Nucleophilic Fluorination with Aqueous Bifluoride Solution: Effect of

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Nucleophilic Fluorination with Aqueous Bifluoride Solution. Effect of the Phase-Transfer Catalyst. Alicja Talko, and Micha# Barbasiewicz ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b00489 • Publication Date (Web): 04 Apr 2018 Downloaded from http://pubs.acs.org on April 4, 2018

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ACS Sustainable Chemistry & Engineering

Nucleophilic Fluorination with Aqueous Bifluoride Solution. Effect of the Phase-Transfer Catalyst. Alicja Talko and Michał Barbasiewicz* Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland [email protected], www.aromaticity.pl

ABSTRACT Nucleophilic fluorination of sulfonyl chlorides, acyl chlorides and alkyl sulfonates with saturated aqueous solution of potassium bifluoride (KHF2) was studied under liquid-liquid two-phase conditions. Original ‘on-water’ procedure, reported by Sharpless (J. Org. Chem. 2016, 81, 11360-11362), was tested on model 1-octanesulfonyl chloride in the presence of phase transfer catalysts, some of which appeared to be beneficial for the reaction rate. Despite high hydration energy of the fluoride ions the catalytic system displayed numerous features typical for interfacial transportation of the nucleophilic species, being controlled by amount and structure of the catalyst, lipophilicity of the catalyst's counter-ion, and rate of stirring. Besides for synthesis of acyl fluorides presence of 1 mol% of tetrabutylammonium chloride affected selectivity of the reaction, by minimizing formation of carboxylic acids and anhydrides. The presented results suggest that aqueous solutions of bifluorides (or synthetically equivalent systems accessible by acidification of alkali metal fluoride solutions) can be efficient sources of the fluoride ions under

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two-phase conditions, provided that rate of the intrinsic reaction is sufficiently high. The methodology supplements family of nucleophilic fluorinations, delivering more reactive form of the solvated anions.

KEYWORDS nucleophilic fluorination, bifluoride anion, phase transfer catalysis, sulfonyl fluorides, acyl fluorides

INTRODUCTION Fluoroorganic compounds are widely applied as pharmaceuticals, plant protection agents, materials and reagents, and their synthesis has received much attention in both academia and industry.1 Methods of incorporation of the fluorine atoms usually apply of two disparate groups of reagents: expensive electrophiles, derived from strongly oxidizing elemental fluorine, and easily available, but latent sources of the fluoride anions.2 The latter class of reagents, although more economically and environmentally favored, displays numerous limitations related to high lattice energy of inorganic fluorides, strong hydrogen bonds of the anions in aqueous solutions,3 and increased basicity of 'naked' fluorides, when the presence of water or other hydrogen bond donors is strictly excluded.4 Based on this, literature methods of nucleophilic fluorination consist of activation of insoluble inorganic fluorides by spray-drying,5 polymer-6 and CaF2-support,7 phase transfer catalysis with crown ethers,8 ammonium9 and phosphonium salts,10 ionic liquids,11 copper complexes,12 and hypervalent stannates,13 or application of stoichiometric amounts of


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soluble tetraalkylammonium fluorides, where presence of the solvating water controls nucleophilicity and basicity of the reacting species.4,14 An opposite trend in the methodology was initiated recently by Kim and Chi.15 Systematic studies of SN2 fluorination of alkyl halides and sulfonates revealed that strongly solvating tertiary alcohols, e.g. tert-BuOH and tert-AmOH, facilitate the process, as compared with polar aprotic solvents, e.g. acetonitrile. The hydrogen-bond promoted nucleophilic fluorination,16 utilizes dual activation of the reacting partners, delivering active form of the fluoride and facilitating departure of the leaving group with hydrogen bonds. The new discoveries find important applications for the synthesis of 18F radiotracers for positron emission tomography (PET), which utilizes aqueous solutions of 18F anions, generated by irradiation of 18O-enriched water. As lifetime of the 18F isotope is relatively short (t1/2=109.7 min) fast methods of incorporation of the aqueous 'hot' fluorides to biologically-active compounds, without need of time-consuming drying,17-19 are of particular demand.15,19-20 In our research project, focused on new applications of sulfur and selenium compounds in organic synthesis, we required to prepare alkanesulfonyl fluorides21 for application as olefinating reagents.22,23 To achieve this goal we applied method reported recently by Sharpless,24,25 in which sulfonyl chloride is vigorously stirred with saturated aqueous solution of potassium bifluoride (KHF2). In our hands the ‘on-water’ procedure appeared to be very efficient for methane-, and ethanesulfonyl fluorides, for which after 4 h substrate was not detected in the reaction mixture. However, under the same conditions 2-propanesulfonyl chloride and in particular 1-octanesulfonyl chloride displayed much diminished reactivity, and addition of acetonitrile as a co-solvent, was only partially helpful. Based on the observations we started studies of the reactions, in order to improve their efficiency.


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RESULTS AND DISCUSSION In model experiment of the Sharpless ‘on-water’ procedure24 we used alkanesulfonyl chloride (20.0 mmol), as an organic phase, and saturated aqueous solution of potassium bifluoride (40.0 mmol; 28% w/w), vigorously stirred in a 25 ml round bottom flask with magnetic bar at 1400 rpm (see the Experimental Section for details). In consistency with Sharpless observations,25 the process displayed excellent characteristics, with practically no byproducts formed, fast phases separation when the stirring was discontinued, and only little corrosion of the glassware, displaying practically no effect on the reaction course. First, we tested a series of alkanesulfonyl chlorides, differing in structure of the carbon chain from mesyl chloride to 1-octanesulfonyl chloride, and analyzed the reaction mixtures with GC. Results are presented at Figure 1.

