Conformational Preference of 2'-Fluoro-Substituted Acetophenone Derivatives Revealed by Through-Space 1H-19F and 13C-19F Spin-Spin Couplings.

The conformational properties of 2'-fluoro-substituted acetophenone derivatives were elucidated based on Hα-F and Cα-F through-space spin-spin couplings (TS-couplings), which occur between two atoms constrained at a distance smaller than the sum of their van der Waals radii. This study revealed that 2'-fluoro-substituted acetophenone derivatives in solutions form exclusively s-trans conformers by analyzing their NMR spectra focused on the TS-couplings. The magnitudes of the coupling constants 5J (Hα, F) and 4J (Cα, F) correlate linearly with the value of the dielectric constant of the solvents. Furthermore, s-trans conformations of the two derivatives were confirmed by X-ray crystallographic analysis. These conformational preferences were consistent with the DFT calculations. The s-cis conformer, in which fluorine and oxygen atoms lie in a syn-periplanar mode, may be subject to strong repulsion between the two polar atoms and become unstable. The s-trans preference of the 2'-fluoro-substituted acetophenone derivatives may be utilized in drug design.

Introduction

Fluorine, which exhibits a range of remarkable chemical, physical, and biological properties, has been recognized as a valuable element in various branches of science, including medicinal chemistry. More than 20% of known drugs contain fluorine atoms, and the immense stereoelectronic effects of fluorine on bioactive organic molecules have been extensively examined.[1] One important tool to comprehend the structural features of fluorine compounds is NMR spectroscopy, in which fluorine (19F; I = 1/2) gives valuable hints regarding the structure and stereochemistry of compounds. One of the most peculiar of the NMR behaviors of fluorine is “through-space spin–spin coupling (TS-coupling).”[2] TS-couplings are observed between two atoms when either has lone-pair electrons and both are constrained at a distance smaller than the sum of their van der Waals radii. Fluorine has lone-pair electrons and has been the object of numerous studies in terms of determining conformations with long-range hydrogen–fluorine (1H–19F) and carbon–fluorine (13C–19F) TS-couplings.[3] For example, the 1H–19F TS-coupling was detected in alkylfluorobenzenes where hydrogen and fluorine were separated by five bonds.[4]13C–19F TS-coupling over five bonds was also observed in 1,4,8-trimethyl-5-fluorophenanthrene.[5] Whenever two nuclei, such as 19F/19F, 19F/1H, and 19F/13C, are in van der Waals contact through space, regardless of how many bonds separate them, they can exchange spin information.[6]

In the course of our studies of bioactive compounds, we synthesized acetophenone derivatives (1a and 1b) (Figure ). In the 1H NMR and 13C NMR spectra of 1a and 1b, we recognized significant magnitudes of TS-couplings between Hα–F and Cα–F. These TS-couplings may mean that two atoms (Hα and F/Cα and F) are constrained at a distance smaller than the sum of their van der Waals radii. Therefore, we deduced that compounds 1a and 1b prefer s-trans conformations to cis conformations (Figure ), suggesting that the fluorine atoms control the conformation of the compound. Various 2′-substituted acetophenones were synthesized, and conformational studies were performed.[7] Among the studies, Schaefer examined TS-coupling of 2-fluoro and 2,6-fluoroacetophenones based on calculations,[3d] but that work has received relatively little attention, although the results are extremely significant.

Figure 1

Through-space spin–spin couplings observed in 1a and 1b.

In this work, we report the TS-couplings observed in the NMR spectra of several 2′-fluoro-substituted acetophenone derivatives. Additional DFT calculations and X-ray structural analyses supported the preference of the s-trans conformers of these derivatives. The conformational properties of these fluorinated compounds can give clues to the design of new drugs containing fluorine atoms.

Results and Discussion

Propiophenone derivatives 1a and 1b were prepared from 2-bromo-2′-fluoroacetophenone (1e)[8] by treatment with malononitrile and ethyl cyanoacetate, respectively. 2′-Fluorobutyrophenone (1c) was prepared by reacting 2′-fluorobenzonitrile (2) with propylmagnesium chloride (Scheme ). Compounds 3,[9]4,[10]5,[11] and 1d–p were commercially available.

Scheme 1

Synthesis of Propiophenone Derivatives 1a, 1b, and 1c

Figure a,b shows the 1H NMR signals of Hα of 1a and 1b, respectively. A splitting pattern of the chemically equivalent methylene protons Hα of 1a (Figure a, left) was observed as a doublet of doublets (dd), which was assumed to be the result of the coupling between Hα and Hβ(J = 6.9 Hz) and the additional coupling between Hα and F (TS-coupling: J = 3.2 Hz). Similarly, the AB part of the ABX signal of the diastereotopic methylene protons (Hα and Hα) (Jαα′ = 18.8 Hz, Jαβ = 6.8 Hz, Jα′β = 6.4 Hz) of 1b [Figure a, right] is further subjected to coupling with F (TS-coupling: JαF = 3.3 Hz, Jα′F = 3.3 Hz).

