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. 2021 Aug 13;6(33):21595–21603. doi: 10.1021/acsomega.1c02825

Revisiting the Balz–Schiemann Reaction of Aryldiazonium Tetrafluoroborate in Different Solvents under Catalyst- and Additive-Free Conditions

Lian Yang 1, Cheng-Pan Zhang 1,*
PMCID: PMC8388107  PMID: 34471763

Abstract

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The thermal and photochemical Balz–Schiemann reaction in commonly used solvents was revisited under catalyst- and additive-free conditions. The study showed that using low- or non-polar solvents could improve the pyrolysis and photolysis of aryldiazonium tetrafluoroborates, enabling effective fluorination at a low temperature or under visible-light irradiation. PhCl and hexane were exemplified as cheap and reliable solvents for both reactions, providing good to excellent yields of aryl fluorides from the corresponding diazonium tetrafluoroborates. The combination of slight heating with visible-light irradiation was beneficial for the transformation of stable aryldiazonium tetrafluoroborates. Nevertheless, the electronic and steric nature of aryldiazonium tetrafluoroborates still had a pivotal effect on both fluorinations even in these solvents.

Introduction

Fluorine-containing compounds have found widespread application in chemistry, biology, and materials and life sciences, because of their unique physicochemical and biological properties.1−6 Fluorine substitution in pharmaceuticals, veterinary drugs, and agrochemicals often serves the purpose of increasing metabolic stability, modulating polarity, lipophilicity, pKa values and/or hydrogen bonding, and exerting specific molecular conformations.2−4 In particular, the replacement of a hydrogen atom of an aromatic ring with a fluorine atom can retard oxidative metabolic pathways and change electronic and steric characteristics as well as other physicochemical features, thus increasing the efficiency and lifetime of an administered medicine.2−4,7−11 Over the past few decades, numerous Caryl–F bond formation methods have been developed for the preparation of aromatic fluorides, which mainly include the Balz–Schiemann reaction, nucleophilic aromatic substitution (SNAr, e.g., the Halex reaction), electrophilic Caryl–H fluorination, and transition-metal-catalyzed fluorination.7−12 Among these approaches, the Balz–Schiemann reaction, first described by Balz and Schiemann in 1927, has been confirmed as an excellent method for the installation of fluorine into the aromatic systems.13−16

The importance of the Balz–Schiemann reaction has been borne out in its wide application in the preparation of both electron-rich and -poor (hetero)aryl fluorides that are inaccessible by other methods.12−16 The traditional procedures of this method involve two steps: (1) the preparation and isolation of dry diazonium tetrafluoroborates from arylamines, and (2) the thermal decomposition of these salts into aromatic fluorides, nitrogen, and boron trifluoride.13−16 The BF4– ion behaves as a nucleophilic fluoride source in the reaction, and a SN1 mechanism via intermediacy of an aryl cation is generally accepted.17 However, the original procedures of the Balz–Schiemann reaction have reproducibility problems, afford yields that were quite dependent upon the structures of arene substrates, and required high temperatures to disassociate the carbon–nitrogen bonds of the aryldiazonium salts, leading to thermal destruction of products or starting materials, which limited its application in practice. To address this, a range of modifications including photoredox catalysis,18−21 flow chemistry,22,23 hypervalent iodine(III) catalysis,24 exchange of fluorinated counteranions,22,23,25,26 employment of special solvents,22,23,27−29 and in situ diazotization protocols using tert-butyl nitrite/Et2O·BF3 or [NO][BF4] in nonaqueous media,15,27,30 have been implemented for increasing the yields, lowering the reaction temperatures, and enhancing the generality and practicality of the Balz–Schiemann reactions. These modifications still suffered from disadvantages such as the use of short-wave ultraviolet-light irradiation, expensive solvents and reagents, narrow substrate scopes, and difficulties of scale-up. In this context, the development of efficient, mild, and general procedures for the Balz–Schiemann reaction in preparation of (hetero)aryl fluorides is very desirable and has emerged as an important target for chemists in both academia and industry.

We endeavored in this article to systematically probe the solvent effects on the Balz–Schiemann reaction under catalyst- and additive-free conditions, which would be helpful for future application of the reaction in the production of aryl fluorides from stable aryldiazonium salts. In the 1940s, Roe and Hawkins disclosed that the use of high-boiling petroleum ether for dampening 3-pyridinediazonium tetrafluoroborate, a very unstable diazonium salt that decomposed spontaneously and violently on becoming dry, allowed for a smooth degradation at 15–20 °C to afford 3-fluoropyridine in 50% yield.13 In this century, Laali and Gettwert reported that using 1-ethyl-3-methylimidazolium tetrafluoroborate ([emim][BF4], ionic liquid) as both the reaction solvent and nucleophilic fluoride source, a series of aryldiazonium tetrafluoroborates were smoothly pyrolyzed to the corresponding aryl fluorides with high efficiency.27 Kirk and co-worker found that UV-irradiated reactions of in situ formed imidazole diazonium fluoroborates in ionic liquids led to the production of fluoroimidazoles at low temperatures.30 Later, Jung and Bräse described a variant of Balz–Schiemann reaction by utilizing C6F14 as a solvent, which resulted in a good thermal decomposition of aryldiazonium salts and triazenes to the respective aryl fluorides at 80 °C.28 These studies indicated that the solvents might have an influence on both the thermal and photochemical evolution of aryldiazonium tetrafluoroborates.22,23,27−32 To gain more insights into this field, we reinvestigated the catalyst- and additive-free Balz–Schiemann reactions of benzenediazonium tetrafluoroborate (1a, selected as an example) in the commonly used solvents.

