Activation of Aromatic C-F Bonds by a N-Heterocyclic Olefin (NHO).

A N-heterocyclic olefin (NHO), a terminal alkene selectively activates aromatic C-F bonds without the need of any additional catalyst. As a result, a straightforward methodology was developed for the formation of different fluoroaryl-substituted alkenes in which the central carbon-carbon double bond is in a twisted geometry.

Compounds containing C−F bond(s) are extremely important in diverse fields ranging from materials chemistry [1] to medicinal chemistry.2 In comparison to the C−H bond, the most striking differences of the C−F bond are its reverse polarity and higher bond energy.3 These features contribute to the unique physical and chemical properties of fluorinated compounds. The synthesis of such compounds and the ability to selectively activate C−F compounds in this family is an important area of research. Low‐valent, low‐coordinate transition‐metal complexes have been known to activate the C−F bond by an oxidative addition.4 Strong Lewis acids as well as frustrated Lewis pairs (FLPs) are also known for electrophilic activation of the C−F bond.5 In 1998, Kuhn et al. reported a nucleophilic aromatic C−F activation using the N‐heterocyclic carbene (NHC) I (Scheme 1).6 Since then, nucleophilic activation of aromatic C−F bonds has been achieved employing various two‐coordinate divalent Group 14 compounds such as different NHCs, cyclic(alkyl)(amino)carbenes (CAACs), N‐heterocyclic silylene II,7 and base stabilized three‐coordinate divalent Group 14 compounds such as base stabilized silylenes and germylenes III (Scheme 1).8 Also, aromatic C−F activation has been reported using N‐heterocyclic aluminylene IV 9 and Jones's MgI−MgI bonded compound V (Scheme 1).10

Scheme 1

Selected examples of low‐valent main‐group compounds that activate aromatic C−F bond (Ar=2,6‐iPr2C6H3).

However, all the above‐mentioned C−F activation of fluoroarenes are restricted in their utility for the synthesis of any general family of organofluorine compounds. This and the consideration of the lack of direct synthetic methodologies for an important class of compounds such as fluoroorgano‐substituted (fluoro, fluoro‐alkyl, fluoro‐aryl) alkenes11 prompted us to consider a N‐heterocyclic olefin (NHO) 1,3,4,5‐tetramethyl‐2‐methyleneimidazoline 1 (Scheme 1).12 We report that this terminal alkene is an excellent reagent for the nucleophilic activation of aromatic C−F bond under the direct formation of different fluoroaryl‐substituted alkenes without using any additional catalyst. Previous syntheses of fluoroaryl‐substituted alkenes have been reported using transition‐metal complex‐catalyzed alkenylation of fluoroarenes.13 Very recently Berkessel and his group have reported carbene‐derived pentafluorophenyl‐substituted alkenes using corresponding fluoroarylaldehyde as a precursor.14 Our method, apart from its novelty, has the advantage of being applied to a wide range of aromatic fluoro hydrocarbons, and also reveals an excellent selectivity.

The reaction of 1 with hexafluorobenzene in a 2:1 ratio in hexane, resulted in the formation of the fluoroaryl‐substituted alkene, that is, a C−F activation product 2 in 67 % yield along with the imidazolium salt 1 (Scheme 2).15 The formation of compound 2, which is air and moisture‐sensitive, has been confirmed by the presence of three singlet resonances at 1.29, 2.42, and 3.96 ppm in a 6:6:1 ratio, respectively, in the 1H NMR spectrum and three multiplets at −176.68, −167.05, and −149.11 ppm in a 1:2:2 ratio, respectively, in the 19F NMR spectrum. In this reaction, 1 also acts as HF scavenger and forms the imidazolium salt 1 containing a mixture of fluoride (F−) and bifluoride (HF2 −) as counter anions.15 The solid‐state molecular structure of 2 revealed that the central C1−C8 bond distance is 1.391(16) Å (Figure 1), which is longer than the corresponding distance in 1 (1.363(3) Å)12 and imidazole–imidazolium‐substituted alkene (1.334(5) Å for E‐isomer and 1.322(6) Å for Z‐isomer).16 The bond elongation is due to the installation of the electron‐withdrawing group in place of the H‐substituent. The notable feature of 2 is a twist angle of 24.79(12)° around the central carbon–carbon double bond.

Scheme 2

Reaction of 1 with hexafluorobenzene.

Figure 1

Molecular structures of 2 (left), 3 (middle), and 4 (right) with thermal ellipsoids at 50 % probability level. All H atoms except C8−H are omitted for clarity.18

After this initial success, we considered more reactive perfluorinated arenes such as pentafluoropyridine and octafluorotoluene for reaction with 1. The 2:1 reaction of 1 with pentafluoropyridine and octafluorotoluene gave regioselectively the corresponding fluoroaryl substituted olefins 3 (87 %) and 4 (72 %), respectively, as deep‐yellow colored solids (Scheme 3). To minimize the employed amount of 1, we considered Et3N as a HF scavenger. However, 1 does always compete as proton scavenger with Et3N even when 10 equivalents of Et3N were used.15 Formation of 3 and 4 was confirmed by solution‐state NMR spectroscopy as well as by single crystal X‐ray diffraction analysis (Figure 1). The twist angle of the exocyclic olefin moiety for compound 3 is as high as 45.76(76)° which is higher than that of compound 4 (35.83(12)°) and compound 2 (24.79(12)°).

Scheme 3

Reactions of 1 with pentafluoropyridine and octafluorotoluene.