Figure 2

400 MHz NMR spectra in CDCl3: (a) Hα of 1a (left) and Hα and Hα of 1b (right); (b) spectra with 19F decoupling of Hα of 1a (left) and Hα and Hα of 1b (right).

To confirm that the splitting of the Hα of 1a and 1b is actually caused by F atoms, 19F-decoupled 1H NMR experiments were carried out. As shown in Figure b, irradiation of 19F resulted in simplification of their signal patterns, and these experiments determined the Hα–F coupling constants of 1a and 1b to be 3.2 and 3.3 Hz. These protons are 5 bonds apart from the fluorine. In general, the through-bond coupling constant (5JFH) is less than 1 Hz, and the observed values of over 3.2 Hz infer that 1H–19F TS-couplings are working in 1a and 1b. In the proton-decoupled 13C NMR spectrum of 1a and 1b, the signals of the Cαs were observed as doublets (4JCF = 10.5 and 10.1 Hz), which were assumed to be caused by the TS-coupling between Cα and F (see the Supporting Information).

To confirm that such a TS-coupling is characteristic of 2′-fluoroacetophenones, the 1H NMR spectra of 3′-fluoroacetophenone (3), 2′-fluorophenylacetone (4), and 2′-fluorophenylethanol (5) (Figure ) were studied. The methyl protons of 3 and 4 appear as sharp singlets without coupling with 19F because the methyl groups are distant from the fluorine. The β-methylene protons of 5, although they are 5 bonds apart from the ortho-fluorine, show a mere triplet, possibly because of the flexible CH2–CH2 bond, which can position the β-CH2 spatially far from the fluorine. It should be noted that the α-CH2 of 4 and 5, which are 4 bonds apart from F, do not show coupling with 19F; that is, through bond coupling, 4JFH is negligible in these compounds. These properties are in contrast with those shown by 1a–c, supporting the deduction that the o-fluoro-substituted benzoyl structure provides the s-trans conformation as a key factor for TS-couplings.

Figure 3

3′-Fluoroacetophenone (3), 2′-fluorophenylacetone (4), and 2-(2′-fluorophenyl)ethanol (5).

In order to confirm the generality, 1H/13C NMR spectra of other acetophenone derivatives (1d–p) were measured. As expected, relatively large Hα–F and Cα–F TS-couplings were observed (5JHF, 3.20–5.03 Hz; 4JCF, 6.70–11.56 Hz) (Table ), which is in accordance with the assumption that the acetophenone derivatives 1a–p prefer s-trans forms exclusively in solution.

Table 1

Through-Space Coupling Constants of Compounds 1a–p

compound	R1	R2	J (Hα, F) (Hz)	J (Cα, F) (Hz)
1a	–CH(CN)2	–H	3.21	10.54
1b	–CH(CN, CO2Et)	–H	3.28	10.11
1c	–CH2CH3	–H	3.20	6.70
1d(12)	–H	–H	5.03	7.71
1e(8)	–Br	–H	3.20	9.63
1f(13)	–CH3	–H	3.20	7.71
1g(14)	–CO2CH2CH3	–H	3.66	8.67
1h(15)	–H	4′-Br	5.03	6.74
1i(16)	–H	5′-Br	5.03	7.71
1j(17)	–H	4′-OH	5.03	7.71
1k(18)	–H	4′-F	5.03	7.71
1l(19)	–H	4′,5′-F	5.03	7.71
1m(20)	–H	5′-NO2	5.03	6.74
1n(21)	–H	4′-OCH3	5.03	7.71
1o(22)	–CH3	4′-F	3.20	7.71
1p(23)	–Cl	4′-F	3.20	11.56

It is worth mentioning that TS-coupling in compounds 1a–p is sensitive to the nature of the substituents at Cα. While the acetophenones 1d and 1h–n with various substituents on their benzene rings have the same coupling constants (5JHF = 5.03 Hz), those of 1a–g (except for 1d) and 1o–p, in which Cα is variously substituted, are smaller in magnitude (5JHF: 3.20–3.66 Hz). These differences may be interpreted by the preceding report that the magnitude of TS-coupling depends not only on the distance between the nuclei but also on the orientation of the orbitals involved in the transmission pathway.[2b] The substituents at Cα can affect the orbitals of Hα and Cα on determining the orientation and the transmission of the nuclei spin information through space.

Next, the solvent effect on the magnitude of TS-coupling was examined. In the 1H and 13C NMR spectra of 2′-fluoroacetophenone (1d), Hα–F and Cα–F TS-couplings were determined for the solutions in various solvents (Table ). It is obvious from the large values of 5JHF and 4JCF that the s-trans conformer is fairly commonly preferred in any of these solutions. Furthermore, variation from low (benzene-d6, ε = 2.28) to high (DMSO-d6, ε = 47.2) dielectric constant solvents produced changes in the magnitudes of the coupling constants 5J (Hα, F) and 4J (Cα, F), which correlate linearly to the dielectric constant of the solvents (Figure ).