Results and Discussion

As shown in Table 1, reactions of 1a at a temperature of 60 °C for 16 h in water, methanol, ethanol, acetone, acetonitrile, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) provided none or small amounts of a mixture of fluorobenzene (2a) and benzene (3a), or small quantities of 2a (entries 1–7, condition A). Similar results were obtained under blue light-emitting diode (LED) irradiation of 1a at ambient temperature in these solvents (entries 1–7, condition B). These observations suggested that the polar protic and aprotic solvents were not suitable media for the pyrolysis of 1a at a low temperature and photolysis of 1a under visible-light irradiation without using additional initiators. Furthermore, the evolution of 1a in ethyl acetate or butyl acetate at 60 °C for 16 h gave only 2a in 45 or 55% yield,23a while the blue-LED-initiated reaction of 1a in the same solvents at ambient temperature furnished 2a as the main product accompanied by trace amounts of 3a (entries 8 and 9). When a mixture of 1a and diethyl ether was heated at 60 °C or irradiated by blue LEDs at ambient temperature, 2a was formed in 27 or 23% yield (entry 10). Taking 1,4-dioxane instead of diethyl ether under those two conditions led to the formation of 2a in 62% yield or a mixture of 2a/3a in 19/3% yield (entry 11). Interestingly, if tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), and diglyme were used as solvents, the reaction at 60 °C supplied 2a as the major product in 34–48% yields, whereas the blue-LED-mediated reaction gave mainly or singly the hydrodediazoniation product (3a) in 62–80% yields (entries 12–14). The formation of the hydrodediazoniation product might proceed through a radical mechanism,32 which was distinct from the fluorodediazoniation process in these reactions (see the Supporting Information). When 1a was decomposed in dichloromethane, 1,2-dichloroethane (DCE), trichloromethane, benzene, and toluene by either heating or visible-light irradiation, the fluorinated product (2a) was formed in good yields (56–91%) (entries 15–19). It seemed that the reactions in medium-polar solvents usually provided moderate yields of 2a and those run in low-polar solvents afforded good to excellent yields of 2a. Additionally, treatment of 1a in p-xylene or m-xylene at 60 °C for 16 h afforded 93 or 96% of fluorobenzene (2a), while photochemical decomposition at ambient temperature in the same solvents provided lower yields of 2a (56–67%) along with trace amounts of 3a (entries 20 and 21). Notably, the reactions of 1a in chlorobenzene, (trifluoromethyl)benzene, and hexane at 60 °C or under visible-light irradiation at ambient temperature gave 68–97% of 2a with no generation of 3a (entries 22–24). These results were comparable to or even better than those of the known procedures which required additives, higher reaction temperatures, ionic liquids, and/or ultraviolet-light irradiation for the synthesis of 2a from 1a.22,24,27,29 Nonetheless, if 1a was heated at 60 °C or initiated by blue LEDs at ambient temperature without using a solvent, 2a was formed in 43 or 32% yield, respectively (entry 25 vs entries 22–24). These experiments demonstrated that both thermal and photochemical conversion of 1a to 2a was enhanced by the low- or non-polar solvents. Such a solvent promotion effect was very significant as the traditional Balz–Schiemann fluorination of aryldiazonium tetrafluoroborates to the corresponding aryl fluorides under solvent-free conditions usually occurred at high temperatures close to their decomposition temperatures.13

Table 1. Catalyst- and Additive-Free Thermal or Photochemical Decomposition of Benzenediazonium Tetrafluoroborate (1a) in Different Solventsa.

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entry solvent condition A (2a/3a, %)b condition B (2a/3a, %)b
1 H2O 0/0 0/0
2c MeOH 13/4 17/7
3c EtOH 22/n.d. 10/n.d.
4c acetone 20/3 17/3
5 CH3CN 13/0 10/0
6 DMF 7/8 10/0
7 DMSO 5/0 2/0
8 EtOAc 45/0 23/2
9 n-BuOAc 55/0 42/3
10 Et2O 27/0 23/0
11 1,4-dioxane 62/0 19/3
12 THF 48/6 0/80
13 DME 40/4 7/66
14 diglyme 34/5 10/62
15 CH2Cl2 86/10 56/11
16 DCE 91/4 72/2
17 CHCl3 86/14 70/10
18 benzene 87/n.d. 70/n.d.
19 toluene 91/5 70/4
20 p-xylene 93/0 56/4
21 m-xylene 96/0 67/3
22 PhCl 97/0 68/0
23 PhCF3 85/0 68/0
24 hexane 85/0 75/0
25 none 43/0 32/0
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a

Condition A: a mixture of 1a (0.5 mmol) and solvent (2 mL) was heated at 60 °C in a sealed tube under an air atmosphere for 16 h. Condition B: a mixture of 1a (0.5 mmol) and solvent (2 mL) was irradiated by blue LEDs (435–455 nm) at ambient temperature in a sealed tube under an air atmosphere for 16 h.

b

Yields were determined by gas chromatography (GC) analysis of the reaction mixtures using hexadecane as an internal standard. “n.d.”: not determined.

c

Solvents were used as received from commercial sources.

