF 3 O -) was also reported as a stable crystalline compound by Farnham and co-workers in 1985, 16 but its synthetic application has not been well investigated.
In the last decade, partially fluorinated ethers, or so-called "hydrofluoroethers (HFE)", have attracted increasing attention as refrigerants especially in industry as promising substitutes for the ozone-depleting chlorofluorocarbons (CFCs).According to Montreal Protocol and its appended amendments, the production and use of CFCs must be discontinued. 17Partially fluorinated ethers (R f OR), as a class of compounds, are particularly spotlighted as promising replacements for CFCs, not only because of their zero ozone depleting potential and low toxicity, but also they exhibit excellent solvent properties-they dissolve both hydrocarbon based and fluorocarbon based materials. 18These partially fluorinated ethers can be extensively used as detergents, solvents, lubricants, heat-transfer media, and so on. 19,20These fluoroethers can be synthesized by two categories of methods: direct fluorination (with elemental fluorine) of the hydrocarbon ether compound, and methods wherein the ether linkage is formed during the reaction with a fluorinated precursor. 18,213][24] Since the acid catalyzed alkylation of perfluoroacyl fluorides normally gives low yields and complex isomerization products, 18 non-catalytic alkylation of perfluoroalkoxides shows the more attractive practical features for industrial applications.Although in the recent years there have been several disclosures on this methodology using different alkylating agents (such as alkyl fluorovinylalkyl ether, 25 dimethyl sulfate 19 and alkyl triflate 26 ); gaseous shortchain perfluoroacyl halides are often used, and the results are only recorded in industrial patents without full characterization or experimental details.
Recently, we were interested in developing new types of fluorinated compounds as low temperature lithium battery electrolyte co-solvents.Partially fluorinated ethers were some of our prime candidates, since these compounds can increase the battery's discharge capacity during charge/discharge cycle, by forming a stable coating on the surface of the negative electrode and suppressing the degradation of the non-aqueous electrolyte. 27,28Herein, we wish to report the synthesis of these partially fluorinated ethers by alkylating fluorinated alkoxides generated in situ by treating short or long chain fluorinated acyl chlorides with potassium fluoride.

Dimethyl sulfate as the alkylating agent
Dimethyl sulfate is a powerful alkylating agent and has been used for the methylation of almost every imaginable nucleophile. 29Using dimethyl sulfate as the methylating agent, we successfully synthesized fluoroalkyl methyl ethers 2 (see Scheme 1).

Scheme 1
Fluorinated acyl chlorides 1 are the preferred precursors for the generation of 1,1difluoroalkoxides, since fluoroacyl chlorides have higher boiling points than the corresponding fluoroacyl fluorides.
During the reaction, fluoroacyl chloride can be fluorinated by KF to fluoroacyl fluoride 4 in situ, 19 and the latter is easily transformed into fluoroalkoxide 5 (see scheme 2).Diglyme is the solvent of choice due to it's high polarity and excellent solvation of the in situ generated fluorinated alkoxides 5. 19,25 Typical reaction condition is as follows: perfluorooctanoyl chloride 1a (30 mmol) is reacted with anhydrous KF (90 mmol) in dry diglyme at 50 0 C for 30 minutes, followed by a slow dropwise addition of dimethyl sulfate (60 mmol) at 70 0 C. The reaction mixture was kept at 70 ~100 0 C for another 1 hour, cooled to room temperature and stirred overnight.The ester byproduct (R f COOMe) can be removed from the ether product 2 simply by stirring the reaction mixture with NaOH aqueous solution.After workup, perfluorooctyl methyl ether 2a can be isolated in 80% yield.
As shown in table 1, both short chain perfluoroacyl (C 1 ~C4 ) 19 and long chain perfluoroacyl chlorides (C 7 ~C9 ) gave good yields of methylated products 2a~2c.For the other nonperfluorinated substrates 1d and 1e, the reactions gave lower yields.For the substrates without fluorine atoms at the α-carbon to the carbonyl group (see 1g and 1h), the reaction did not take place.Varying yields of fluoroethers can be roughly explained by the stability and the nucleophilicity of each fluoroalkoxide 5 (R f CF 2 O -) generated in situ in the reaction.Since these fluoroalkoxides exist in equilibrium with metal fluoride and fluoroacyl fluorides under the reaction conditions, as shown in scheme 2, the weaker fluoroalkoxide would have a higher tendancy to decompose into the metal fluoride and acyl fluoride.Among these fluoroalkoxides 5, the trifluoromethoxide ion (i.e.R f = F) is the most stable one, because the negative charge on the trifluoromethoxide ion rests formally on the oxygen atom, with the negative charge being shared to some extent by the three fluorine atoms because of their greater electronegativity. 10When the R f is changed to a perfluoroalkyl group, such as in 1a, 1b and 1c, the longer the perfluoroalkane chain makes the carbon atom connecting to CF 2 O -less electronegative, resulting in the lower stability of the resulting alkoxide and then somewhat lower yields of the ethers.When R f = Cl (1d), the ether yield is moderate; and when R f = phenyl group (1e), the yield of ether is much lower because the phenyl group has even weaker electron-withdrawing ability than the chlorine atom.In the case of 1g-1i, although these acyl chlorides can be transformed into corresponding acyl fluorides 4g-4i (characterized by NMR), they failed to produce the ether product 2g, 2h or 2i indicating that these acyl fluorides 4g-4i are not further fluorinated into alkoxides 5g-5i, probably due to their instability.Finally, it is also remarkable that the diacyl chloride 1f can be transformed into the diether 2f in good yield.The relative stability and nucleophilicity of fluoroalkoxide 5 can also be explained by the negative hyperconjugation (HCJ) 30 as shown in Scheme 3. Farnham and coworkers have explained the structural parameters of (Me 2 N) 3 S + CF 3 O -by HCJ.Their evidence for HCJ is that the X-ray structure shows the C-O bond to be unusually short (1.227 Å) and the C-F bond is extraordinarily long (1.390-1.397Å). 16a Thus we can derive that for the other fluorinated alkoxides (R f ≠ F), strong electron-withdrawing property of R f group may facilitate the HCJ between 5a, 5b and 5c, which stabilizes the corresponding alkoxides and increases their propensity to react with alkylating agents such as dimethyl sulfate.