Table 2

Solvent Effect on the Coupling Constant (Hz) of 1d

solvent	εa	5J (Hα, F) (Hz)	4J (Cα, F) (Hz)
DMSO-d6	47.2	4.12	5.78
CH3OH-d4	33.0	4.57	6.74
acetone-d6	21.0	4.57	6.74
CH2Cl2-d2	8.93	5.03	7.71
CHCl3-d1	4.81	5.03	7.71
benzene-d6	2.28	5.03	7.71

ε = Dielectric constant.[24]

Figure 4

Plots of the coupling constants 5J (H, F) and 4J (C, F) observed in 1d and the dielectric constant of the solvent.

As mentioned above, the preference for the s-trans conformer of acetophenone derivatives 1a–p was clarified. In order to obtain information on the stability of the s-trans conformation compared with the s-cis conformation, 1a–p were analyzed by DFT calculations. First, the conformational ensembles of 1a–p were generated from 2D chemical structures as the initial structures for the DFT calculations. These conformations generated were optimized with the RDKit using the universal force field (UFF) and clustered using a tolerance of 0.2 Å root-mean-square derivation. For each conformer, Hartree–Fock (HF) calculations were carried out to obtain optimized geometries and energies at the RHF/6-31G(d) and B3LYP/6-31G(d) levels. Due to insufficient formation of conformations in compounds 1d and 1h–n, we calculated the energy surfaces defined by a dihedral angle (∠O=C–C1′-C2′) to obtain stable conformers at the B3LYP/STO-3G level.

For the most stable structure in each cis/trans isomer, the geometries were further optimized at a more accurate level, i.e., RB3LYP/6-31G(d) on the SCRF/IEFPCM model in CHCl3 and RmPW1PW91/6-311G(d,p) on the SCRF/IEFPCM model in CHCl3. Zero-point energy (ZPE) correction was made on the basis of the frequency calculation with RmPW1PW91/6-311G(d,p) on the SCRF/IEFPCM model in CHCl3. As expected, the DFT calculation for 1a–p confirmed that trans conformers are more stable than cis conformers. Further, using the energy differences (ΔG) between cis/trans conformers calculated by DFT, the ratios (cis/trans) based on the Boltzmann distribution were also calculated (Table ). It was revealed that compounds 1a–p exist predominantly as trans conformers.

Table 3

Difference in Energy and Ratio (cis/trans) of Compounds 1a–p Calculated at mPW1PW91/6-311G(d,p), IEFPCM: CHCl3.

compound	R1	R2	ΔGtrans/cis (kcal/mol)	trans/cis
1a	–CH(CN)2	–H	2.57	99:1
1b	–CH(CN, CO2Et)	–H	2.91	99:1
1c	–CH2CH3	–H	2.28	98:2
1d	–H	–H	3.56	>99:1
1e	–Br	–H	2.09	97:3
1f	–CH3	–H	4.13	>99:1
1g	–CO2CH2CH3	–H	2.67	99:1
1h	–H	4′-Br	3.51	>99:1
1i	–H	5′-Br	3.60	>99:1
1j	–H	4′-OH	2.40	98:2
1k	–H	4′-F	1.99	97:3
1l	–H	4′,5′-F	2.48	99:1
1m	–H	5′-NO2	3.02	99:1
1n	–H	4′-OCH3	1.75	95:5
1o	–CH3	4′-F	2.95	99:1
1p	–Cl	4′-F	3.23	>99:1

When these s-trans conformations of compounds 1a–p were optimized at the mPW1PW91/6-311G(d,p) level, the Hα–F and Cα–F internuclear distances of 1a–p were estimated (Table ). In all cases, Hα–F internuclear distances are smaller than the sum of van der Waals radii of fluorine and hydrogen (∼2.67 × 10–10 m), and Cα–F distances are also smaller than that of fluorine and carbon (∼3.23 × 10–10 m).[25]

Table 4

Hα–Fand Cα–F Internuclear Distances of the s-trans Conformations of Compounds 1a–p Calculated at mPW1PW91/6-311G(d,p), IEFPCM: CHCl3

			internuclear distance (10–10 m)
compound	R1	R2	Hα–F	Cα–F
1a	–CH(CN)2	–H	2.40	2.71
1b	–CH(CN, CO2Et)	–H	2.43	2.73
1c	–CH2CH3	–H	2.43	2.76
1d	–H	–H	2.48	2.74
1e	–Br	–H	2.25	2.81
1f	–CH3	–H	2.43	2.76
1g	–CO2CH2CH3	–H	2.38	2.75
1h	–H	4′-Br	2.48	2.75
1i	–H	5′-Br	2.48	2.75
1j	–H	4′-OH	2.48	2.75
1k	–H	4′-F	2.48	2.75
1l	–H	4′,5′-F	2.49	2.76
1m	–H	5′-NO2	2.50	2.76
1n	–H	4′-OCH3	2.49	2.75
1o	–CH3	4′-F	2.43	2.77
1p	–Cl	4′-F	2.30	2.81