It was rationalized that the polar and medium-polar solvents tend to dissociate the benzenediazonium cation and tetrafluoroborate anion in solutions by solvation effects, which interrupted the fluorine transfer process and accelerated the hydrogenation or other side reactions with solvents, leading to much poor yields of the fluorinated product. In contrast, the low- or non-polar solvents probably form intimate ion pairs of benzenediazonium tetrafluoroborate in solutions, thus lowering the energy barrier and benefiting the fluorination. Especially, the use of relatively electron-deficient low-polar aromatic systems (e.g., chlorobenzene and (trifluoromethyl)benzene) as well as nonpolar solvent (e.g., hexane) bearing inert Csp3–H bonds could fully inhibit the production of the hydrodediazoniation byproduct (3a), affording fluorobenzene in excellent yields. The progress of reactions in low- or nonpolar solvents was easy to identify as the disappearance of insoluble solid into solvents implied successful conversion of aryldiazonium tetrafluoroborate to organic molecules. This judgment was also supported by the thin-layer chromatography (TLC) detection of the reaction mixtures. Decreasing the reaction temperature of 1a in hexane from 60 to 50 and 40 °C gave 2a in 86 and 9% yields, respectively; nonetheless, elevating the temperature from 60 to 70 and 80 °C did not obviously change the yield of 2a (see the Supporting Information). Based on these data, we chose 50 or 60 °C as a minimum temperature to examine the solvent-involving Balz–Schiemann fluorination of aryldiazonium tetrafluoroborates under catalyst- and additive-free conditions (see the Supporting Information).

Meanwhile, the UV–visible light absorption spectra of 1a in the above solvents were tested (see the Supporting Information). Since 1a has very different solubility in these solvents, 0.2 or 0.5 mmol/L solutions of 1a in water, methanol, ethanol, acetone, acetonitrile, DMF, DMSO, ethyl acetate, and diglyme, as well as the saturated solutions of 1a in n-butyl acetate, diethyl ether, 1,4-dioxane, THF, DME, dichloromethane, 1,2-dichloroethane, trichloromethane, benzene, toluene, p-xylene, m-xylene, chlorobenzene, (trifluoromethyl)benzene, and hexane, were prepared for the measurement. The DMF, Et2O, DME, diglyme, benzene, toluene, xylenes, PhCl, PhCF3, and hexane solutions showed maximum absorptions in a range of 270–290 nm, and the others except acetone solution exhibited maximum absorption peaks at around 260 nm. Moreover, the methanol, ethanol, acetone, CH3CN, DMF, DMSO, EtOAc, n-BuOAc, 1,4-dioxane, THF, DME, diglyme, CH2Cl2, DCE, CHCl3, benzene, toluene, xylene, PhCl, PhCF3, and hexane solutions showed weak absorptions above 380 nm, which matched the visible light sources and might explain in part the feasibility of visible-light-mediated decomposition of 1a in these solvents (see the Supporting Information). The solutions of 1a in acetone and DMF had an absorption peak at 327 nm or a broad absorption with a peak at 286 nm. Unfortunately, such features did not promote the catalyst-free photolysis of 1a to 2a under blue-LED irradiation.

Next, the catalyst- and additive-free pyrolysis of aryldiazonium tetrafluoroborates in chlorobenzene or hexane (as an example of low- or nonpolar solvent, respectively) was employed to explore the substrate scope of the procedures (Scheme 1). Both electron-poor and -rich aryldiazonium tetrafluoroborates (e.g., 1b–i) were readily converted at 70–80 °C to form the corresponding aryl fluorides (2b–i) in good yields. The ester, ketone, carbon–carbon double bond, methoxy, and active methylene groups of substrates were well tolerated in the reactions. Treatment of biphenyldiazonium tetrafluoroborates (1j–t) at 60–80 °C in PhCl or hexane could also favorably give fluorinated products (2j–t). The position of aryl substituents on the phenyl rings of diazonium tetrafluoroborates had an effect on this fluorination. The catalyst- and additive-free Balz–Schiemann reactions of [1,1′-biphenyl]-3-diazonium (1k), [1,1′-biphenyl]-2-diazonium (1l), 4′-methoxy-[1,1′-biphenyl]-3-diazonium (1n), and 3′,5′-dimethyl-[1,1′-biphenyl]-3-diazonium (1q) tetrafluoroborates in PhCl or hexane at 60 °C for 3–16 h provided 2k, 2l, 2n, and 2q in 70–95% yields. Similar evolution of [1,1′-biphenyl]-4-diazonium (1j), 4′-methoxy-[1,1′-biphenyl]-4-diazonium (1m), and 3′,5′-dimethyl-[1,1′-biphenyl]-4-diazonium (1p) tetrafluoroborates at 70–80 °C for 16–82 h afforded 2j, 2m, and 2p in 74–90% yields. It appeared that fluorination was benefited from the ortho- and meta-aryl substitution on biphenyldiazonium tetrafluoroborates, which may cause certain steric hindrances and subtle electronic changes. In contrast, biphenyldiazonium substrates bearing para-aryl substituents (less sterically hindered) on the phenyl rings required higher temperatures and longer times to complete the reaction. The choice of either PhCl or hexane as a solvent also had an impact on the thermal conversion of some of the aryldiazonium tetrafluoroborates to aryl fluorides, e.g., 2c (72% in PhCl vs trace in hexane) and 2r (81% in PhCl vs trace in hexane), wherein PhCl always behaved as an effective medium at lower reaction temperatures. The better solubility of aryldiazonium tetrafluoroborates in PhCl than in hexane might account for these differences. It should be mentioned that the electronic nature of aryldiazonium tetrafluoroborates greatly affected the Balz–Schiemann reaction. The catalyst- and additive-free pyrolysis of 4-(3-ethoxy-3-oxoprop-1-en-1-yl)benzenediazonium tetrafluoroborate (1u) in hexane at 70 °C for 58 h furnished 2u in 83% yield, while the similar reaction of 4-styrylbenzenediazonium tetrafluoroborate (1v) in PhCl at 80 °C for 64 h provided 2v in 35% yield. More seriously, treatment of 4-bromobenzenediazonium (1w) and 4-acetamidobenzenediazonium (1x) tetrafluoroborates in PhCl at 80 °C for 16–48 h gave only trace amounts of 2w–x. Increasing the reaction temperature from 80 to 90 °C could luckily supply 78% of 2w and 67% of 2x. These solvent-involving reactions, albeit running at lower temperatures, showed similar trends to the solvent-free Balz–Schiemann reactions, wherein the outcomes of the reactions were largely dependent upon the substitution pattern on the aryl rings of aryldiazonium tetrafluoroborates.13 Furthermore, this fluorodediazoniation reaction was applicable to heteroaromatic systems as evolution of the stable 4-(ethoxycarbonyl)pyridine-3-diazonium tetrafluoroborate (1y) in PhCl or hexane at 60 °C for 4 h provided ethyl 3-fluoroisonicotinate (2y) in 63 or 66% yield, respectively.