Figure 1. GC profiles of reactions between alkanesulfonyl chlorides (R=methyl, ethyl, 1-propyl, 2-propyl, and 1-octyl), and saturated aqueous solution of potassium bifluoride carried out according to the ‘on-water’ procedure described by Sharpless.24,25


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Rates of the reactions under study displayed a gradual decrease, starting form mesyl chloride, which reacted within minutes to the completion, to 1-octanesulfonyl chloride, which after 4 h gave only traces of the expected fluoride. Interestingly, the latter reaction displayed only ca. 10% of conversion after one week of continuing stirring, in striking contrast to shorter carbon chain analogs. Interestingly, in a separate experiment dilution of the organic phase with equal volume of acetonitrile, applied by Sharpless for dissolution of solid substrates,25 raised the conversion to 20% after 4 h, and 94% after 7 days. However, for preparative purposes further improvement was required, considering that sulfonyl chlorides and fluorides display similar boiling points, and their separation is rather tedious. The observed trends in activity correlated well with length and branching of the alkyl chain, suggesting limited miscibility of aqueous and organic phases for more lipophilic substrates. To overcome this problem we decided to test presence of phasetransfer catalysts, widely applied in liquid-liquid two-phase systems, in which nucleophilic anions are transferred from aqueous to organic phase, entering reaction with organic substrates. Although Sharpless concluded that for synthesis of sulfonyl fluorides ‘phase transfer agents do not provide much benefit’,25,26 his further observations with Wu on SuFEx-based polycondensation between bisalkylsulfonyl fluorides and bisphenol bis(tert-butyldimethylsilyl)ethers revealed, that ammonium and phosphonium bifluorides display excellent catalytic activity, as compared with inactive KHF2, AgHF2, and moderately active crown ether/KHF2 system.27 For our studies we applied a set of tetraalkylammonium salts (1-5), tetraphenylarsonium chloride hydrochloride hydrate (6),28 and 18-crown-6 (7), as presented at Chart 1. The catalysts, used in 1 mol%, were tested in model reaction with 1-octanesulfonyl chloride, and results are shown at Figure 2.


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Chart 1. Phase-transfer catalysts tested in model reaction with 1-octanesulfonyl chloride.

Figure 2. GC profiles of reactions of 1-octanesulfonyl chloride and saturated aqueous solution of potassium bifluoride catalyzed with phase transfer catalysts.

Surprisingly, the catalysts applied at 1 mol%, displayed a range of activities from negligible effect of tetramethylammonium chloride (1) and benzyldimethyl(2-hydroxyethyl)ammonium


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chloride (3), to moderate activity of benzyltriethylammonium chloride (2) and 18-crown-6 (7), and to highly efficient tetraphenylarsonium chloride hydrochloride hydrate (6), tetrabutylammonium chloride (4a) and methyltrioctylammonium chloride (5).29 Although origin of the observed differences in activity was not entirely clear, we believed that lipophilicity of the catalyst cation, which forms an ion pair entering the organic phase, is a predominant factor.30 Considering extractive mechanism of the phase transfer catalysis,31 at the interfacial region lipophilic cation of the catalyst forms an ion pair with inorganic anion dissolved in the aqueous phase, which then enters the organic phase and reacts, giving an organic product and a new ion pair with leaving group of the substrate. The new ion pair again exchanges anion at the interfacial region, and migrate to the organic phase, closing the catalytic cycle. Key aspect of the efficient transportation is related with hydration energies of anions extracted from and released to the aqueous phase, and resulting anion-partitioning selectivity.32 If anion released in reaction running in the organic phase is more lipophilic (less solvated) than anion extracted from the aqueous phase, the process easily stops at low conversion of the substrate due to ‘poisoning effect’ of the catalyst, which forms a stable ion pair. Therefore poorly solvated iodides, delivered as catalyst’s counter ions33 or released in the catalyzed reaction,34 are able to poison the catalytic system. Interestingly, early studies of Brändström,35 concerning extraction of fluoride ions from aqueous solutions with ammonium salts, and further observations of Sasson on solid-liquid systems,9 indicated that even in the presence of chlorides extraction of fluorides to the organic phase is disfavored. The literature data clearly contrasted with our observations, where progress of the reaction remained constant, despite increased concentration of chlorides released to the aqueous phase from substrate. To obtain more insights into the catalytic system, and nature of


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the extracted species, we tested effect of counter ions of tetrabutylammonium salts (chloride 4a, hydrogensulfate 4b, and iodide 4c, Figure 3).

Figure 3. GC profiles of reactions of 1-octanesulfonyl chloride and saturated aqueous solution of potassium bifluoride catalyzed with tetrabutylammonium salts (4a-c).

In a series of tetrabutylammonium catalysts hydrophilic hydrogensulfate salt (4b) displayed essentially the same activity as chloride (4a), whereas iodide anion in catalyst 4c was able to noticeably decelerate the process. So evidently lipophilic iodides, although present in catalytic amount, were able to partially ‘poison’ the catalyst under these conditions.

Next, composition of the aqueous phase was varied. First, we checked reaction carried out with 28% aqueous solution of potassium fluoride (KF), instead of potassium bifluoride (KHF2). Intriguingly the obtained profile displayed initially fast conversion of the sulfonyl chloride, but


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after 5 min (ca. 20% of conversion) the reaction rate substantially lowered, and remained practically constant within next 4 hours (Figure 4).

Figure 4. GC profiles of reactions of 1-octanesulfonyl chloride and various sources of aqueous fluoride ions catalyzed with tetrabutylammonium chloride (4a).