Since acetophenone derivatives 1m and 1n were obtained as single crystals, the solid states were examined by X-ray crystallography. In each crystal, only the s-trans conformer was present (Figures and 6, left). The Hα–F and Cα–F internuclear distances of compounds 1m and 1n were measured (1m: Hα–F = 2.39 × 10–10 m, Cα–F = 2.77 × 10–10 m; 1n: Hα–F = 2.48 × 10–10 m, Cα–F = 2.74 × 10–10 m), which were smaller than the sum of van der Waals radii of fluorine and hydrogen and that of fluorine and carbon. In Figures and 6 (right), s-trans conformers of 1m and 1n as calculated by the DFT method reflecting the contribution of CHCl3 are shown for comparison. The structures and the Hα–F and Cα–F internuclear distances obtained by calculation are very similar to those of the solid state. Additionally, it was found that the benzene ring and carbonyl group are almost coplanar. The dihedral angle C2′–C1′-C=O of the solid state of compound 1m is 169.9° and that of 1n is 179.8°.

Figure 5

X-ray crystal structure (left) and the calculated one optimized by calculation at mPW1PW91/6-311G(d,p), IEFPCM: CHCl3 (right) of 1m.

Figure 6

X-ray crystal structure (left) and the calculated one optimized by calculation at mPW1PW91/6-311G(d,p), IEFPCM: CHCl3 (right) of 1n.

All of these findings make it clear that 2′-fluoroacetophenone derivatives form s-trans conformations exclusively, and as a result, Hα–F and Cα–F TS-couplings are observed in their NMR spectra. A high polarization of Cδ+–Fδ− and the presence of three lone pairs on fluorine might suggest that the fluorine of the C–F bond could act as a hydrogen bond acceptor. However, it is known that fluorine in organic molecules forms relatively weak hydrogen bonds. The Hα–F internuclear distances of compounds 1m and 1n in the crystal state were 2.39 × 10–10 m and 2.48 × 10–10 m, respectively (Figures and 6). Such relatively long distances, meaning a weaker interaction compared with a typical hydrogen bond (e.g., ROH···O=C ∼ 1.9 × 10–10 m),[1b] give less conclusive proof of the conformational preference. The understanding of this phenomenon requires a discussion of the ionic nature of the C–F bond, which causes a large dipole moment (μ). The dipole of the C–F bond plays a significant part in determining the conformational behavior of fluorinated organic molecules. For example, α-fluorocarbonyl compounds prefer a conformation where the C–F bond lies anti-periplanar to the carbonyl group, in which carbonyl and C–F dipoles oppose each other to minimize the dipole of the entire molecule.[26] Based on this point of view, the s-cis conformation where the C–F bond lies syn-periplanar to the carbonyl group should maximize the dipole of the entire molecule, which makes the s-cis conformation unstable. On the other hand, s-trans conformers, in which the benzene ring and carbonyl group are almost coplanar, minimize the repulsive dipoles of the C–F bond and carbonyl group. As a result, acetophenone derivatives 1a–p might prefer s-trans conformers to cis conformers (Figure ).

Figure 7

Conformational property of 2′-fluoroacetophenone derivatives.

Conclusion

Hα–F and Cα–F TS-couplings were observed in the NMR spectra of 2′-fluoro-substituted acetophenone derivatives 1a–p, and the over whelming s-trans conformational preference was elucidated. The magnitudes of the coupling constants 5J (Hα, F) and 4J (Cα, F) correlate with the nature of the substituents at Cα and the value of the dielectric constant of solvents. Additionally, X-ray structural analysis suggested that the benzene ring and carbonyl group are almost coplanar in the s-trans conformation, which makes the Hα–F and Cα–F internuclear distances smaller than the sum of their van der Waals radii. Such conformations were reproduced with DFT calculations. Considering the ionic nature of the C–F bond, which causes a large dipole moment (μ), it was assumed that the s-trans conformation, in which the C–F dipole detaches from the carbonyl group repulsively, minimizes the dipole of the entire molecule. The dipole of the C–F bond must play a significant part in determining the conformational behavior of 2′-fluoro-substituted acetophenones. The 2′-fluoro-substituted acetophenones with the preferable s-trans conformations are expected to be utilized as new basic scaffolds for the design of bioactive compounds in medicinal chemistry in the future.

Experimental Section

General Information

Materials were obtained from commercial suppliers. Although all of the fluoro compounds in this work are known and their NMR data have been presented, the more detailed NMR properties, which we newly determined, were defined in order to demonstrate TS-coupling. NMR spectra were recorded on a spectrometer at 400 or 600 MHz for 1H NMR and 100 or 150 MHz for 13C NMR. Chemical shifts are given in parts per million (ppm) downfield from tetramethylsilane as an internal standard, and coupling constants (J) are reported in hertz (Hz). Splitting patterns are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). IR spectra were recorded on an FT-IR spectrometer equipped with ATR (Diamond). The high-resolution mass spectra (HRMS) were recorded on a TOF-MS instrument with an ionization mode of ESI and APCI. Melting points were recorded on a melting point apparatus and are uncorrected. Analytical thin-layer chromatography was performed on precoated, glass-backed silica gel plates. Column chromatography was performed using silica gel (45–60 μm). Extracted solutions were dried over anhydrous MgSO4 or Na2SO4. Solvents were evaporated under reduced pressure. Since compounds 3, 4, 5, and 1d–p were commercially available, characterization data of 1H NMR and 13C NMR were described.

