Reactions of 4-substituted-1-[(difluoromethyl)sulfinyl]polyfluorobenzenes with phenolate anion

The reactions of 4-substituted-polyfluorinated-[(difluoromethyl)sulfinyl]benzenes ([4-X-C 6 F 4 S(O)CHF 2 [X = H, CF 3 and C 6 F 5 S(O)]) with phenolate anion in benzene, Et 2 O and CH 3 CN have been investigated. The reactions of the substrate (X = H, CF 3 ) and sodium phenolate in equal amounts resulted in the formation of mixtures of the starting compound, 2-phenoxyderivative and disubstituted products. The two-fold amount of the phenolate afforded the 2,6-disubstituted products for X = H in MeCN and for X = CF 3 in Et 2 O. At the same time, 4-CF 3 - C 6 F 4 S(O)CHF 2 in CH 3 CN gave a mixture of the 2,6-and 2,5-bis(phenoxy) derivatives. Quantum chemical calculations have been performed to explain this phenomenon. For X = C 6 F 5 S(O) in MeCN, the reaction was accompanied by sulfinyl moiety ipso-substitution.


Introduction
Polyfluorinated organic compounds have found wide practical application. 1 Recently, research into functional derivatives and, in particular, sulfur-containing compounds, has been developing in the area of polyfluorinated organic compounds. 1The reactions of sulfur-containing polyfluoroarenes with nucleophiles are being studied. 2,3,4The sulfur atom oxidation state in such compounds can significantly affect the rate and direction of the reaction. 5or polyfluoroaromatic compounds, nucleophilic substitution reactions are most typical. 6,7The presence of an acceptor in the polyfluorinated ring, for example, the difluorosulfinyl group, should facilitate the substitution of fluorine atom, which opens up wide possibilities for various transformations.
.10 Sulfoxides containing four or more fluorine atoms, however, are practically unknown.Meanwhile, difluoromethyl derivatives of sulfoxides can be obtained on the basis of available polyfluorinated arene thiols 11,12 by their reaction with chlorodifluoromethane, followed by oxidation of the resulting sulfanes.
In connection with the foregoing, we have focused our attention on polyfluoroaromatic sulfoxides bearing a difluoromethyl group since compounds of such structure have not been reported.For this reason, it was reasonable to study the properties and transformations of such compounds.
Recently we have shown that [(difluoromethyl)sulfinyl]pentafluorobenzene, C 6 F 5 S(O)CHF 2 , readily undergoes attack on the polyfluoroaromatic core, with substitution of the para-fluorine atom for OMe, OPh, NHMe and SH groups under the action of the charged (NaOMe, NaOPh, KSH) or uncharged (NH 2 Me) nucleophiles.The direction of substitution is consistent with the expected one. 6Surprisingly, the action of alkali (NaOH) on C 6 F 5 S(O)CHF 2 led to its decomposition, with formation of pentafluorobenzene.This result might be attributed to the attack on the sulfur atom. 14he task of the current research was to study the transformations of para-substituted [(difluoromethyl)sulfinyl]tetrafluorobenzenes, 4-XC 6 F 4 S(O)CHF 2 [where X = H (1), CF 3 (2) and S(O)C 6 F 5 (3)] in reactions with nucleophiles, e.g., the phenolate ion.Such substrates do not have a para-fluorine atom, are sensitive to nucleophilic attack and, thus, new routes of reaction may be revealed.Phenolate ion is widely used in test experiments and kinetic measurements. 15Since it was necessary for this study to avoid the presence of water in the reaction mixture, sodium phenolate was obtained by the action of sodium hydride on phenol.The reaction process was monitored by means of 19 F NMR spectroscopy.Further confirmation of the structures of the reaction products, if necessary, were proven by counter (alternative) syntheses.
We have shown that reactions of [(difluoromethyl)sulfinyl] benzenes (1-3) with sodium phenolate led to the nucleophilic substitution of fluorine in the neighboring position of the [(difluoromethyl)sulfinyl] group for phenoxide (1).The subsequent substitution reaction also occurred, however, its selectivity depended on the electronic properties of the substituent in the polylfluoroaryl core and solvent polarity.The obtained experimental results are also discussed using quantum-chemical calculations.
Scheme 2 The resulting products, however, were not stable under GC-MS analysis conditions.For these reasons, we tried to reduce S-O fragments of the obtained sulfinylbenzenes.This would have simplified the reaction-mixture composition, since sulfane moieties were not able to form optical isomers.A control experiment consisting of the reduction of compound 3, using AcCl 16 under reflux conditions, resulted in the formation of (difluoromethyl)[2,3,5,6-tetrafluoro-4-(perfluorophenylthio)phenyl]sulfane (9) (92% isolated yield), and demonstrated the feasibility of this approach (Scheme 3).
Such a reduction procedure for non-fluorinated sulfoxides is known to demand not such severe conditions, but the reactivity of the polyfluorinated substrates turned out to be remarkably less. 16The electron-withdrawing character of polyfluoroaryl moiety seems to prevent the effective coordination of the acetyl chloride and sulfinyl group.
In connection with the foregoing, the reaction mixtures were also subjected to the action of acetyl chloride at reflux temperature.To prevent the chlorination of phenoxy groups, toluene was added to the reaction mixture; the resulting formation of benzyl chloride was recorded using GC-MS spectrometry.Nevertheless, even after the action of acetyl chloride, the obtained mixtures were rather complex and it was not possible to separate them into individual compounds.For this reason, the individual compounds have been synthesized by counter synthesis to provide us with reliable data about the products' structures.
Therefore, the resulting mixtures were analyzed by means of GC-MS spectrometry and 19 F NMR spectroscopy for comparison with these specially prepared compounds' spectra.The yields of the products were calculated using 19 F NMR spectroscopy with an internal quantitative standard.
Elucidation of the structures of the products obtained are supported by NMR spectra included in the Supplementary Materials.