In the following experiment a solution of KF was treated with half equivalent of hydrochloric acid (2KF + HCl  KHF2 + KCl), giving an inhomogeneous mixture of solution and precipitated salt. Fluorination of sulfonyl chloride with that mixture run at essentially the same rate as with solution of KHF2, suggesting that both systems (KHF2 and 2KF/HCl) are synthetically equivalent, without influence of the excessive chloride ions present in the system. Finally, we tested also what happens, when the solution of KHF2 is acidified with one equivalent of HCl, giving formally hydrogen fluoride (KHF2 + HCl  2HF + KCl). In this case extraction of the nucleophilic species was no longer possible, and the reaction stopped. It is worth to stress that


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form of the fluorides in the aqueous phase, can be easily changed from F− to HF2− and to HF by addition of acid, and solution of bifluorides, expectedly less nucleophilic then fluorides, reacts evidently faster with model 1-octanesulfonyl chloride. Although the observed reaction profiles are superposition of rates of ion extraction, intrinsic reaction running in the organic phase, activation of sulfonyl group and departing chloride anion with hydrogen bonds, presence of solvating water, etc. control of pH of aqueous solutions of fluorides seems to be an important factor for their practical application. In the next step we tested also effect of amount of the catalyst 4a, and rate of stirring on the reaction course (Figure 5).

Figure 5. GC profiles of reactions of 1-octanesulfonyl chloride and saturated aqueous solution of potassium bifluoride catalyzed with various amount of tetrabutylammonium chloride (4a) (0.1-5 mol%), and at different rates of stirring (500-1400 rpm).


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Amount of the catalyst controlled rate of the reaction stirred at 1400 rpm, which was completed after 15 min with 5 mol% of 4a, or led only to 34% of conversion after 4 h, when amount of the catalyst was decreased to 0.1 mol%. In turn stirring at 1400 rpm and 1000 rpm with 1 mol% of 4a led to very similar profiles, whereas at 500 rpm reaction progress was evidently slower, suggesting a limited interfacial area, where the ion exchange process takes place, or diffusion problems. Last, but not least effect of the phase transfer catalyst 4a was evaluated on a series of sulfonyl chlorides, and compared with original Sharpless 'on-water' conditions, successfully applied to plenty of substrates described in the literature.25 The original procedure usually utilizes acetonitrile as a co-solvent, which dissolves solid reactants, and improves miscibility of organic and aqueous phases. Therefore we tested three model substrates: 1-octanesulfonyl chloride, benzenesulfonyl chloride, and 2-propanesulfonyl chloride under conditions varied with the presence of 1 mol% of catalyst 4a, and the presence of acetonitrile (used in equal volume as substrate). The results are presented on Figures 6-8.


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Figure 6. GC profiles of reactions of 1-octanesulfonyl chloride and saturated aqueous solution of potassium bifluoride varied with the presence of tetrabutylammonium chloride (4a, 1 mol%) and solvent (acetonitrile or dichloromethane).


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Figure 7. GC profiles of reactions of benzenesulfonyl chloride and saturated aqueous solution of potassium bifluoride varied with the presence of tetrabutylammonium chloride (4a, 1 mol%) and solvent (acetonitrile).

Figure 8. GC profiles of reactions of 2-propanesulfonyl chloride and saturated aqueous solution of potassium bifluoride varied with the presence of tetrabutylammonium chloride (4a, 1 or 5 mol%) and solvent (acetonitrile).

Interestingly, in all cases under study presence of tetrabutylammonium chloride (4a) fastened formation of sulfonyl fluorides, whereas effect of the solvent was less straightforward. In general, dilution of the reaction mixtures with acetonitrile displayed positive or neutral effect on uncatalyzed reactions, and negative or neutral effect, when 4a was present. We reckon that


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improved miscibility of phases, caused by acetonitrile, substantially broadens interfacial region, where uncatalyzed reaction takes place, but at the same time fluoride anions become more solvated and less nucleophilic, that slows down the catalytic process. The idea was supported by the fact that dilution of catalyzed reaction with poorly miscible DCM slightly improved conversion (Figure 6), in contrast to observations of Sharpless, who reported that for original (uncatalyzed) procedure 'less polar solvents (CH2Cl2, toluene) give slower reactions'.25 Finally, to demonstrate practical aspects of the kinetic studies we carried out synthesis of 1-octanesulfonyl fluoride, benzenesulfonyl fluoride, and 2-propanesulfonyl fluoride at 100 mmol scale using our improved procedure with 1 mol% of 4a, without solvent. After work-up and distillation products were obtained in 95%, 93% and 74%36 of yield, respectively (see the Experimental Section for details).

Next we turned our attention to carbonyl analogs of sulfonyl fluorides - acyl fluorides. Acyl fluorides are important reagents applied e.g. for fluorination of chloropyridines,37 and their methods of preparation cover a range of reagents from bench-stable (Me4N)SCF3, easily converting carboxylic acids at r.t.,38 to dry solid KHF2, which slowly converts acyl chlorides on heating (100-170 °C) for a prolonged time.39 To the best of our knowledge method of synthesis of acyl fluorides in the presence of stoichiometric amount of water was never published.40 We tested original ‘on-water’ procedure (without solvent), varied with the presence of 4a as a catalyst (1 mol%) on two model substrates: octanoyl chloride and benzoyl chloride. The experiments were carried out at 20 mmol scale with 40 mmol of saturated aqueous solution of


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KHF2 stirred in a 25 ml round bottom flask at 1400 rpm for 4 h. The results are shown at Figure 9.

Figure 9. GC profiles of reactions of 1-octanoyl chloride (left) and benzoyl chloride (right), and saturated aqueous solution of potassium bifluoride with (bottom) and without (top) 1 mol% of catalyst 4a.


