Facile synthesis of R₄NF(HFIP)₃ complexes from KF and their application to electrochemical fluorination

Abstract

By exploiting the difference in solubility between KF and KBr in the co-solvent HFIP/CH₂Cl₂, R₄NF(HFIP)₃ complexes were synthesised in excellent yields from the ion exchange reaction between KF and R₄NBr. The resulting Bu₄NF(HFIP)₃ was found to have extremely low hygroscopicity and to be effective as a supporting electrolyte and fluorinating reagent in electrochemical fluorination.

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Organofluorine compounds are widely used in pharmaceuticals,¹ agrochemicals,² functional materials³ and positron emission tomography (PET) imaging.⁴ However, organofluorine compounds are rarely found in nature.⁵ Therefore, a number of fluorinating reagents have been developed to synthesise organofluorine compounds.⁶ HF is industrially produced from the natural resource CaF₂ (fluorite) as shown in Scheme 1⁷ and is therefore the most typical nucleophilic fluorinating reagent. In addition, HF is readily converted to alkali metal fluorides such as potassium fluoride (KF) and quaternary ammonium fluorides such as tetrabutylammonium fluoride (Bu₄NF).⁸ KF is safe and inexpensive, but is insoluble in aprotic solvents.⁹ On the other hand, anhydrous Bu₄NF has very high nucleophilicity but also high hygroscopicity.¹⁰ This means that the naked fluoride ion (F⁻) is highly nucleophilic due to the bulky tetrabutylammonium cation (Bu₄N⁺), but its hygroscopicity significantly reduces the nucleophilicity.

Scheme 1 Production and application of HF derived from CaF₂ (fluorite) as a natural resource.

The most straightforward method of obtaining anhydrous Bu₄NF is to remove the water from the corresponding hydrate salt. However, attempts to dry the hydrate salt by heating under reduced pressure resulted in rapid Hofmann elimination due to the high basicity of naked F⁻.¹¹ As an alternative method to obtain anhydrous Bu₄NF, the in situ generation of Bu₄NF from tetrabutylammonium cyanide (Bu₄NCN) and hexafluorobenzene (C₆F₆) has been reported.¹² This is a promising method for the production of anhydrous Bu₄NF, but presents challenges in terms of cost. On the other hand, tetrabutylammonium tetra(tert-butyl alcohol)-coordinated fluoride (Bu₄NF(t-BuOH)₄) has previously been shown to have low basicity and thus low hygroscopicity despite good nucleophilicity (Scheme 1(b)).¹³ In aliphatic alcohols, the coordination number has been reported to vary from 2 to 4, depending on the steric bulk of the alcohols.¹⁴ Tetrabutylammonium tetra(2,2,2-trifluoroethanol)-coordinated fluoride (Bu₄NF(TFE)₄) has also been reported using 2,2,2-trifluoroethanol (TFE) as the fluorinated alcohol (Scheme 1(c)).¹⁵ However, when Bu₄NF(t-BuOH)₄ and Bu₄NF(TFE)₄ are used as supporting electrolytes and fluorinating agents in electrochemical fluorination, there is a concern that t-BuOH and TFE will not only undergo oxidation but also act as nucleophiles. On the other hand, 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) has high oxidation resistance, low nucleophilicity, high polarity and high hydrogen bond donating ability due to the strong electron-withdrawing CF₃ groups.¹⁶ With these facts in mind, we report here the synthesis of quaternary ammonium tri(1,1,1,3,3,3-hexafluoroisopropanol)-coordinated fluoride (R₄NF(HFIP)₃) complexes (Scheme 1(a)) from KF and their application to electrochemical fluorination.

The strategy for the synthesis of R₄NF(HFIP)₃ from KF is to use the ion exchange reaction between KF and R₄NBr (eqn (1)). KF is highly soluble in HFIP¹⁷ because HFIP and F⁻ are strong hydrogen bond donor and acceptor, respectively. Since HFIP is strongly coordinated to F⁻, KF should dissolve even when dichloromethane (CH₂Cl₂) is added to the HFIP solution as an aprotic solvent. In contrast, KBr should not dissolve in the co-solvent HFIP/CH₂Cl₂ because the bromide ion (Br⁻) is not a strong hydrogen bond acceptor. The use of the co-solvent HFIP/CH₂Cl₂ would therefore shift the equilibrium (eqn (1)) to the right as KBr generated by the ion exchange reaction precipitates.

Based on this strategy, the synthesis of Bu₄NF(HFIP)₃ from KF was investigated as shown in Scheme 2. KF and Bu₄NBr were first dissolved in HFIP and CH₂Cl₂ respectively. They were mixed and stirred for 30 minutes. A white precipitate, possibly KBr, formed during the reaction and was separated by filtration after the reaction. When the filtrate was evaporated under reduced pressure, a viscous and clear liquid was obtained as the product. ¹H and ¹⁹F NMR measurements indicated that the product was Bu₄NF(HFIP)₃ with three molecules of HFIP coordinated to F⁻. Bu₄NF(HFIP)₃ may be a deep eutectic solvent.¹⁸ It is noteworthy that Bu₄NF(HFIP)₃ was isolated in 95% yield simply by evaporation of the solvent under reduced pressure. Furthermore, the ¹H and ¹⁹F NMR spectra were in good agreement with those of Bu₄NF(HFIP)₃ synthesised from Bu₄NF(H₂O)₃ as shown in Scheme 3. The coordination number of TFE¹⁵ to F⁻ was reported to be 4, whereas the coordination number of HFIP to F⁻ was 3. This result suggests that the coordination number is not only influenced by the steric bulk of the alcohols,¹⁴ but also by the hydrogen bond donating ability.