Mechanistic rationale
The results obtained might be explained in terms of an aromatic nucleophilic substitution mechanism.Aromatic nucleophilic substitution in polyfluoroarenes is known to proceed in a step-wise addition-elimination process; addition of the nucleophile is usually a rate-determine stage. 17,18The regioselectivity of substitution of fluorine in monosubstituted pentafluorobenzenes (C 6 F 5 X) is governed mainly by the other fluorine atoms rather that the group X, with the exception of powerful electron-donating groups. 6robably for similar reasons, the starting sulfoxide (1 or 2) and phenoxyderivative (4 or 6, respectively) demonstrated very similar reaction capabilities.Fluorine atoms in position 2 of the starting sulfoxides are activated by the difluoromethylsulfinyl group toward nucleophilic aromatic substitution.The fluorine atoms in position 6 of the substituted products ( 4) and ( 6) undergo the same degree of activation, while the influence of the phenoxy group situated in the meta position is low.
At the same time, the reaction abilities of the fluorine atoms in position 5 of products ( 4) and ( 6) vary depending on the character of the group X. Compound (4) reacts with sodium phenolate selectively at position 6, while the fluorine atom in position 5 remains unreactive.On the contrary, sulfoxide (6) undergoes nucleophilic substitution at positions 5 and 6 with formation of compounds ( 8) and (7), respectively.This effect is obviously a result of a strong electron-withdrawing influence of the trifluoromethyl group, such that it can stabilize the carbanion formed by addition of the phenolate-anion at position 5 of sulfoxide (6).