2-[2-(2-Fluorophenyl)-2-oxoethyl]propanedinitrile (1a)

To 2-bromo-2′-fluoroacetophenone (1.81 mL, 13.1 mmol) in ethyl acetate (EtOAc) (17 mL) were added malononitrile (1.24 mL, 19.7 mmol) and diisopropylethylamine (3.42 mL, 19.7 mmol) at 0 °C under an argon stream, and the mixture was stirred at room temperature for 3 h. Then aq. NH4Cl was added, the mixture was extracted with EtOAc, and the extract was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was dried in vacuo and purified by silica gel column chromatography (hexane/dichloromethane = 1:1) to afford 1a, 2.44 g, yield 92%, as colorless crystals.

1H NMR (400 MHz, CDCl3, ppm): δ 8.02 (ddd, J = 7.2, 7.2, 2.0 Hz, 1H), 7.639–7.63 (m, 1H), 7.32 (dd, J = 7.2, 7.2 Hz, 1H), 7.22 (dd, J = 11.6, 8.4 Hz, 1H), 4.38 (t, J = 6.9 Hz, 1H), 3.76 (dd, J = 6.9, 3.2 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 189.5, 162.6 (C–F, 1JC–F = 255.9 Hz), 136.7 (C–F, 3JC–F = 9.6 Hz), 131.0, 125.1 (C–F, 3JC–F = 2.9 Hz), 122.6 (C–F, 2JC–F = 12.5 Hz), 117.0 (C–F, 2JC–F = 24.0 Hz). 112.3, 43.7 (C–F, 4JC–F = 10.5 Hz), 17.7 (C–F, 5JC–F = 3.8 Hz). IR-ATR: 2260, 1675 cm–1. HRMS (APCI-TOF) m/z: [(M – H)−] calcd for C11H6N2OF–, 201.0470; found, 201.0451.

Ethyl 2-Cyano-4-(2-fluorophenyl)-4-oxobutanoate (1b)

To ethyl cyanoacetate (615 μL, 5.77 mmol) in tetrahydrofuran (THF) (1 mL) was added K2CO3 powder (1.2 g, 8.66 mmol), and the mixture was stirred at 40–45 °C (oil bath) for 30 min. To this stirred suspension was slowly added 2-bromo-2′-fluoroacetophenone (1 mL, 6.35 mmol) in THF (5.1 mL) dropwise over a period of 20 min at room temperature, and then the mixture was stirred at room temperature for 14 h, filtered, and concentrated under reduced pressure. The residue was extracted with EtOAc, and the extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane/EtOAc = 4:1) to yield compound 1b, 0.52 g, 36%, as a yellow oil.

1H NMR (400 MHz, CDCl3, ppm): δ 7.95 (ddd, J = 7.6, 7.6, 1.6 Hz, 1H), 7.62–7.57 (m, 1H), 7.27 (ddd, J = 7.6, 7.6, 0.8 Hz, 1H), 7.19 (ddd, J = 11.6, 8.4, 0.8 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 4.11 (t, J = 6.4 Hz, 1H), 3.76 (ddd, J = 18.8, 6.4, 3.3 Hz, 1H), 3.60 (ddd, J = 18.8, 6.8, 3.3 Hz, 1H), 1.35 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 192.2, 165.3, 162.5 (CF, 1JC–F = 255.8 Hz), 135.9 (C–F, 3JC–F = 10.1 Hz), 130.9, 124.8 (C–F, 3JC–F = 2.9 Hz), 123.6 (C–F, 2JC–F = 11.6 Hz), 116.9 (C–F, 2JC–F = 24.6 Hz), 116.2, 63.2, 42.5 (C–F, 4JC–F = 10.1 Hz), 32.0 (C–F, 5JC–F = 2.9 Hz), 13.9. IR-ATR: 2254, 1744, 1686 cm–1. HRMS (ESI-TOF) m/z: [(M + Na)+] calcd for C13H12NO3FNa, 272.0693; found, 272.0698.

1-(2-Fluorophenyl)-1-butanone (1c)

2-Fluorobenzenitrile (1 mL, 9.4 mmol) was added to a solution of propylmagnesium chloride (9.4 mL, 18.8 mmol) in toluene (8 mL) under ice cooling, and the mixture was stirred at room temperature for 4.5 h. Sulfuric acid (2 mL) was carefully poured into the mixture under ice cooling, and the mixture was stirred at room temperature for 30 min. The mixture was then extracted with EtOAc, and the extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane/EtOAc = 20:1) to yield compound 1c, 0.84 g, 53%, as a colorless oil.