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For both substrates reactions carried out without catalyst caused only a gradual consumption of the substrate (acyl chloride, purple), accompanied with formation of octanoic anhydride (pink) and acid (yellow, Figure 9, top left), or a mixture of acyl fluoride (red), anhydride and acid in reaction of benzoyl chloride (Figure 9, top right). In turn addition of 1 mol% of the catalyst 4a in both cases made formation of the acyl fluoride a privileged process, and only after a prolonged stirring octanoyl fluoride, initially accumulated in the mixture, was slowly hydrolyzing. Interestingly, under the same conditions with 28% aqueous solution of KF and 1 mol% of 4a formation of acyl fluorides was very fast (maximum concentration was achieved in  15 min), but both products displayed limited stability, giving 50% of anhydride in the reaction mixture after 4 h. The data clearly indicated that catalytic system utilizing aqueous solution of potassium bifluoride and lipophilic tetraalkylammonium salt can be applied for nucleophilic fluorination of other electrophilic substrates. On the basis of the kinetic studies, without further optimization, we prepared two acyl fluorides by stirring of acyl chlorides (100 mmol) with two-fold excess of saturated aqueous solution of KHF2 and 1 mol% of catalyst 4a. The reactions were carried out at r.t. until conversion of the substrate was complete (1 h for octanoyl chloride, and 4 h for benzoyl chloride, as estimated from data shown at Figure 9). Then the mixtures were transferred to the separatory funnel, extracted with DCM, and combined organic phases were washed with saturated aqueous NaHCO3, and dried with MgSO4. After filtration, and evaporation of the solvent residues were distilled under reduced pressure to obtain octanoyl and benzoyl fluoride of high purities in 67% and 61% of yield, respectively (see the Supporting Information file for NMR spectra reproductions of the distillates). The mild reaction conditions, cheap and easily accessible substrates, and simple scalable procedure seem to be method of choice for laboratory gram-scale preparations of simple carboxylic fluorides.


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In the last part of our studies the catalytic system was tested on two other classes of substrates, usually used in benchmark reactions with fluorinating agents: nitroarenes,17,37 and alkyl halides and sulfonates.14,15,41 Solid nitroarenes were dissolved in 1,1,2,2-tetrachloroethane and vigorously stirred with aqueous solution of KHF2 and 5 mol% of 4a at 100 °C for 48 h. Under these conditions 3,4,5-trichloro-1-nitrobenzene, 1,4-dinitrobenzene, and 2-chloro-6nitrobenzonitrile17 failed to react, whereas 1-chloro-2,4-dinitrobenzene displayed ca. 20% of conversion to 1-fluoro-2,4-dinitrobenzene, as confirmed with GC and NMR. In turn alkylating agents (1-chlooctane, 1-octyl mesylate, and 1-octyl triflate) displayed more complex behavior (Figure 10).

Figure 10. Reactions of 1-chlorooctane, 1-octyl mesylate and 1-octyl triflate with saturated aqueous solution of potassium bifluoride and catalyst 4a.

Under mild conditions at r.t. with 1 mol% of 4a 1-chlorooctane and 1-octyl mesylate remained intact, but 1-octyl triflate12,41 slowly converted to di(1-octyl) ether, which after 48 h was isolated by distillation in 77% of yield. In crude mixture of the latter reaction we detected only traces of


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the expected 1-fluorooctane, accompanied with 1-chlorooctane and 1-octanol. However, under more vigorous conditions (100 °C, 48 h, 5 mol% of 4a) 1-chlooctane still remained unchanged, but 1-octyl mesylate led to a complex mixture, containing, according to GC, unreacted 1-octyl mesylate (15%), 1-fluorooctane (43%), 1-chlorooctane (5%), 1-octanol (19%), and di(1-octyl) ether (18%).

CONCLUSIONS Nucleophilic fluorination remains a challenging synthetic problem, and aqueous solutions of alkali metal fluorides are rarely applied for this purpose, due to high hydration energy of the fluoride ions.42 In our studies we demonstrated that aqueous solutions of fluorides, in particular bifluorides43 predominating at lower pH values, can be continuously extracted to the organic phase with lipophilic tetraalkylammonium cations, and react with electrophilic substrates, as sulfonyl chlorides and acyl chlorides. Preparation of acyl fluorides in the presence of stoichiometric amount of water is unprecedented in chemical literature. Our observations shed a new light on behavior of the fluoride ions under phase transfer conditions, inspiring design and testing of more efficient fluoride carriers, e.g. based on reversible covalent binding of the anions.17,18,28 Studies toward development of environmentally-benign fluorination protocols are presently ongoing in our laboratory.


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EXPERIMANTAL SECTION General Informations. 1-Octanesulfonyl chloride, 2-propanesulfonyl chloride, trifluoromethanesulfonyl anhydride were purchased from Fluorochem. Ethanesulfonyl chloride, 1-propanesulfonyl chloride, benzenesulfonyl chloride, octanoyl chloride, benzoyl chloride, 1,4dinitrobenzene, 3,4,5-trichloro-1-nitrobenzene, 1,4-diisopropylbenzene, potassium fluoride, tetramethylammonium chloride, benzyldimethyl(2-hydroxyethyl)ammonium chloride, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium hydrogensulfate, tetrabutylammonium iodide, methyltrioctylammonium chloride, 18-crown-6, tetraphenylarsonium chloride hydrochloride hydrate, 1,1,2,2-tetrachloroethane, 1-chlorooctane, 1-octanol, and pyridine were purchased from Sigma-Aldrich (presently Merck). Potassium bifluoride (Honeywell), methanesulfonyl chloride (Fluka), 1-chloro-2,4-dinitrobenzene (International Enzymes Limited), 2-chloro-6-nitrobenzonitrile (AlfaAesar) and triethylamine (Avantor Performance Materials Poland S.A.) were available from other sources. Commercially available solvents and materials were used without further purification. Filtration of solution of 1-octyl triflate was performed on silica gel (high purity grade, pore size 60 Å, 230-400 mesh particle size, 40-63 m, 60737). Analytical gas-liquid chromatography (GLC) was performed on a Perkin Elmer Clarus 580 chromatograph equipped with a flame ionization detector, and a GL Sciences InertCap 5MS/Sil column with helium as a carrier gas (column 0.25 mm30 m, carrier flow 1.5 ml/min, method parameters 50C, +10 C/min to 300 C, then 15 min at 300 C). 1H, 19