Investigation of reversibility formation of bisphenoxy compounds (7) and (8)
For a better comprehension of the formation process of compounds 7 and 8, it was necessary to find out if these compounds could transform into each other under the reaction conditions.A mixture of bisphenoxy derivatives ( 7) and ( 8) (ratio 66 : 34 by 19 F NMR) and NaF was obtained from the interaction of sulfoxide (2)  with PhONa (2 eq) after 0.5 h in MeCN.A pure sample of individual compound (7) (0.22 eq) was added to the specified mixture, so that the ratio of compounds ( 7) and ( 8) became 72 : 28 ( 19 F NMR).The resulting mixture was kept at the reaction conditions for an additional 0.5 h and then analyzed by means of 19 F NMR.The ratio of 7 and 8 was not effectively changed indicating no significant reversibility of aromatic nucleophilic substitution; the fluoride anion could not split the carbon-oxygen bond formed, and no equilibrium between isomers ( 7) and ( 8), under the reaction conditions employed (Scheme 6).Scheme 6. Reversibility experiment results showing no reversibility or equilibrium for arenes (7) and (8).

Quantum chemical calculations
The ratio of diphenoxy derivatives in the interaction of compounds ( 4) and ( 6) with the one equivalent of sodium phenolate was determined by means of the quantum chemical calculations of the relative stabilities of sigma-complexes (type A and B), which are generally considered to be on the path of the nucleophilic substitution reaction (Scheme 7).
The results of quantum-chemistry calculations provided evidence that the probability of the reaction of the nucleophile with the carbon atom in position 5 of sulfoxide (4) is ca. 5 kcal per mole more likely than that in position 6, while positions 5 and 6 of the sulfoxide (6) revealed nearly the same reactivities.Scheme 7. Formation of sigma-complexes from compounds 4 or 6 and the phenolate anion.
As shown below in Table 3, the difference in the total energies of the resulting sigma-complexes is greater in the case of compound 4 (X = H) than for compound 6 (Х = CF 3 ).Independent of the solvent, in the case of X = H, 2,6-bisphenoxy derivative (5) will form predominantly.In the case of Х = CF 3 , however, sigma-complexes of types A and B turn out to be close in terms of total energy values, so we should expect the formation of both products 7 and 8.The calculations even predict the approximately equal reaction ability of positions 5 and 6 of compound 6.Where ΔE = E (B) -E (A).

Reactions of compounds (4) and (6) with ammonium phenolates
We tried to check this assumption by implementation of the same set of chemical transformations of sulfinylbenzenes ( 4) and ( 6) with ammonium phenolate.Tetraalkylammonium salts are considered to display almost pure ionic character between cation and anion species; therefore, such salts are used extensively as phase transfer catalysts. 19We supposed that the change in the nature of the cation could affect the ratio of the products of the reaction of compound 6 and the phenolate ion.1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) is known to be a weakly nucleophilic base and is widely used in organic synthesis. 20Reaction of 3-[(difluoromethyl)sulfinyl]-1,2,5-trifluoro-4-phenoxybenzene (4) with phenol in the presence of DBU expectedly led, exclusively, to the formation of product (5) (Scheme 8).No differences in the direction of the process were observed (Table 4: entries 1, 2).On the contrary, the combination of DBU and phenol in the reaction with substrate (6) led to formation of various mixtures of products ( 7) and ( 8), depending on the polarity of the solvent employed.The ratio of 7 : 8 turned out to be 72 : 28 in non-polar PhH, 64 : 36 in ether and 50 : 50 in polar MeCN (Table 4, entries 3-5).This result provides evidence that the observed reaction of aromatic fluorine substitution with sodium phenolate probably involves ion pairs, but not the pure phenolate anion.For this reason, the looser ion pair formed by means of DBU displays higher reactivity.
To further verify our assumption, we synthesized benzyltriethylammonium phenolate by an exchange reaction of sodium phenolate with excess of benzyltriethylammonium chloride (TEBAC).The excess of TEBAC was sufficient to prevent introduction of sodium cation to the desired ammonium phenolate.When compound (6) was subjected to the action of [NBnEt 3 ][OPh] (1 eq.), either at room or at cold temperatures, a complex mixture of unidentified byproducts, together with 7 and 8, was formed.For this reason, and due to the high reactivity of this ammonium salt, further experiments were performed with a less-than-equivalent quantity of reagent at low temperature.It was demonstrated that the reaction of compound (6) with 0.45 eq. of [NBnEt 3 ][OPh] in Et 2 O gave compounds (7) and ( 8) in a ratio of 28 : 13 (Table 4, entry 6), while reaction with 0.3 mole of [NBnEt 3 ][OPh] in MeCN resulted in the formation of equal amounts of products ( 7) and (8) (Table 4, entry 7).This result, in comparison with the reaction with sodium phenolate, shows that cation has some sort of influence on the reaction ability of the phenolate anion.