Scheme 2 Experimental procedure for the synthesis of Bu₄NF(HFIP)₃ from KF.

Scheme 3 Experimental procedure for the synthesis of Bu₄NF(HFIP)₃ from Bu₄NF(H₂O)₃.

Based on this approach, the ion exchange reaction with KF was applied to some quaternary ammonium bromides (R₄NBr) and R₄NF(HFIP)₃ complexes were synthesised. As shown in Fig. 1. Et₄NF(HFIP)₃ and Pr₄NF(HFIP)₃ were viscous and clear liquids, while Me₄NF(HFIP)₃ was a white solid. These products were also isolated by simple evaporation of the solvent, all in excellent yields. A comparison of the hygroscopicity of Me₄NF(HFIP)₃ and KF at about 50–80% humidity showed that Me₄NF(HFIP)₃ hardly deliquesced after 2 hours of exposure to air, while KF deliquesced completely, as shown in Fig. 2. Furthermore, Me₄NF(HFIP)₃ did not completely deliquesce after 24 hours. It is therefore clear that Me₄NF(HFIP)₃ is much less hygroscopic than KF. On the other hand, the weight of Me₄NF(HFIP)₃ in air gradually decreased as it deliquesced, whereas the weight of KF increased. These results indicate that the HFIP coordinated to the F⁻ of Me₄NF was partially replaced by atmospheric moisture (H₂O).

Fig. 1 Appearance of R₄NF(HFIP)₃ (R = Me, Et and Pr).

Fig. 2 Appearance of Me₄NF(HFIP)₃ before and after exposure to air.

In order to clarify the electrochemical properties of Bu₄NF(HFIP)₃, the linear sweep voltammograms of Bu₄NF(H₂O)₃ and Bu₄NF(HFIP)₃ were measured. As shown in Fig. 3, Bu₄NF(H₂O)₃ was easily oxidised from 1.5 V vs. Ag|Ag⁺. This could be due to the oxidation of H₂O. On the other hand, Bu₄NF(HFIP)₃ was stable up to 2.5 V vs. Ag|Ag⁺, because HFIP is highly resistant to oxidation due to two strong electron-withdrawing CF₃ groups. These results suggest that Bu₄NF(HFIP)₃ has a wide potential window on the oxidation side and can be used as a supporting electrolyte and fluorinating reagent for electrochemical fluorination. Furthermore, no oxidation of Br⁻ was observed in 1 M Bu₄NF(HFIP)₃/MeCN, indicating that Bu₄NF(HFIP)₃ did not contain Br⁻ as an impurity.

Fig. 3 Linear sweep voltammograms of 1 M Bu₄NF(H₂O)₃/MeCN and 1 M Bu₄NF(HFIP)₃/MeCN, recorded at a Pt disc electrode (ϕ = 1 mm). The scan rate was 100 mV s⁻¹.

The electrochemical fluorination of a sulphide 1 was comparatively investigated using Bu₄NF complexes as supporting electrolytes and fluorinating reagents. As shown in Table 1, the corresponding fluorinated product 2 was hardly generated with Bu₄NF(H₂O)₃ and Bu₄NF(t-BuOH)₄ (entries 1 and 2). In these cases, H₂O and t-BuOH acted as nucleophiles and the corresponding hydroxylated and alkoxylated products were formed. When Bu₄NF(TFE)₄ was used, a small amount of 2 was formed (entry 3). This is probably due to the relatively low nucleophilicity of TFE. On the other hand, the use of Bu₄NF(HFIP)₃ gave 2 in good yield (entry 4). To clarify the necessity of using Bu₄NF(HFIP)₃, Bu₄NF(HFIP)₃ was formed in the reaction system from Bu₄NF(H₂O)₃ and HFIP and used for the electrochemical fluorination of 1 (entry 5). This led to the formation of 2 in low yield. In this case it appears that the water derived from Bu₄NF(H₂O)₃ not only underwent oxidation but also acted as a nucleophile. These results indicate that HFIP is more resistant to oxidation and less nucleophilic than H₂O, t-BuOH and TFE. It is therefore clear that Bu₄NF(HFIP)₃ is more effective for electrochemical fluorination. Since Bu₄NF(HFIP)₃ showed good solubility in different polar solvents, the electrochemical fluorination of 1 was carried out in MeCN, HFIP, 1,2-dimethoxyethane (DME) and CH₂Cl₂ (entries 4, 6–8). The results showed that 2 was formed in almost similar yields except when HFIP was used. When HFIP was used as solvent, not only 2 but also the corresponding difluorinated product 3 was formed significantly (entry 6). This indicates that due to the high oxidation resistance of HFIP, 3 was formed by further oxidation of 2. These results suggest that over-oxidation of the products can occur in HFIP with high oxidation resistance. On the other hand, the yield of 2 was not temperature dependent (entries 7, 9 and 10). Even at 60 °C, HFIP could be strongly coordinated to F⁻. Just as the hydrogen bonding between t-BuOH and F⁻ suppressed the hygroscopicity of Bu₄NF(t-BuOH)₄, it is expected that the hygroscopicity of Bu₄NF(HFIP)₃ is also strongly suppressed. In addition, Bu₄NF(HFIP)₃ should be less hygroscopic than Me₄NF(HFIP)₃, because Bu₄NF(HFIP)₃ is a viscous liquid whereas Me₄NF(HFIP)₃ is a solid. To assess the hygroscopicity of Bu₄NF(HFIP)₃, ¹H NMR measurements were performed before and after Bu₄NF(HFIP)₃ was stored in air at room temperature for three months. As shown in Fig. 4, Bu₄NF(HFIP)₃ did not absorb any water. The electrochemical fluorination of 1 with Bu₄NF(HFIP)₃ stored for three months (entry 11) showed no significant change in the yield of 2 when Bu₄NF(HFIP)₃ was used before storage (entry 8). These results indicate that Bu₄NF(HFIP)₃ has extremely low hygroscopicity and can be stored in air for long periods.