F and 13C NMR spectra were recorded on Agilent 400 MHz NMR spectrometer. Chemical

shifts (δ) are given in parts per million (ppm) with the solvent resonance as the internal standard (for CDCl3: 7.24 ppm, and 77.0 ppm), or with CFCl3 in CDCl3 (0.0 ppm for 19F NMR). Spin


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multiplicity was abbreviated as follows: s – singlet, d – doublet, t – triplet, q – quartet, hept – heptet.

General procedure for kinetic experiments. A 25 mL round-bottom flask was charged with potassium bifluoride (3.12 g; 40.0 mmol) and water (8.03 g), and stirred at r.t. for 1 h. Then, sulfonyl chloride or acyl chloride (20.0 mmol), 1,4-diisopropylbenzene (ca. 0.75 g; not used for reactions of methane-, ethane-, and 1-propanesulfonyl chlorides), and catalyst 4a (0.056 g; 0.20 mmol; 1 mol%) were added, and the mixture was stirred with magnetic bar (fish; 1020 mm) at 1400 rpm. Samples (one drop of the organic phase) were taken in time intervals of 0 min, 5 min, 15 min, 1 h, 2 h, and 4 h, when stirring was discontinued for a short period, until phases separated. Samples were dissolved in DCM or ethyl acetate (ca. 1.7 ml), and analyzed with GC (each sample was analyzed two times, and results were averaged). Analysis of the collected data revealed that reaction profiles plotted using calculations based on the internal standard, and based on a sum of the mixture components are very similar, and thus plots shown at Figures 1-9 were created using calculations based on sum of the mixture components. In all reactions carried out with 28% aqueous solution of KF we used 80 mmol of the reagent. In crude reaction mixtures of acyl chlorides GC analyses revealed presence of 4 peaks: acyl chloride (substrate), acyl fluoride (compared with sample obtained in a preparative experiment), and two other components assigned as carboxylic acid and anhydride with NMR and GC/MS.


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Preparative synthesis of 1-octanesulfonyl fluoride. A 100 ml round-bottom flask was charged with potassium bifluoride (15.63 g; 200.1 mmol) and water (40.17 g), and stirred at r.t. for 1 h. Then, 1-octanesulfonyl chloride (21.28 g; 100.0 mmol) and tetrabutylammonium chloride (4a; 0.279 g; 1.0 mmol; 1 mol%) were added, and the mixture was stirred with magnetic bar (fish; 1533 mm) at 1400 rpm. After 4 h the mixture was transferred to the separatory funnel, extracted with DCM (2×100 ml), and combined organic phases were dried with MgSO4 . The mixture was filtered, evaporated and residue was distilled under reduced pressure to obtain 1-octanesulfonyl fluoride (18.67 g; 95.14 mmol; 95%) collected at 56-66 C/1.510-2 mbar as a colorless liquid. 1

H NMR (400 MHz, CDCl3) δ 3.37-3.28 (m, 2H), 1.98-1.85 (m, 2H), 1.51-1.39 (m, 2H), 1.37-

1.18 (m, 8H), 0.89-0.82 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 50.8 (d, 2JC-F=16.0 Hz), 31.6, 28.76, 28.71, 27.8, 23.3, 22.5, 14.0. 19F NMR (376 MHz, CDCl3) δ 52.69 (t, 3JF-H=4.2 Hz), 52.65 (t, 3JF-H=4.3 Hz, resonance of 34S molecule, ca. 5%).

Preparative synthesis of benzenesulfonyl fluoride. A 100 ml round-bottom flask was charged with potassium bifluoride (15.62 g; 200.1 mmol) and water (40.17 g), and stirred at r.t. for 1 h. Then, benzenesulfonyl chloride (17.66 g; 100.0 mmol) and tetrabutylammonium chloride (4a; 0.278 g; 1.0 mmol; 1 mol%) were added, and the mixture was stirred with magnetic bar (fish; 1533 mm) at 1400 rpm. After 2 h the mixture was transferred to the separatory funnel, extracted with DCM (2×100 ml), and combined organic phases were dried with MgSO4 . The mixture was filtered, evaporated and residue was distilled under reduced pressure to obtain


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benzenesulfonyl fluoride (14.88 g; 92.92 mmol; 93%) collected at 69-71 C/8 mbar as a colorless liquid. 1

H NMR (400 MHz, CDCl3) δ 8.02-7.96 (m, 2H), 7.80-7.73 (m, 1H), 7.66-7.57 (m, 2H). 13C

NMR (100 MHz, CDCl3) δ 135.6 (d, 3JC-F=0.8 Hz), 132.9 (d, 2JC-F=24.2 Hz), 129.6, 128.3. 19F NMR (376 MHz, CDCl3) δ 65.43, 65.39 (resonance of 34S molecule, ca. 5%).