1H NMR (400 MHz, CDCl3, ppm): δ 7.84 (ddd, J = 9.6, 7.6, 1.6 Hz, 1H), 7.53–7.47 (m, 1H), 7.22 (ddd, J = 7.6, 7.6, 0.8 Hz, 1H), 7.13 (ddd, J = 11.2, 8.0, 0.8 Hz, 1H), 2.93 (dt, J = 7.2, 3.2 Hz, 2H), 1.75 (sext, J = 7.2 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 198.9, 161.8 (C–F, 1JC–F = 254.3 Hz), 134.2 (C–F, 3JC–F = 8.7 Hz), 130.6, 125.9 (C–F, 2JC–F = 13.5 Hz), 124.4, 116.6 (C–F, 2JC–F = 24.1 Hz), 45.5 (C–F, 4JC–F = 6.7 Hz), 17.4, 13.8. IR-ATR: 1686 cm–1. HRMS (APCI-TOF) m/z: [(M + H)+] calcd for C10H12OF, 167.0867; found, 167.0873.

1-(2-Fluorophenyl)ethanone (1d)

Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.88 (ddd, J = 8.0, 8.0, 2.0 Hz, 1H), 7.55–7.50 (m, 1H), 7.23 (ddd, J = 8.0, 8.0, 0.8 Hz, 1H), 7.14 (ddd, J = 11.6, 7.2, 0.8 Hz, 1H), 2.65 (d, J = 5.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 196.0, 162.2 (C–F, 1JC–F = 254.3 Hz), 134.7 (C–F, 3JC–F = 8.7 Hz), 130.6, 125.7 (C–F, 2JC–F = 12.5 Hz), 124.4 (C–F, 3JC–F = 2.9 Hz), 116.6 (C–F, 2JC–F = 23.1 Hz), 31.5 (C–F, 4JC–F = 7.7 Hz).

2-Bromo-1-(2-fluorophenyl)ethanone (1e)

White crystalline solid. 1H NMR (400 MHz, CDCl3, ppm): δ 7.95 (ddd, J = 7.6, 7.6, 1.6 Hz, 1H), 7.61–7.56 (m, 1H), 7.28 (dd, J = 11.2, 11.2 Hz, 1H), 7.19 (dd, J = 11.2, 11.2 Hz, 1H), 4.53 (d, J = 3.2 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 189.1, 161.7 (C–F, 1JC–F = 254.3 Hz), 135.6 (C–F, 3JC–F = 9.6 Hz), 131.5, 124.9 (C–F, 3JC–F = 2.9 Hz), 122.8 (C–F, 2JC–F = 13.5 Hz), 116.7 (C–F, 2JC–F = 24.1 Hz), 36.0 (C–F, 4JC–F = 9.6 Hz).

1-(2-Fluorophenyl)propanone (1f)

Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.87 (ddd, J = 7.8, 7.8, 1.8 Hz, 1H), 7.53–7.48 (m, 1H), 7.22 (ddd, J = 7.8, 7.8, 0.9 Hz, 1H), 7.13 (ddd, J = 11.4, 8.7, 0.9 Hz, 1H), 3.01 (dq, J = 7.2, 3.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 199.3 (C–F, 3JC–F = 3.9 Hz), 161.9 (C–F, 1JC–F = 253.4 Hz), 134.3 (C–F, 3JC–F = 8.7 Hz), 130.6 (C–F, 4JC–F = 2.9 Hz), 125.7 (C–F, 2JC–F = 13.5 Hz), 124.4 (C–F, 3JC–F = 3.9 Hz), 116.6 (C–F, 2JC–F = 23.1 Hz), 36.8 (C–F, 4J—F = 7.7 Hz), 8.0.

Ethyl 3-(2-Fluorophenyl)-3-oxopropanoate (1g) (2:1 Mixture of Keto and Enol Tautomers)

Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.94 (ddd, J = 7.6, 7.6, 2.0 Hz, 1H), 7.87 (ddd, J = 8.0, 8.0, 2.0 Hz, 0.5 Hz), 7.57–7.53 (m, 1H), 7.42–7.40 (m, 0.5H), 7.29–7.20 (m, 2H), 7.17–7.09 (m, 1H), 5.84 (s, 0.5H), 4.27 (q, J = 7.2 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.99 (d, J = 3.7 Hz, 2H), 1.34 (t, J = 7.2 Hz, 1.5H), 1.25 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 190.3 (C–F, 3JC–F = 3.9 Hz), 173.3, 167.4, 162.2 (C–F, 1JC–F = 254.3 Hz), 135.4 (C–F, 3JC–F = 8.7 Hz), 132.3 (C–F, 3JC–F = 9.6 Hz), 130.9 (C–F, 4JC–F = 1.9 Hz), 129.2, 124.7 (C–F, 3JC–F = 2.9 Hz), 124.6 (C–F, 2JC–F = 12.5 Hz), 124.3 (C–F, 2JC–F = 13.5 Hz), 124.3 (C–F, 3JC–F = 3.9 Hz), 116.5 (C–F, 2JC–F = 24.1 Hz), 116.4 (C–F, 2JC–F = 24.1 Hz), 92.6 (C–F, 4JC–F = 13.5 Hz), 61.3, 60.5, 49.9 (C–F, 4JC–F = 8.7 Hz), 14.2, 14.0.