Scheme 1. Catalyst- and Additive-Free Balz–Schiemann Reactions of Aryldiazonium Tetrafluoroborates in Chlorobenzene or Hexane at 60–90 °C.

Scheme 1

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The reactions were carried out with 0.5 mmol of aryldiazonium tetrafluoroborates (1) in PhCl or hexane (2 or 4 mL) at 60–90 °C under an air atmosphere in a sealed tube. Isolated yields.

Solvent-free conditions.

Yields were determined by 19F NMR analysis of the reaction mixtures using 1-fluoronaphthalene or PhF as an internal standard.

Although solvents were usually thought to facilitate the pyrolysis of aryldiazonium tetrafluoroborates,22,23,27,28 there were exceptions in our systems (e.g., 1d, 1j, 1k, and 1m vs 1i and 1r), for which comparable yields of the fluorinated products (2d, 2j, 2k, and 2m) were obtained under solvent-free conditions (Scheme 1). Thus, the thermal decomposition of aryldiazonium tetrafluoroborates to aryl fluorides was dependent not only on the solvents but also heavily on their structures.13 Even so, the use of solvent was preferable as it prohibited the formation of dark and sticky tars from solid aryldiazonium salts in the reactions. It was significant that this catalyst- and additive-free Balz–Schiemann reaction gave the fluorinated products in yields close to that obtained using the hypervalent iodine(III) reagent and Et2O·BF3 as catalysts at comparable temperatures in the literature,24 e.g., 2c (72 vs 77% (catalysts/80 °C/36 h/PhCl)), 2e (70 or 76 vs 78% (catalysts/60 °C/36 h/PhCl)), 2f (86 or 87 vs 68% (catalysts/80 °C/36 h/PhCl)), 2g (65 vs 66% (catalysts/45 °C/36 h/PhCF3)), 2h (49 or 50 vs 64% (catalysts/60 °C/36 h/PhCl)), 2i (83 vs 68% (catalysts/60 °C/36 h/PhCl)), 2j (85 or 90 vs 72% (catalysts/60 °C/36 h/PhCl)), and 2v (83% vs 75% (catalysts/60 °C/36 h/PhCl)).

Besides, the visible-light-mediated evolution of aryldiazonium tetrafluoroborates in chlorobenzene or hexane was investigated (Scheme 2). Blue- or purple-LED irradiation of 1i in hexane or PhCl at ambient temperature for 72 h afforded 2i in 25 or 32% yield. Photolysis of 1k in hexane under blue-LED irradiation at ambient temperature for 48 h provided a trace amount of 2k. Encouragingly, the replacement of blue LEDs by purple LEDs in the same reaction provided 67% of 2k. When 1l, 1n, 1o, and 1t were treated in PhCl or hexane at an ambient temperature under blue-LED irradiation for 16–32 h, the fluorinated products (2l, 2n, 2o, and 2t) were formed in 51–85% yields. The combination of heating with visible-light irradiation was beneficial for the conversion of stable aryldiazonium tetrafluoroborates to the corresponding aryl fluorides. For instance, purple-LED-mediated reactions of 1m, 1p, 1q, 1r, and 1u in PhCl or hexane at a temperature up to 50 °C (this temperature was easily reached by simply turning off the fan, see the Supporting Information) furnished 2m, 2p, 2q, 2r, and 2u in 34–79% yields, while the same reactions run at ambient temperature gave very low yields of the products (e.g., 2p (trace vs 60%), 2q (trace vs 69%), 2r (11 vs 77%)). The reasons for these synergistic effects by combining heat and visible-light irradiation remain unknown. Again, the use of solvents could promote the visible-light-mediated fluorination of aryldiazonium tetrafluoroborates as the photochemical decomposition of 1i, 1k, and 1m under solvent-free conditions gave lower yields of the fluorinated products (Scheme 2, for other examples, see the Supporting Information). In addition, treatment of 1w, 1x, and 4-methoxybenzenediazonium tetrafluoroborate (1z) in PhCl under purple-LED irradiation at a temperature up to 50 °C afforded no desired products. These results suggested once again that in addition to solvents, the electronic and steric nature of aryldiazonium tetrafluoroborates also had a central influence on the catalyst- and additive-free visible-light-mediated fluorination.

Scheme 2. Blue- or Purple-LED-Irradiated Fluorination of Aryldiazonium Tetrafluoroborates in Chlorobenzene or Hexane under Catalyst- and Additive-free Conditions.

Scheme 2

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The reactions were carried out with 0.5 mmol of aryldiazonium tetrafluoroborates (1) in PhCl or hexane (2 or 4 mL) under blue (435–455 nm) or purple (385–415 nm) LED irradiation and an air atmosphere in a sealed tube. Isolated yields.

Solvent-free conditions.