Preparative synthesis of 2-propanesulfonyl fluoride. A 100 ml round-bottom flask was charged with potassium bifluoride (15.62 g; 200.1 mmol) and water (40.17 g), and stirred at r.t. for 1 h. Then, 2-propanesulfonyl chloride (14.26 g; 100.0 mmol) and tetrabutylammonium chloride (4a; 0.279 g; 1.0 mmol; 1 mol%) were added, and the mixture was stirred with magnetic bar (fish; 1533 mm) at 1400 rpm. After 28 h the mixture was transferred to the separatory funnel, extracted with DCM (2×100 ml), and combined organic phases were dried with MgSO4 . The mixture was filtered, evaporated and residue was distilled under reduced pressure to obtain 2-propanesulfonyl fluoride (9.58 g; 75.9 mmol; 74%) collected at 48-52 C/35 mbar as a colorless liquid. 1

H NMR (400 MHz, CDCl3) δ 3.54 (heptd, J=6.9, 2.1 Hz, 1H), 1.50 (dd, J=6.9, 0.9 Hz, 6H).

13

C NMR (100 MHz, CDCl3) δ 53.5 (d, 2JC-F=14.6 Hz), 16.5. 19F NMR (376 MHz, CDCl3) δ

38.62, 38.58 (resonance of 34S molecule, ca. 5%).

Preparative synthesis of octanoyl fluoride. A 100 ml round-bottom flask was charged with potassium bifluoride (15.63 g; 200.1 mmol) and water (40.17 g), and stirred at r.t. for 1 h. Then,


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octanoyl chloride (16.27 g; 100.0 mmol) and tetrabutylammonium chloride (4a; 0.278 g; 1.0 mmol; 1 mol%) were added, and the mixture was stirred with magnetic bar (fish; 1533 mm) at 1400 rpm. After 1 h the mixture was transferred to the separatory funnel, extracted with DCM (2×100 ml), combined organic phases were washed with saturated aqueous solution of NaHCO3 (50 ml), and dried with MgSO4 . The mixture was filtered, evaporated and residue was distilled under reduced pressure to obtain octanoyl fluoride (9.78 g; 66.9 mmol; 67%) collected at 64-66 C/30 mbar as a colorless liquid. 1

H NMR (400 MHz, CDCl3) δ 2.47 (td, J=7.4, 1.2 Hz, 2H), 1.64 (tt, J=7.5, 7.4, Hz, 2H), 1.40-

1.19 (m, 8H), 0.89-0.82 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 163.6 (d, 1JC-F=361 Hz), 32.3, 31.8, 31.5, 28.7 (d, 2JC-F= 8.4 Hz), 23.9 (d, 3JC-F= 1.8 Hz), 22.5, 14.0. 19F NMR (376 MHz, CDCl3) δ 44.6.

Preparative synthesis of benzoyl fluoride. A 100 ml round-bottom flask was charged with potassium bifluoride (15.63 g; 200.1 mmol) and water (40.17 g), and stirred at r.t. for 1 h. Then, benzoyl chloride (14.06 g; 100.0 mmol) and tetrabutylammonium chloride (4a; 0.280 g; 1.0 mmol; 1 mol%) were added, and the mixture was stirred with magnetic bar (fish; 1533 mm) at 1400 rpm. After 4 h the mixture was transferred to the separatory funnel, extracted with DCM (2×100 ml), combined organic phases were washed with saturated aqueous solution of NaHCO3 (3×50 ml), and dried with MgSO4 . The mixture was filtered, evaporated and residue was distilled under reduced pressure to obtain benzoyl fluoride (7.57 g; 61.0 mmol; 61%) collected at 56 C/27 mbar as a colorless liquid.


23


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Page 24 of 35

H NMR (400 MHz, CDCl3) δ 8.03-7.97 (m, 2H), 7.72-7.63 (m, 1H), 7.53-7.45 (m, 2H). 13C

NMR (100 MHz, CDCl3) δ 157.3 (d, 1JC-F=344 Hz), 135.2 (d, 5JC-F=1.2 Hz), 131.3 (d, 3JC-F=3.8 Hz), 129.0 (d, 4JC-F=1.3 Hz), 124.8 (d, 2JC-F=60.7 Hz). 19F NMR (376 MHz, CDCl3) δ 17.6.

Reactions of nitroarenes. A 25 mL round-bottom flask was charged with potassium bifluoride (3.12 g; 40.0 mmol; 10:1 molar excess) and water (8.04 g), and stirred at r.t. for 1 h. Then, nitroarene (4.0 mmol), 1,1,2,2-tetrachloroethane (3.5 ml), and tetrabutylammonium chloride (4a; 0.056 g; 0.20 mmol; 5 mol%) were added, and the mixture was stirred with magnetic bar (fish; 1020 mm) at 700 rpm in oil bath at 100 °C. After 48 h the mixture was cooled to r.t., and sample was analyzed with GC and NMR. In case of reaction with 1-chloro2,4-dinitrobenzene NMR spectra of the reaction mixture revealed presence of 1-fluoro-2,4dinitrobenzene: 1H NMR (400 MHz, CDCl3): δ 8.98-8.92 (m, 1H), 8.53 (ddd, J=9.2, 3.7, 2.8 Hz, 1H), 7.50 (t, J=9.1 Hz, 1H). 19F NMR (376 MHz, CDCl3) δ -106.1 (ddd, J=9.8, 6.4, 3.6 Hz).