Subsequently, to see the regioselectivity of 1 towards the C−F activation as well as to obtain different fluoroaryl‐substituted olefins we have considered partially fluorinated compounds such as pentafluorobenzene, 1,2,3,4‐tetrafluorobenzene, 1,2,3,5‐tetrafluorobenzene, and chloropentafluorobenzene along with octafluoronaphthalene and decafluorobiphenyl (Scheme 4). The reaction of 1 with pentafluorobenzene, 1,2,3,4‐tetrafluorobenzene, and 1,2,3,5‐tetrafluorobenzene leads to exclusive regioselective C−F activation products 5, 6, and 7, respectively (Scheme 4). These compounds show unique 19F and 1H splitting patterns due to the presence of an extended 19F−19F/19F−1H/1H−1H scalar‐coupling network.

Scheme 4

Reactions of 1 with different fluoroarenes.

To characterize and assign these resonances, the splitting patterns of all resonances were fitted using simulations providing values of the scalar couplings and the likely connectivity. In case of compound 6, for instance, three 19F resonances and two 1H resonances from the fluoroaryl substituent were unambiguously assigned using their scalar‐coupling constants and the experimentally obtained 1H, 1H{19F}, 19F, and 19F{1H} NMR spectra match well with the simulated spectra (Figure 2). The formation of compound 7 was further confirmed by its solid‐state molecular‐structure determination (Figure 3).

Figure 2

Experimental and simulated 1H (A), 19F (B), 1H{19F} (C), and 19F{1H} NMR (D) spectra of compound 6.

Figure 3

Molecular structures of 7 (left), 8 (middle), and 9 (right) with thermal ellipsoids at 50 % probability level. All H atoms except C8−H are omitted for clarity reasons.18

The reaction of 1 with chloropentafluorobenzene leads to selective C−F activation resulting in 8 with 56 % yield (Scheme 4). The molecular X‐ray structure of 8 shows a twist angle of the exocyclic olefin moiety of only 18.34(22)° which is more acute than that of 2 (24.79(12)°), 3 (45.76(76)°), 4 (35.83(12)°), and 7 (32.10(11)°). On treatment of 1 with octafluoronaphthalene, compound 9 was obtained in 56 % yield as a bright orange colored solid as a result of selective C2−F activation (Scheme 4). Its structural analysis exhibits a twist angle of the exocyclic olefin moiety of 24.29(16)° (Figure 3).

The reaction of 1 with decafluorobiphenyl leads to compound 10 (Scheme 4). A small amount of the double C−F activation product 11 was also noticed, even when a strict 1:1 stoichiometry was imposed. Subsequently, the bis‐alkenyl moiety functionalized octafluorobiphenyl system 11 was synthesized on purpose by reacting 10 with 1 (Scheme 5). The X‐ray structural analyses reveal twist angles of the exocyclic olefin moieties of 34.79(11)° in 10 and of 26.74(19)° and 32.34(17)° in 11 (Figure 4).

Scheme 5

Synthesis of 11.

Figure 4

Molecular structures of 10 (left) and 11 (right) with thermal ellipsoids at 50 % probability level. All H atoms except C8−H (for 10) and C8−H and C21−H (for 11) are omitted for clarity reasons.18

We propose that the reaction of 1 with fluoroarenes proceeds through an aromatic nucleophilic substitution reaction (Scheme 6). A nucleophilic attack of 1 at the electrophilic C‐center of the C−F moiety of fluoroarenes leads to a transition state, TS. This TS can directly lead to the product 2 by an elimination of HF (pathway a) or it can evolve into an ionic intermediate (Int, [2H), which has different fates depending on the conditions (pathway b).

Scheme 6

Proposed mechanism of aromatic C−F bond activation by NHO 1.

One of the observed routes is the subsequent elimination of HF leading to 2. This route was computationally observed when a relaxed surface scan starting with 1+C was performed in hexane as pseudo solvent, without inclusion of additional molecules. In this case Int was not the final structure, but 2+HF (pathway a). The intermediate Int could be stabilized if a molecule of Et3N was added, leading to deprotonation of [2H, through TS2 and final products 2+Et (pathway b in Scheme 6 and Figure S51 in the Supporting Information). This proposed pathway is supported by the theoretical calculation at PBEO/def2‐TZVP level of theory.15 The energy barrier of TS in hexane is 22.1 kcal mol−1 whereas the formation of 2 is exergonic by ΔG 300=−21.7 kcal mol−1, when the fluoride anion acts as a proton scavenger (Figure 5).15 The intermediate Int could also be stabilized if DMF was chosen as pseudo solvent in the calculations (pathway b), which also resulted in a slight lowering of the activation barrier to 21.3 kcal mol−1 (Figure S50).

Figure 5

The reaction energy profile diagram for the C−F bond activation of C6F6 by 1 (all energy values are in kcal mol−1).

In conclusion, we have demonstrated that the N‐heterocyclic olefin (NHO), as a terminal alkene selectively activates a large variety of aromatic C−F bonds without any additional catalyst. The aromatic C−F activation by NHO results in a straightforward formation of fluoroaryl‐substituted alkenes, which have a twisted central carbon–carbon double bond with an angle varying from 18.34° to 45.76°, depending on the fluoroaryl substituent. Considering that a large variety of NHOs are already available,17 and that new NHO designs can be readily adapted to our strategy, our reported synthetic methodology is extremely versatile.

Conflict of interest

The authors declare no conflict of interest.

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Supplementary

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