Conclusions

In summary, we have revisited the solvent effects on the Balz–Schiemann reaction under thermal and photochemical conditions. The choice of an appropriate solvent could improve the catalyst- and additive-free pyrolysis and photolysis of aryldiazonium tetrafluoroborates, enabling effective fluorination at a low temperature or under visible-light irradiation. The reactions conducted in low- or non-polar solvents by heat or visible-light irradiation afforded good to excellent yields of the fluorinated products. PhCl and hexane were exemplified as reliable media for the conversions, producing a variety of aryl fluorides from the corresponding aryldiazonium tetrafluoroborates. The combination of heat with visible-light irradiation was beneficial for the evolution of stable aryldiazonium tetrafluoroborates. It should be noted that the chemical structures of aryldiazonium tetrafluoroborates themselves had a significant impact on the Balz–Schiemann reactions under catalyst- and additive-free conditions even in the preferred solvents. This observation was analogous to the performance of the well-established solvent-free Balz–Schiemann reactions in the literature.13 Nevertheless, the relationships between chemical structures and decomposition/fluorination of these salts require further investigation.

Experimental Section

General Information

All reactions were carried out under an air atmosphere. Blue LEDs (435–455 nm) were used for blue-light irradiation and purple LEDs (385–415 nm) were used for purple-light irradiation. A fan attached to the apparatus was used to maintain the temperature inside the “box” at ambient temperature. Unless otherwise specified, the NMR spectra were recorded in CDCl3 on a 500 MHz (for 1H NMR), 471 MHz (for 19F NMR), and 126 MHz (for 13C NMR) spectrometer. All chemical shifts were reported in ppm relative to TMS for 1H NMR (0 ppm) and PhCF3 for 19F NMR (−63.0 ppm) as an internal or external standard. The coupling constants were reported in Hertz (Hz). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and brs = broad singlet. 19F NMR yields were determined using 1-fluoronaphthalene or fluorobenzene as an internal standard. GC yields were determined using hexadecane as an internal standard. Biphenylamines and arenediazonium tetrafluoroborates were synthesized according to the literature.24,33 Solvents were purified according to the literature.34 Other reagents in the reactions were all purchased from commercial sources and used without further purification.

Note: Caution should be taken during the preparation, purification, and storage of arenediazonium salts, as well as the operation, quenching, and workup of the Balz–Schiemann reactions.

General Procedures for Thermal and Photochemical Decomposition of Aryldiazonium Tetrafluoroborates (1)

Procedure A

Under an air atmosphere, a sealed tube was charged with aryldiazonium tetrafluoroborate (1, 0.5 mmol) and solvent (2 or 4 mL, PhCl or hexane) under vigorous stirring. The mixture was heated at 60–90 °C until the solid fully disappeared. Then, the reaction mixture was quenched with water (4 drops) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the desired product.

Procedure B

Under an air atmosphere, a sealed tube was charged with aryldiazonium tetrafluoroborate (1, 0.5 mmol) and solvent (2 mL or 4 mL, PhCl or hexane) under vigorous stirring. The mixture was irradiated by blue LEDs (λ 435–455 nm) or purple LEDs (λ 385–415 nm) with a cooling fan to maintain the reaction at ambient temperature (the temperature could increase to 50 °C if turning off the fan). After the solid disappeared, the reaction mixture was quenched with water (4 drops) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the desired product.

Procedure C

Under an air atmosphere, a sealed tube was charged with aryldiazonium tetrafluoroborate (1, 0.5 mmol). The solid was heated or irradiated by blue LEDs (λ 435–455 nm) or purple LEDs (λ 385–415 nm) without using solvent (e.g., 1r). The residue was quenched with water (4 drops) and purified by column chromatography on silica gel to give the desired product.

Methyl 4-fluorobenzoate (2b)35

2b was obtained as a colorless liquid. A mixture of petroleum ether/ethyl acetate = 40:1 (v/v) was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 8.06 (m, 2H), 7.11 (t, J = 8.7 Hz, 2H), 3.91 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 166.1, 165.8 (d, J = 254.0 Hz), 132.2 (d, J = 9.2 Hz), 126.4 (d, J = 3.0 Hz), 115.5 (d, J = 21.9 Hz), 52.2. 19F NMR (471 MHz, CDCl3) δ −105.75 to −105.85 (m, 1F).

Dimethyl 5-fluoroisophthalate (2c)24

2c was obtained as a white solid, mp: 57.2–58.5 °C. A mixture of petroleum ether/ethyl acetate = 20:1 (v/v) was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 8.47 (t, J = 1.3 Hz, 1H), 7.89 (dd, J = 8.6, 1.4 Hz, 2H), 3.95 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 165.1 (d, J = 2.8 Hz), 162.4 (d, J = 248.5 Hz), 132.7 (d, J = 7.4 Hz), 126.4 (d, J = 3.0 Hz), 120.8 (d, J = 23.4 Hz), 52.7. 19F NMR (471 MHz, CDCl3) δ −111.27 (t, J = 8.6 Hz, 1F).

(4-Fluorophenyl)(phenyl)methanone (2d)36

2d was obtained as a white solid, mp: 47.8–48.3 °C. A mixture of petroleum ether/ethyl acetate = 40:1 (v/v) was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.85 (m, 2H), 7.77 (dm, J = 8.4 Hz, 2H), 7.59 (tt, J = 7.4, 1.2 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 7.16 (t, J = 8.6 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 195.3, 165.4 (d, J = 254.2 Hz), 137.5, 133.8 (d, J = 3.0 Hz), 132.7 (d, J = 9.1 Hz), 132.5, 129.9, 128.4, 115.5 (d, J = 21.9 Hz). 19F NMR (471 MHz, CDCl3) δ −105.91 to −106.01 (m, 1F).