Synthesis of 1-octyl mesylate. A 500 ml round-bottom flask was charged with 1-octanol (26.39 g; 202.7 mmol), triethylamine (31.0 ml; 22.5 g; 222 mmol), DCM (100 ml), and flushed with argon. To the resulted solution mesyl chloride (25.26 g; 220.5 mmol) was added dropwise with stirring, when the mixture became yellowish. After 30 min water (100 ml) was added, the mixture was transferred to the separatory funnel, extracted with ethyl acetate (3×100 ml), and combined organic phases were washed with water (100 ml), brine (100 ml), and dried with MgSO4 . The mixture was filtered, evaporated and residue was distilled under reduced pressure


24

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at 2.0×10-1 mbar (bath temp.=120 °C) to obtain 1-octyl mesylate (30.75 g; 186.0 mmol; 92%) collected as a colorless liquid. 1

H NMR (400 MHz, CDCl3) δ 4.10 (t, J=6.6 Hz, 2H), 2.89 (s, 3H), 1.68-1.58 (m, 2H), 1.35-

1.25 (m, 2H), 1.25-1.09 (m, 8H), 0.81-0.73 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 70.1, 36.8, 31.4, 28.78, 28.76, 28.66, 25.1, 22.3, 13.7.

Reaction of 1-octyl mesylate at 100 C. A 25 mL round-bottom flask was charged with potassium bifluoride (3.13 g; 40.0 mmol) and water (8.04 g), and stirred at r.t. for 1 h. Then, 1-octyl mesylate (4.16 g; 20.0 mmol), and tetrabutylammonium chloride (4a; 0.276 g; 1.0 mmol; 5 mol%) were added, and the mixture was stirred with magnetic bar (fish; 1020 mm) at 700 rpm in oil bath at 100 °C. After 48 h the mixture was cooled to r.t., and sample was analyzed with GC/MS and NMR. NMR spectra revealed mixture of products, containing 1-fluorooctane: 1

H NMR (400 MHz, CDCl3)  4.39 (dt, J=47.4, 6.2 Hz, 4H). 19F NMR (376 MHz, CDCl3) 

-218.0 (tt, J=47.4, 24.8 Hz).

Synthesis of 1-octyl triflate. A 100 ml Schlenk flask was argonated, and charged with 1-octanol (5.5 ml; 4.55 g; 34.9 mmol), anhydrous pyridine (3.4 ml; 3.33 g; 42.0 mmol) and anhydrous DCM (50 ml). The flask was cooled in acetone bath to -10 °C, and trifluoromethanesulfonyl anhydride (6.5 ml; 10.9 g; 38.6 mmol) was added dropwise with stirring over 2 min. A white precipitate was formed. The stirring was continued for 30 min, when temperature was kept at -10 to -5 °C. Then, the mixture was poured into aqueous H2SO4 (0.5 M;


25


Page 26 of 35

50 ml), transferred to separatory funnel, and extracted with DCM (2×50 ml). Combined organic phases were washed with water (50 ml), brine (50 ml), and dried with MgSO4. The mixture was filtered through a pad of silica gel (ø 60 mm; height 70 mm; the filtration removed polar UVvisible spot on TLC, likely N-octylpyridinium salt), rinsed with DCM (500 ml), and evaporated under high vaccum to obtain 1-octyl triflate (5.14 g; 19.6 mmol; 56%) as a yellowish turbid liquid. 1

H NMR (400 MHz, CDCl3) δ 4.51 (t, J=6.5 Hz, 2H), 1.84-1.76 (m, 2H), 1.45-1.36 (m, 2H),

1.36-1.19 (m, 8H), 0.89-0.83 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 118.7 (q, 1JC-F=319 Hz), 77.8, 31.7, 29.2, 29.0, 28.8, 25.0, 22.6, 14.0. 19F NMR (376 MHz, CDCl3) δ -75.5.

Reaction of 1-octyl triflate at r.t. A 25 mL round-bottom flask was charged with potassium bifluoride (3.13 g; 40.0 mmol) and water (8.04 g), and stirred at r.t. for 1 h. Then, 1-octyl triflate (4.98 g; 19.0 mmol), and tetrabutylammonium chloride (4a; 0.053 g; 0.19 mmol; 1 mol%) were added, and the mixture was stirred with magnetic bar (fish; 1020 mm) at 1400 rpm for 48 h, when GC analysis showed complete conversion of the substrate (after 8 h conversion was ca. 50%, according to GC). Then, the mixture was transferred to the separatory funnel, extracted with DCM (2×50 ml), and combined organic phases were dried with MgSO4 . The mixture was filtered, evaporated and residue was distilled under reduced pressure at 2.0-4.010-2 mbar (bath temp.=130 C) to obtain di(1-octyl) ether (1.78 g; 7.33 mmol; 77%) a colorless oil. 1

H NMR (400 MHz, CDCl3) δ 3.35 (t, J=6.7 Hz, 4H), 1.58-1.48 (m, 4H), 1.36-1.15 (m, 20H),

0.89-0.79 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 70.9, 31.8, 29.8, 29.5, 29.3, 26.2, 22.7, 14.1.


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ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 1

H, 19F and 13C NMR spectra of isolated fluorides and intermediates (PDF)

AUTHOR INFORMATION Corresponding Author * Tel. (+48) 22 55 26 750. Fax: (+48) 22 822 59 96. E-mail: [email protected]. Web: www.aromaticity.pl. ORCID: Michał Barbasiewicz: 0000-0002-0907-7034. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS This work was financed by the SONATA BIS program of the National Science Centre, Poland (NCN, Grant No. DEC-2013/10/E/ST5/00030).

ABBREVIATIONS NMR, nuclear magnetic resonance; DCM, dichloromethane; GC, gas chromatography; Am, amyl (pentyl); Bu, butyl; Et, ethyl; Me, methyl; Ph, phenyl.