Table 1 Electrochemical fluorination of 1 with Bu₄NF complexes

Entry	Bu4NF complex	Temp. (°C)	Solvent	Yield^a (%)
				2	3
a ^19F NMR yield using monofluorobenzene as an internal standard. b 2 F mol^−1 was passed. c The reaction was carried out with 0.5 M Bu4NF(t-BuOH)4. d Bu4NF(HFIP)3 stored in air at room temperature for 3 months was used.
1^b	Bu4NF(H2O)3	rt	MeCN	0	0
2^c	Bu4NF(t-BuOH)4	35	MeCN	Trace	0
3	Bu4NF(TFE)4	rt	MeCN	19	Trace
4	Bu4NF(HFIP)3	rt	MeCN	54	Trace
5	Bu4NF(H2O)3 + 3HFIP	rt	MeCN	10	Trace
6	Bu4NF(HFIP)3	rt	HFIP	17	19
7	Bu4NF(HFIP)3	rt	DME	63	3
8	Bu4NF(HFIP)3	rt	CH2Cl2	66	4
9	Bu4NF(HFIP)3	40	DME	65	Trace
10	Bu4NF(HFIP)3	60	DME	66	Trace
11	Bu4NF(HFIP)3^d	rt	CH2Cl2	57	9

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Fig. 4 Presumed structure and appearance of Bu₄NF(HFIP)₃, and ¹H NMR spectra of Bu₄NF(HFIP)₃ before and after three months storage at room temperature.

To clarify the effect of the size of the quaternary ammonium ions, the electrochemical fluorination of 1 was then investigated using Me₄NF(HFIP)₃, Et₄NF(HFIP)₃, Pr₄NF(HFIP)₃ and Bu₄NF(HFIP)₃ in DME as shown in Table 2. However, Me₄NF(HFIP)₃ was hardly soluble in DME (entry 1). On the other hand, 2 was obtained in similar yields when Et₄NF(HFIP)₃, Pr₄NF(HFIP)₃ and Bu₄NF(HFIP)₃ were used (entries 2–4). These results suggest that F⁻ was strongly coordinated by HFIP due to its hydrogen bond even in the solvent DME. Therefore, the nucleophilicity of F⁻ should not be affected by the counter cation and indeed the yields of 2 were similar regardless of the size of the quaternary ammonium ions.

Table 2 Electrochemical fluorination of 1 with R₄NF(HFIP)₃

Entry	R4NF(HFIP)3	Yield^a (%)
		2	3
a ^19F NMR yield using monofluorobenzene as an internal standard. b Me4NF(HFIP)3 was hardly soluble in DME.
1	Me4NF(HFIP)3^b	—	—
2	Et4NF(HFIP)3	64	Trace
3	Pr4NF(HFIP)3	67	1
4	Bu4NF(HFIP)3	63	3

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In conclusion, we have successfully demonstrated the facile synthesis of R₄NF(HFIP)₃ complexes (R = Me, Et, Pr and Bu) from KF and their application to electrochemical fluorination. By exploiting the difference in solubility between KF and KBr in the co-solvent HFIP/CH₂Cl₂, R₄NF(HFIP)₃ was obtained in excellent yields from the ion exchange reaction between KF and R₄NBr. The obtained Bu₄NF(HFIP)₃ was found to have extremely low hygroscopicity and could be stored for long periods. In addition, Bu₄NF(HFIP)₃ was found to be effective as a supporting electrolyte and fluorinating reagent in electrochemical fluorination. Therefore, Bu₄NF(HFIP)₃ is expected to be an easily synthesised fluoride source from KF with low hygroscopicity in nucleophilic fluorination, especially in electrochemical fluorination.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d5cc01341k

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