(3-Fluorophenyl)(phenyl)methanone (2e)24

2e was obtained as a white solid, mp: 53.2–53.8 °C. A mixture of petroleum ether/ethyl acetate = 40:1 (v/v) was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J = 8.0 Hz, 2H), 7.45–7.39 (m, 2H), 7.35–7.28 (m, 4H), 7.11 (tm, J = 8.4 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 195.3 (d, J = 2.1 Hz), 162.5 (d, J = 248.0 Hz), 139.7 (d, J = 6.4 Hz), 137.1, 132.8, 130.0, 130.0 (d, J = 7.8 Hz), 128.4, 125.8 (d, J = 3.1 Hz), 119.5 (d, J = 21.4 Hz), 116.8 (d, J = 22.6 Hz). 19F NMR (471 MHz, CDCl3) δ −111.93 to −111.98 (m, 1F).

7-Fluoro-2-phenyl-4H-chromen-4-one (2f)24

2f was obtained as a white solid, mp: 99.9–101.1 °C. A mixture of petroleum ether/ethyl acetate = 10:1 (v/v) was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 8.26 (dd, J = 8.8, 6.4 Hz, 1H), 7.92 (dd, J = 8.1, 1.2 Hz, 2H), 7.59–7.53 (m, 3H), 7.28 (dm, J = 8.9 Hz, 1H), 7.17 (td, J = 8.5, 2.3 Hz, 1H), 6.82 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 177.4, 165.7 (d, J = 254.9 Hz), 163.7 (d, J = 0.9 Hz), 157.3 (d, J = 13.3 Hz), 131.8, 131.4, 129.1, 128.3 (d, J = 10.6 Hz), 126.2, 120.8 (d, J = 2.3 Hz), 114.0 (d, J = 22.8 Hz), 107.6, 104.8 (d, J = 25.3 Hz). 19F NMR (471 MHz, CDCl3) δ −102.82 to −102.87 (m, 1F).

Ethyl 2-(4-fluorophenyl)acetate (2g)24

2g was obtained as a colorless liquid. A mixture of petroleum ether/ethyl acetate = 20:1 (v/v) was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.24 (m, 2H), 7.00 (tm, J = 8.7 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.58 (s, 2H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 171.5, 162.0 (d, J = 245.1 Hz), 130.8 (d, J = 8.2 Hz), 129.9 (d, J = 3.3 Hz), 115.4 (d, J = 21.4 Hz), 60.9, 40.5, 14.2. 19F NMR (471 MHz, CDCl3) δ −115.84 to −115.91 (m, 1F).

5-Fluoro-1,2,3-trimethoxybenzene (2h)36

2h was obtained as a white solid, mp: 55.8–57.3 °C. A mixture of petroleum ether/ethyl acetate =10:1 (v/v) was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 6.31 (d, J = 10.4 Hz, 2H), 3.83 (s, 6H), 3.79 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 159.4 (d, J = 240.3 Hz), 153.8 (d, J = 12.8 Hz), 134.3 (d, J = 4.2 Hz), 93.0 (d, J = 27.0 Hz), 61.0, 56.2. 19F NMR (471 MHz, CDCl3) δ −115.35 (t, J = 10.4 Hz, 1F).

2-Fluoro-9,9-dimethyl-9H-fluorene (2i)24

2i was obtained as a light yellow oil. Hexane was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.71–7.67 (m, 2H), 7.45 (dm, J = 7.1 Hz, 1H), 7.38–7.31 (m, 2H), 7.16 (dd, J = 8.9, 2.4 Hz, 1H), 7.06 (tm, J = 8.8 Hz, 1H), 1.51 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 162.9 (d, J = 245.3 Hz), 156.0 (d, J = 7.4 Hz), 153.5 (d, J = 2.0 Hz), 138.4, 135.2 (d, J = 2.1 Hz), 127.2, 127.0, 122.6, 121.1 (d, J = 8.8 Hz), 119.7, 114.1 (d, J = 23.1 Hz), 110.1 (d, J = 22.7 Hz), 47.1 (d, J = 2.2 Hz), 27.1. 19F NMR (471 MHz, CDCl3) δ −114.55 to −114.60 (m, 1F).

4-Fluoro-1,1′-biphenyl (2j)24

2j was obtained as a white solid, mp: 72.6–73.5 °C. Hexane was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.59–7.56 (m, 4H), 7.47 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 7.16 (t, J = 8.7 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 162.5 (d, J = 246.3 Hz), 140.3, 137.4 (d, J = 3.2 Hz), 128.8, 128.7 (d, J = 8.1 Hz), 127.3, 127.0, 115.6 (d, J = 21.4 Hz). 19F NMR (471 MHz, CDCl3) δ −115.81 to −115.87 (m, 1F).

3-Fluoro-1,1′-biphenyl (2k)37

2k was obtained as a colorless oil. Hexane was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 8.1 Hz, 2H), 7.47 (t, J = 7.4 Hz, 2H), 7.44–7.38 (m, 3H), 7.31 (dm, J = 10.1 Hz, 1H), 7.06 (tm, J = 8.6 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 163.4 (d, J = 245.5 Hz), 143.7 (d, J = 7.6 Hz), 140.1 (d, J = 2.1 Hz), 130.4 (d, J = 8.4 Hz), 129.0, 128.0, 127.2, 122.9 (d, J = 2.7 Hz), 114.3 (d, J = 0.9 Hz), 114.1 (d, J = 2.3 Hz). 19F NMR (471 MHz, CDCl3) δ −113.10 to −113.15 (m, 1F).