Possible mechanism for the reaction of polyfluorinated sulfinylbenzenes and sodium phenolate
We supposed that the selective formation of compound (7) in the reaction of 2 with sodium phenolate in ether (Table 2, entry 4) might be explained by a specific interaction between the reagents in non-polar solvents through coordination of the sodium atom with the oxygen atom of the difluoromethylsulfinyl group, according to Scheme 9 below.Such an association would promote the attack of the carbon atom in position 6 of compound (6) by the phenolate ion, with the formation of the sigma-complex (6C).The carbon-fluorine bond is then cleaved to give compound (7), and sodium fluoride is formed and precipitates out.The analogous schemes as possible explanations were suggested by various researchers to describe the reactivity of pentafluoropyridine and pentafluoronitrobenzene. 21,22 Scheme 9. Possible mechanism for the reaction of polyfluorinated sulfinylbenzene (6) and sodium phenolate.
Compared to sulfinylbenzenes (1) and ( 2), the behavior of compound (3) in reactions with sodium phenolate is obviously more complicated, if only because there are two polyfluoroaromatic rings and two sulfinyl groups capable of reactions.At the same time, the solvent polarity also determines the direction of the transformations of compound 3.
As the polarity of benzene is low, the dissociation of sodium phenolate is hardly possible.It is more likely that sodium phenolate coordinates with the oxygen atoms of the sulfinyl groups of 3 which is analogous to the way it is presented in Scheme 9.The difluoromethylsulfinyl group seems to be less hindered and, therefore, preferable for coordination than the diarylsulfinyl group.For this reason, the para-position of structure 3 likely becomes inaccessible for the phenolate ion to attack, and nucleophilic attack on the adjacent carbon atom would, therefore, seem to be the most natural way.The substituted products thus formed are reduced by acetyl chloride to give compounds 13, 14 and 15, respectively.
On the other hand, a polar solvent such as MeCN likely promotes the dissociation of sodium phenolate so that the phenolate ion displaces the fluorine atom from the para-position of compound 3.
Another observed direction of the process was the attack of the phenolate ion at the carbon atom bonded to the sulfinyl group (ipso attack).In this case, the sulfinyl group acts as a good leaving group.As a result of this process, the C-S bond is cleaved and a C-OPh bond is formed.The products derived from compound 3 by this method are reduced by acetyl chloride to give compounds 11 and 12, respectively.Substitution of the sulfinyl group by the action of hydroxy anion in reactions of aromatic compounds containing strong electron withdrawing NO 2 -group in the para-position, has also been previously described. 23

Conclusions
Phenolate ion reacts with 4-substituted-[(difluoromethyl)sulfinyl]tetrafluorobenzenes mainly by the mechanism of nucleophilic aromatic substitution.In the examples considered in this paper, mixtures of the starting sulfoxide, as well as mono-and disubstituted products, were obtained.The direction of the process depended on the structure of the substrate, the phenolate-salt cation, and the polarity of the solvent.In nonpolar solvents such as benzene and diethyl ether, the main route of the reaction of difluoromethyl aryl sulfoxides and sodium phenolate is substitution of the fluorine atom adjacent to the difluoromethylsulfinyl group.This process is likely facilitated by the coordination of the sodium cation of the reagent with the oxygen atom of the (difluoromethyl)sulfinyl group.
For compound 3 in polar MeCN, an unexpected direction of the process associated with the replacement of the sulfoxide function with the phenoxy group was also found, apparently the result of an ipso-attack.