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Page 28 of 35

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28. For application of tetraarylarsonium salts as phase transfer catalysts, see: Grudzień, K.; Basak, T.; Barbasiewicz, M.; Wojciechowski, T. M.; Fedoryński, M. Synthesis, properties and application of electronically-tuned tetraarylarsonium salts as phase transfer catalysts (PTC) for the synthesis of gem-difluorocyclopropanes. J. Fluor. Chem. 2017, 197, 106-110 DOI 10.1016/j.jfluchem.2017.03.014. 29. Industrial equivalent of methyltrioctylammonium chloride is known as Aliquat 336®. 30. For recent studies of effect of the catalyst lipophilicity in two-phase system, see: Hamkalo, M.; Fita, P.; Fedorynski, M.; Makosza, M. Interfacial Generation of a Carbanion: The Key Step of PTC Reaction Directly Observed by Second Harmonic Generation. Chem. Eur. J. 2018, accepted DOI: 10.1002/chem.201705597. 31. Starks, C. M. Phase-Transfer Catalysis. I. Heterogeneous Reactions Involving Anion Transfer by Quaternary Ammonium and Phosphonium Salts. J. Am. Chem. Soc. 1971, 93, 195199 DOI 10.1021/ja00730a033. 32. For a discussion of ion effects in concentrated aqueous solutions, see: Hyde, A. M.; Zultanski, S. L.; Waldman, J. H.; Zhong, Y.-L.; Shevlin, M.; Peng. F. General Principles and Strategies for Salting-Out Informed by the Hofmeister Series. Org. Process Res. Dev. 2017, 21, 1355-1370 DOI 10.1021/acs.oprd.7b00197. 33. Bar, R.; de la Zerda, J.; Sasson, Y. Kinetics in Phase-transfer Catalysis: a Theoretical Study. Part 1. Poisoning Effect by Catalyst Foreign Ion. J. Chem. Soc., Perkin Trans. 2 1984, 1875-1879 DOI 10.1039/P29840001875.


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34. Gordon, J. E.; Kutina, R. E. On the Theory of Phase-Transfer Catalysis. J. Am. Chem. Soc. 1977, 99, 3903-3909 DOI 10.1021/ja00454a002. 35. Brändström, A. Principles of Phase-Transfer Catalysis by Quaternary Ammonium Salts. Adv. Phys. Org. Chem. 1977, 15, 267-330 DOI 10.1016/S0065-3160(08)60120-3. 36. Isolated yield of 2-propanesulfonyl fluoride was improved to 79%, when 5 mol% of the catalyst 4a was applied and the reaction was carried out for 4 h, however distillate contained ca. 2% of substrate, according to 1H NMR. When experiment with 1 mol% of 4a was repeated with D2O solution of KHF2 (28 h, 20 mmol scale), and aqueous phase was directly analyzed with NMR we observed presence of only traces of two components in 4:1 ratio, assigned as 2-propanesulfonyl fluoride: 1H NMR (400 MHz, D2O) δ 3.71 (heptd, J=6.9, 3.5 Hz, 1H), 1.26 (dd, J=6.9, 0.8 Hz, 6H), 19F NMR (376 MHz, D2O) δ 37.30 (d, 3JF-H=3.5 Hz), 37.26 (d, 3JF-H=3.5 Hz, resonance of 34S molecule, ca. 5%); and 2-propanesulfonic acid: 1H NMR (400 MHz, D2O) δ 2.79 (hept, J=6.9 Hz, 1H), 1.00 (d, J=6.9 Hz, 6H). No other byproducts were detected in the reaction mixture. 37. Ryan, S. J.; Schimler, S. D.; Bland, D. C.; Sanford, M. S. Acyl Azolium Fluorides for Room Temperature Nucleophilic Aromatic Fluorination of Chloro- and Nitroarenes. Org. Lett. 2015, 17, 1866-1869 DOI 10.1021/acs.orglett.5b00538. 38. Scattolin, T.; Deckers, K.; Schoenebeck, F. Direct Synthesis of Acyl Fluorides from Carboxylic Acids with the Bench-Stable Solid Reagent (Me4N)SCF3. Org. Lett. 2017, 19, 57405743 DOI 10.1021/acs.orglett.7b02516.


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39. Oláh, G.; Kuhn, S.; Beke, S. Darstellung und Untersuchung organischer Fluorverbindungen XX.

Darstellung

von

Säurefluoriden.

Chem.

Ber.

1956,

89,

862-864

DOI

10.1002/cber.19560890404. 40. Catalytic amount of water (1%) was applied to promote reaction of acyl chlorides with KF: Tordeux, M.; Wakselman, C. Reaction of Potassium Fluoride in the Presence of Tetraalkylammonium Halides. Preparation of Acylfluorides and Fluoroformates. Synth. Commun. 1982, 12, 513-520 DOI 10.1080/00397918208063689. 41. Kim, K.-Y.; Kim, B. C.; Lee, H. B.; Shin, H. Nucleophilic Fluorination of Triflates by Tetrabutylammonium Bifluoride. J. Org. Chem. 2008, 73, 8106-8108 DOI 10.1021/jo8015659. 42. Yang, L.; Dong, T.; Revankar, H. M.; Zhang, C.-P. Recent progress on fluorination in aqueous media. Green Chem. 2017, 19, 3951-3992 DOI 10.1039/C7GC01566F. 43. Ramabhadran, R. O.; Liu, Y.; Hua, Y.; Ciardi, M.; Flood, A. H.; Raghavachari, K. An Overlooked yet Ubiquitous Fluoride Congenitor: Binding Bifluoride in Triazolophanes Using Computer-Aided Design. J. Am. Chem. Soc. 2014, 136, 5078-5089 DOI 10.1021/ja500125r.


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GRAPHICAL ABSTRACT

SYNOPSIS An aqueous solution of potassium bifluoride with lipophilic tetraalkylammonium catalyst fluorinates acyl and sulfonyl chlorides under ambient conditions.


35

Nucleophilic Fluorination with Aqueous Bifluoride Solution: Effect of

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