2-Fluoro-1,1′-biphenyl (2l)24

2l was obtained as a white solid, mp: 74.3–75.0 °C. Hexane was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 8.1 Hz, 2H), 7.50-7.46 (m, 3H), 7.41 (t, J = 7.4 Hz, 1H), 7.34 (m, 1H), 7.24 (td, J = 7.5, 1.0 Hz, 1H), 7.19 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 159.8 (d, J = 247.8 Hz), 135.9 (d, J = 0.9 Hz), 130.8 (d, J = 3.6 Hz), 129.2, 129.1 (d, J = 2.8 Hz), 129.0 (d, J = 8.2 Hz), 128.5, 127.7, 124.4 (d, J = 3.7 Hz), 116.2 (d, J = 22.8 Hz). 19F NMR (471 MHz, CDCl3) δ −117.96 to −118.01 (m, 1F).

4-Fluoro-4′-methoxy-1,1′-biphenyl (2m)28

2m was obtained as a white solid, mp: 87.3–88.6 °C. A mixture of petroleum ether/ethyl acetate = 40:1 (v/v) was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.54–7.49 (m, 4H), 7.13 (tm, J = 8.7 Hz, 2H), 7.00 (dm, J = 8.8 Hz, 2H), 3.88 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 162.2 (d, J = 245.6 Hz), 159.1, 137.0 (d, J = 3.2 Hz), 132.9, 128.3 (d, J = 7.9 Hz), 128.1, 115.6 (d, J = 21.4 Hz), 114.3, 55.4. 19F NMR (471 MHz, CDCl3) δ −116.64 to −116.79 (m, 1F).

3-Fluoro-4′-methoxy-1,1′-biphenyl (2n)38

2n was obtained as a white solid, mp: 66.1–66.7 °C. A mixture of petroleum ether/ethyl acetate = 40:1 (v/v) was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.53 (dm, J = 8.8 Hz, 2H), 7.40–7.34 (m, 2H), 7.27 (dm, J = 10.3 Hz, 1H), 7.03-6.98 (m, 3H), 3.87 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 163.3 (d, J = 245.2 Hz), 159.6, 143.2 (d, J = 7.8 Hz), 132.5 (d, J = 2.2 Hz), 130.2 (d, J = 8.5 Hz), 128.2, 122.3 (d, J = 2.7 Hz), 114.3, 113.5 (d, J = 21.9 Hz), 113.4 (d, J = 21.3 Hz), 55.4. 19F NMR (471 MHz, CDCl3) δ −113.22 to −113.28 (m, 1F).

2-Fluoro-4-methoxy-1,1′-biphenyl (2o)39

2o was obtained as a light yellow oil. A mixture of petroleum ether/ethyl acetate = 40:1 (v/v) was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 7.9 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.39–7.34 (m, 2H), 6.80 (dd, J = 8.5, 2.5 Hz, 1H), 6.74 (dd, J = 12.3, 2.5 Hz, 1H), 3.85 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 160.3 (d, J = 247.7 Hz), 160.3 (d, J = 10.9 Hz), 135.8 (d, J = 1.4 Hz), 131.1 (d, J = 5.5 Hz), 128.9 (d, J = 3.0 Hz), 128.5, 127.2, 121.5 (d, J = 13.8 Hz), 110.3 (d, J = 3.1 Hz), 102.1 (d, J = 26.6 Hz), 55.6. 19F NMR (471 MHz, CDCl3) δ −115.65 (t, J = 12.3 Hz, 1F).

4′-Fluoro-3,5-dimethyl-1,1′-biphenyl (2p)40

2p was obtained as a white solid, mp: 27.0–28.0 °C. Hexane was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.56 (m, 2H), 7.19 (s, 2H), 7.14 (tm, J = 8.7 Hz, 2H), 7.03 (s, 1H), 2.41 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 162.4 (d, J = 245.9 Hz), 140.3, 138.4, 137.6 (d, J = 3.2 Hz), 128.9, 128.7 (d, J = 7.9 Hz), 125.0, 115.5 (d, J = 21.4 Hz), 21.4. 19F NMR (471 MHz, CDCl3) δ −116.06 to −116.14 (m, 1F).

3′-Fluoro-3,5-dimethyl-1,1′-biphenyl (2q)41

2q was obtained as a colorless oil. Hexane was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.43–7.38 (m, 2H), 7.32 (dm, J = 10.2 Hz, 1H), 7.23 (s, 2H), 7.08–7.03 (m, 2H), 2.42 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 163.2 (d, J = 244.9 Hz), 143.8 (d, J = 7.7 Hz), 140. 0 (d, J = 1.8 Hz), 138.4, 130.1 (d, J = 8.6 Hz), 129.5, 125.1, 122.8 (d, J = 2.7 Hz), 114.1 (d, J = 21.9 Hz), 113.9 (d, J = 21.3 Hz), 21.4. 19F NMR (471 MHz, CDCl3) δ −113.27 to −113.33 (m, 1F).

2-Fuoro-5-methyl-1,1′-biphenyl (2r)42

2r was obtained as a colorless oil. Hexane was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.58 (dm, J = 8.1 Hz, 2H), 7.47 (t, J = 7.3 Hz, 2H), 7.40 (tt, J = 7.3, 1.2 Hz, 1H), 7.27 (dd, J = 7.3, 1.9 Hz, 1H), 7.13 (m, 1H), 7.07 (dd, J = 10.5, 8.4 Hz, 1H), 2.40 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 158.0 (d, J = 245.2 Hz), 136.1 (d, J = 1.2 Hz), 133.7 (d, J = 3.8 Hz), 131.2 (d, J = 3.2 Hz), 129.4 (d, J = 7.9 Hz), 129.1 (d, J = 2.7 Hz), 128.7 (d, J = 13.6 Hz), 128.4, 127.6, 115.8 (d, J = 22.8 Hz), 20.7. 19F NMR (471 MHz, CDCl3) δ −123.47 to −123.49 (m, 1F).