Table 1. Preparation of fluoroethers 2 from fluorinated acyl chlorides 1, KF and dimethyl sulfate in diglyme
The relative stability and nucleophilicity of fluoroalkoxide 5 can also be explained by the negative hyperconjugation (HCJ) 30 as shown in Scheme 3. Farnham and coworkers have explained the structural parameters of (Me 2 N) 3 S + CF 3 O -by HCJ.Their evidence for HCJ is that the X-ray structure shows the C-O bond to be unusually short (1.227 Å) and the C-F bond is extraordinarily long (1.390-1.397Å). 16a Thus we can derive that for the other fluorinated alkoxides (R f ≠ F), strong electron-withdrawing property of R f group may facilitate the HCJ between 5a, 5b and 5c, which stabilizes the corresponding alkoxides and increases their propensity to react with alkylating agents such as dimethyl sulfate.

Alkyl sulfonates as alkylating agents
Besides dimethyl sulfate, we also attempted to use other strong alkylating agents to prepare partially fluorinated ethers, such as methyl trifluoromethanesulfonate (methyl triflate), ethyl triflate, hexyl triflate, methyl methanesulfonate (methyl mesylate) and methyl p-toluenesulfonate (methyl tosylate).The reaction conditions were similar to previously studied reactions with dimethyl sulfate (Scheme 4).

Scheme 4
The results are summarized in Table 2.The effect of different alkylating agents on the yields of ether product 6 can be clearly seen from Table 2 (entries a-c).Since the order of methylating ability is methyl triflate > methyl mesylate > methyl tosylate, the yields of methyl perfluorooctyl ether are in the same order.It is interesting note that in the case of ethylation and hexylation reactions using ethyl triflate and hexyl triflate, respectively (entries d and e), each reaction gives the methyl ether (n-C 8 F 17 OCH 3 ) besides expected product (6d or 6e).The mechanism of formation of methyl ether is proposed as shown in Scheme 5 involving disproportionation reactions.

Scheme 5
At first, ethyl or hexyl triflate can react with diglyme solvent to form Meerwein-type 31 oxonium ion 7, which can further methylate the fluorinated alkoxide to form 2a.

Attempted reactions with other electrophiles
We have also attempted to react fluorinated alkoxide 5a with other electrophiles, such as methyl iodide, acetyl chloride, benzoyl chloride, triflic anhydride, allyl bromide, acryloyl chloride, methyl chloroformate, propyl chloroformate, and N,N-carbonyl diimidazole (Scheme 6).Unfortunately, all these reactions did not give the expected products.This means that besides the facile formation of perfluoroalkoxides 5, very strong electrophilicity of the alkylating agents is also necessary (Scheme 6).

1f 10
Scheme 7 Hexafluorofluoroglutaryl chloride (3.6 mmol) was reacted with KF (21.6 mmol) in diglyme at 50 o C for 30 min, followed by addition of ethylene glycol bistriflate 10 (3.6 mmol) and the resulting reaction mixture was stirred at 70 o C for 20 h.It turns out that the major products are some oligomeric compounds, and only around 5 % yield of relatively high molecular weight polymer was obtained as an oily liquid (average molecular weight = 1,413 according to SEC measurement using poly(ethylene oxide), PEO as a standard).

Conclusions
In conclusion, we have synthesized partially fluorinated ethers by the direct alkylation of fluorinated alkoxides generated in situ from fluoroacyl chlorides with potassium fluoride in diglyme.The success and yields of the reaction are affected by two factors: the stability and nucleophilicity of the fluorinated alkoxide generated in situ; and the other is the electrophilicity of alkylating agents.The new fluoroethers prepared have been found to be promising candidates for the lithium battery applications. 38perimental Section General Procedures.KF was dried at 300 o C under high vacuum for 10 hours and stored under argon.Diglyme was distilled over calcium hydride.Dimethyl sulfate was purchased from Aldrich chemical Co., and other fluoroacyl chlorides were purchased from Synquest laboratories, Inc. or prepared from the corresponding carboxylic acid with PCl 5 or SOCl 2 .

a
All are isolated yields; b methyl triflate was also tried as methylating reagent, but the reaction was not successful.

19 F
NMR chemical shifts were determined relative to internal CFCl 3 at δ 0.0.Infrared spectra were obtained on a Perkin-Elmer Spectrum 2000 FT-IR spectrophotometer.Mass spectra were recorded on Hewlett Packard 5890 Gas Chromatograph with a Hewlett Packard 5971 Mass Selective Detector at 70 eV.