Experimental Section
General.The NMR spectra of reaction mixtures or individual compounds were recorded on Bruker AV-300 [300.C) MHz] spectrometers for solutions of samples in CCl 4 : CDCl 3 4:1 v/v [for 19 F], CDCl 3 [for 1 H and 13 C] or CD 3 CN [for 1 H].NMR coupling constants (J) were measured in Hertz (Hz).IR spectra were recorded on a Bruker Vector 22 spectrophotometer from pellets with KBr for solids and from films for liquid samples.UV spectra were obtained on a Hewlett Packard 8453 spectrophotometer from solutions in ethanol.The molecular mass and elemental composition were determined from high resolution mass spectra taken on a Thermo Electron Corporation DFS instrument (ionizing electrons energy 70 eV).GC-MS spectra were measured on a Hewlett-Packard G1081A instrument equipped with a gas chromatograph HP 5890 Series II and a mass-selective detector HP 5971 (EI, 70 eV), capillary column HP-5 (5% of diphenyl-, 95% dimethylsiloxane) 30 m × 0.25 mm × 0.25 μm, carrier gas helium, flow rate 1 mL/min.Injector temperature 280 °С, ion source temperature 173 °С.Scanning rate 1.2 scan/s in mass region 30-650 а.u.m.Analytic GLC was carried out on a Hewlett Packard 5980 chromatograph, equipped with a quartz capillary column HP-5 (stationary phase dimethyl diphenyl polysiloxane block copolymer), 30 m × 0.52 mm × 2.6 μm, and a thermal conductivity detector.

Materials.
Starting compounds were widely used commercially available products of reagent grade and were purified in the usual manner whenever necessary prior to use.Sodium hydride was used as the commercially available product (CAS 7646-69-7) and wasn't purified.Solvents were purified as usual.
3-[(difluoromethyl)sulfinyl]-1,2,4,5-tetrafluorobenzene (1), (difluoromethyl)[2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl]sulfane ( 16), (difluoromethyl)[2,3,5,6-tetrafluoro-4-(perfluorophenylthio)phenyl]sulfane (9), were obtained according to our previous work. 24he studied (difluoromethylsulfinyl)tetrafluorobenzenes compounds (1-3) were synthesized from the corresponding sulfanes by the action of 100% nitric acid according to our previous work. 24Compound (3) was used as a 1 : 1 mixture of diastereomers.Characteristic features of the 19 F NMR spectra of 1-3 are the presence of diastereotopic fluorine atoms in the CF 2 H moiety, which showed bonding to an asymmetrical center represented by the sulfoxide function.Quantum chemical calculations.Calculations of the electron structures for polyfluoroaryl sulfoxides were performed within restricted DFT theory with the B3LYP functional and 6-31G(d) basis set.All calculations were done with the GAMESS 25 package.Stationary potential energy surface points were located and their types and interrelationships were determined by the normal vibrations analysis.The influence of polar media was taken into account within the polarizable continuum model (PCM 26,27 , SMD 28 ), using built-in parameters for benzene, acetonitrile and diethyl ether.Molecular-orbital and molecular-structure images were constructed by MOLDEN. 29eparation of 4-substituted-[(difluoromethyl)sulfinyl]tetrafluorobenzenes General procedure.Fuming nitric acid was added to the sulfane with stirring at room temperature.The reaction mixture was stirred at 50 o С for 3 days.The resulting solution was dissolved in 300 mL of solvent [CHCl 3 in case of sulfane ( 16); CH 2 Cl 2 in case of sulfane ( 9)], then 300 mL H 2 O were added.To the resulting mixture, Na 2 CO 3 was added until pH 8 was obtained.The organic layer was separated, dried using MgSO 4 , and the solvent was evaporated to afford the desired [(difluoromethyl)sulfinyl]tetrafluorobenzene.

Table 3 .
Difference between the calculated B3LYP//6-31G(d) total energies of the corresponding sigma complexes depending on the solvent (in the case of PCM SMD)