3-Fluoro-4′-nitro-1,1′-biphenyl (2s)43

2s was obtained as a white solid, mp: 86.0–87.2 °C. A mixture of petroleum ether/ethyl acetate = 40:1 (v/v) was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.47 (m, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.32 (dt, J = 9.8, 1.9 Hz, 1H), 7.14 (tm, J = 8.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 163.3 (d, J = 247.2 Hz), 147.5, 146.2 (d, J = 2.3 Hz), 141.0 (d, J = 7.7 Hz), 130.8 (d, J = 8.4 Hz), 127.9, 124.2, 123.1 (d, J = 3.2 Hz), 115.8 (d, J = 21.2 Hz), 114.4 (d, J = 22.5 Hz). 19F NMR (471 MHz, CDCl3) δ −111.95 to −112.01 (m, 1F).

Methyl 2′-fluoro-[1,1′-biphenyl]-4-carboxylate (2t)44

2t was obtained as a white solid, mp: 59.0–60.1 °C. A mixture of petroleum ether/ethyl acetate = 40:1 (v/v) was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 8.5 Hz, 2H), 7.63 (dd, J = 8.4, 1.6 Hz, 2H), 7.46 (td, J = 7.8, 1.7 Hz, 1H), 7.36 (m, 1H), 7.23 (td, J = 7.6, 1.1 Hz, 1H), 7.18 (m, 1H), 3.95 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 166.9, 159.8 (d, J = 249.0 Hz), 140.4 (d, J = 0.9 Hz), 130.7 (d, J = 3.2 Hz), 129.9 (d, J = 8.4 Hz), 129.7, 129.3, 129.0 (d, J = 3.2 Hz), 128.1 (d, J = 13.1 Hz), 124.6 (d, J = 3.9 Hz), 116.3 (d, J = 22.7 Hz), 52.2. 19F NMR (471 MHz, CDCl3) δ −117.42 to −117.47 (m, 1F).

Ethyl (E)-3-(4-fluorophenyl)acrylate (2u)24

2u was obtained as a wight yellow oil. A mixture of petroleum ether/ethyl acetate = 40:1 (v/v) was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 16.0 Hz, 1H), 7.50 (dd, J = 8.7, 5.4 Hz, 2H), 7.06 (t, J = 8.6 Hz, 2H), 6.35 (d, J = 16.0 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.9, 163.9 (d, J = 251.2 Hz), 143.3, 130.7 (d, J = 3.4 Hz), 129.9 (d, J = 8.5 Hz), 118.1 (d, J = 2.3 Hz), 116.0 (d, J = 21.9 Hz), 60.5, 14.3. 19F NMR (471 MHz, CDCl3) δ −109.75 to −109.81 (m, 1F).

(E)-1-Fluoro-4-styrylbenzene (2v)45

2v was obtained as a white solid, mp: 122.0–123.0 °C. Hexane was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 7.52–7.48 (m, 4H), 7.37 (t, J = 7.5 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.10–7.01 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 162.4 (d, J = 247.8 Hz), 137.2, 133.6 (d, J = 3.3 Hz), 128.7, 128.5 (d, J = 2.3 Hz), 128.0 (d, J = 7.7 Hz), 127.7, 127.5, 126.5, 115.7 (d, J = 21.7 Hz). 19F NMR (471 MHz, CDCl3) δ −114.20 to −114.31 (m, 1F).

N-(4-Fluorophenyl)acetamide (2x)46

2x was obtained as a white solid, mp: 153.9–155.2 °C. A mixture of petroleum ether/ethyl acetate = 1:1 (v/v) was used as the eluent for column chromatography. 1H NMR (500 MHz, CD3COCD3) δ 9.17 (br, 1H), 7.64 (dd, J = 8.2, 5.1 Hz, 2H), 7.03 (t, J = 8.7 Hz, 2H), 2.05 (s, 3H). 13C NMR (126 MHz, CD3COCD3) δ 173.1, 163.8 (d, J = 240.0 Hz), 141.2 (d, J = 2.3 Hz), 126.0 (d, J = 20.2 Hz), 120.2 (dd, J = 22.7 Hz), 28.4. 19F NMR (471 MHz, CD3COCD3) δ −116.17 to −116.22 (m, 1F).

Ethyl 3-fluoroisonicotinate (2y)24

2y was obtained as a light yellow oil. A mixture of petroleum ether/diethyl ether = 4:1 (v/v) was used as the eluent for column chromatography. 1H NMR (500 MHz, CDCl3) δ 8.59 (d, J = 2.3 Hz, 1H), 8.52 (d, J = 4.9 Hz, 1H), 7.75 (t, J = 5.6 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 162.8 (d, J = 2.7 Hz), 157.1 (d, J = 268.6 Hz), 145.9 (d, J = 5.9 Hz), 140.4 (d, J = 25.5 Hz), 125.7 (d, J = 8.6 Hz), 124.3, 62.2, 14.1. 19F NMR (471 MHz, CDCl3) δ −125.08 (d, J = 5.6 Hz, 1F).

Acknowledgments

We thank the Wuhan University of Technology and the “Hundred Talent” Program of Hubei Province (China) for financial support.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.1c02825.

  • Survey of the reaction conditions, UV–visible light absorption spectra, control experiments, and characterization data of the products and NMR spectra (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao1c02825_si_001.pdf (4.1MB, pdf)

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