1-(4-Bromo-2-fluorophenyl)ethanone (1h)

White crystalline solid. 1H NMR (400 MHz, CDCl3, ppm): δ 7.77 (dd, J = 8.4, 8.4 Hz, 1H), 7.40–7.35 (m, 2H), 2.63 (d, J = 5.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 194.7 (C–F, 3JC–F = 2.9 Hz), 161.8 (C–F, 1JC–F = 259.1 Hz), 131.7 (C–F, 4JC–F = 2.9 Hz), 128.2 (C–F, 3JC–F = 10.6 Hz), 128.0 (C–F, 3JC–F = 3.9 Hz), 124.5 (C–F, 2JC–F = 13.5 Hz), 120.7 (C–F, 2JC–F = 27.9 Hz), 31.4 (C–F, 4JC–F = 6.7 Hz).

1-(5-Bromo-2-fluorophenyl)ethanone (1i)

Pale yellow crystalline solid. 1H NMR (400 MHz, CDCl3, ppm): δ 7.99 (dd, J = 6.4, 2.8 Hz, 1H), 7.63–7.59 (m, 1H), 7.05 (dd, J = 10.0, 10.0 Hz, 1H), 2.64 (d, J = 5.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 194.4, 161.2 (C–F, 1JC–F = 255.2 Hz), 137.3 (C–F, 3JC–F = 8.7 Hz), 133.3 (C–F, 3JC–F = 2.9 Hz), 127.1 (C–F, 2JC–F = 14.5 Hz), 118.6 (C–F, 2JC–F = 26.0 Hz), 117.3, 31.3 (C–F, 4JC–F = 7.7 Hz).

1-(2-Fluoro-4-hydroxyphenyl)ethanone (1j)

Pale pink crystalline solid. 1H NMR (400 MHz, CDCl3, ppm): δ 7.85 (dd, J = 8.8, 8.8 Hz, 1H), 6.68 (dd, J = 8.8, 2.4 Hz, 1H), 6.39 (dd, J = 12.4, 2.4 Hz, 1H), 5.78 (d, J = 0.9 Hz, 1H), 2.60 (d, J = 5.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 196.1, 164.2 (C–F, 1JC–F = 256.2 Hz), 162.3 (C–F, 3JC–F = 12.5 Hz), 132.5 (C–F, 3JC–F = 3.9 Hz), 118.2 (C–F, 2JC–F = 12.5 Hz), 112.2, 103.6 (C–F, 2JC–F = 27.0 Hz), 31.1 (C–F, 4JC–F = 7.7 Hz).

1-(2,4-Difluorophenyl)ethanone (1k)

Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.94 (ddd, J = 8.4, 8.4, 6.8 Hz, 1H), 6.98–6.93 (m, 1H), 6.88 (ddd, J = 10.8, 8.8, 2.8 Hz, 1H), 2.63 (d, J = 5.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 194.3 (C–F, 3JC–F = 3.9 Hz), 165.9 (C–F, 1JC–F = 257.2, 3JC–F = 12.5 Hz), 163.0 (C–F, 1JC–F = 258.2 Hz, 3JC–F = 12.5 Hz), 132.6 (C–F, 2JC–F = 10.6 Hz, 4JC–F = 3.9 Hz), 122.2 (C–F, 3JC–F = 13.5 Hz), 112.1 (C–F, 2JC–F = 22.2 Hz, 4JC–F = 3.9 Hz), 104.7 (C–F, 2JC–F = 27.9 Hz, 2JC–F = 27.0 Hz), 31.3 (C–F, 4JC–F = 7.7 Hz).

1-(2,4,5-Trifluorophenyl)ethanone (1l)

Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.79–7.72 (m, 1H), 7.02 (ddd, J = 10.0, 10.0, 6.0 Hz, 1H), 2.63 (d, J = 5.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 193.1 (C–F, 3JC–F = 3.9 Hz), 157.9 (C–F, 1JC–F = 252.4 Hz, 3JC–F = 9.6 Hz, 4JC–F = 1.9 Hz), 153.3 (C–F, 1JC–F = 260.1 Hz, 2JC–F = 15.4 Hz, 3JC–F = 12.5 Hz), 147.1 (C–F, 1JC–F = 247.6 Hz, 2JC–F = 12.5 Hz, 4JC–F = 3.9 Hz), 122.0 (C–F, 2JC–F = 11.6 Hz, 3JC–F = 3.9 Hz), 118.4 (C–F, 2JC–F = 20.2 Hz, 3JC–F = 3.8 Hz, 3JC–F = 3.8 Hz), 106.7 (C–F, 2JC–F = 30.8 Hz, 2JC–F = 30.8 Hz), 31.3 (C–F, 4JC–F = 7.7 Hz).

1-(2-Fluoro-5-nitrophenyl)ethanone (1m)

Pale yellow crystalline solid. 1H NMR (400 MHz, CDCl3, ppm): δ 8.78 (dd, J = 6.0, 2.8 Hz, 1H), 8.43–8.39 (m, 1H), 7.34 (dd, J = 9.6, 9.2 Hz, 1H), 2.70 (d, J = 5.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 193.3, 165.0 (C–F, 1JC–F = 264.9 Hz), 144.5, 129.4 (C–F, 3JC–F = 10.6 Hz), 126.9 (C–F, 3JC–F = 3.9 Hz), 126.4 (C–F, 2JC–F = 16.4 Hz), 118.3 (C–F, 2JC–F = 26.0 Hz), 31.2 (C–F, 4JC–F = 6.7 Hz).

1-(2-Fluoro-4-methoxyphenyl)ethanone (1n)

White crystalline solid. 1H NMR (400 MHz, CDCl3, ppm): δ 7.89 (dd, J = 8.8, 8.8 Hz, 1H), 6.70 (dd, J = 8.8, 2.0 Hz, 1H), 6.62 (dd, 13.2, 2.0 Hz, 1H), 3.86 (s, 3H), 2.60 (d, J = 5.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 194.5, 164.9 (C–F, 3JC–F = 11.6 Hz), 163.8 (C–F, 1JC–F = 255.3 Hz), 132.1 (C–F, 3JC–F = 3.9 Hz), 118.6 (C–F, 2JC–F = 13.5 Hz), 110.6, 101.6 (C–F, 2JC–F = 27.9 Hz), 55.8, 31.2 (C–F, 4JC–F = 7.7 Hz).

1-(2,4-Difluorophenyl)propanone (1o)

Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.96–7.90 (m, 1H), 6.94 (dddd, J = 8.6, 7.6, 2.4, 0.8 Hz, 1H), 6.85 (ddd, J = 11.2, 8.8, 2.4 Hz, 1H), 2.97 (dq, J = 6.8, 3.2 Hz, 2H), 1.19 (dt, J = 6.8, 1.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 197.6 (C–F, 3JC–F = 4.8 Hz), 165.7 (C–F, 1JC–F = 256.2 Hz, 3JC–F = 12.5 Hz), 162.8 (C–F, 1JC–F = 257.2, 3JC–F = 12.5 Hz), 132.6 (C–F, 3JC–F = 10.6 Hz, 3JC–F = 10.6 Hz), 122.1 (C–F, 2JC–F = 13.5 Hz), 112.1 (C–F, 2JC–F = 21.2 Hz, 4JC–F = 2.9 Hz), 104.7 (C–F, 2JC–F = 26.0 Hz, 2JC–F = 26.0 Hz), 36.7 (C–F, 4JC–F = 7.7 Hz), 7.92.

2-Chloro-1-(2,4-difluorophenyl)ethanone (1p)

Pale brown crystalline solid. 1H NMR (400 MHz, CDCl3, ppm): δ 8.03 (ddd, J = 8.4, 8.4, 6.4 Hz, 1H), 7.05–7.00 (m, 1H), 6.92 (ddd, J = 11.2, 8.8, 2.4 Hz, 1H), 4.70 (d, J = 3.2 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 187.8, 166.5 (C–F, 1JC–F = 259.2 Hz, 3JC–F = 12.5 Hz), 162.6 (C–F, 1JC–F = 257.2 Hz, 3JC–F = 12.5 Hz), 133.3 (C–F, 3JC–F = 10.6 Hz, 3JC–F = 10.6 Hz), 119.4 (C–F, 2JC–F = 14.5 Hz), 112.9 (C–F, 2JC–F = 24.1 Hz, 4JC–F = 2.9 Hz), 104.8 (C–F, 2JC–F = 27.0 Hz, 2JC–F = 26.0 Hz), 49.8 (C–F, 4JC–F = 11.6 Hz).

3′-Fluoroacetophenone (3)

Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.74 (ddd, J = 8.0, 1.6, 1.6 Hz, 1H), 7.64 (ddd, J = 9.6, 1.6, 1.6 Hz, 1H), 7.45 (ddd, J = 8.0, 8.0, 5.6 Hz, 1H), 7.29–7.23 (m, 1H), 2.60 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 196.8 (C–F, 3JC–F = 1.9 Hz), 162.8 (C–F, 1JC–F = 248.5 Hz), 139.2 (C–F, 3J—F = 5.8 Hz), 130.2 (C–F, 3JC–F = 7.7 Hz), 124.1 (C–F, 4JC–F = 2.9 Hz), 120.1 (C–F, 2JC–F = 21.2 Hz), 115.0 (C–F, 2JC–F = 22.2 Hz), 26.8.

2′-Fluorophenylacetone (4)

Pale yellow oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.30–7.24 (m, 1H), 7.18 (ddd, J = 8.0, 8.0, 2.0 Hz, 1H), 7.13–7.05 (m, 2H), 3.74 (s, 2H), 2.20 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 205.0, 161.0 (C–F, 1JC–F = 245.6 Hz), 131.6 (C–F, 3JC–F = 4.8 Hz), 129.0 (C–F, 3JC–F = 8.7 Hz), 124.3 (C–F, 4JC–F = 3.9 Hz), 121.6 (C–F, 2JC–F = 16.4 Hz), 115.4 (C–F, 2JC–F = 22.2 Hz), 43.9 (C–F, 4JC–F = 1.93 Hz), 29.5.

2-(2′-Fluorophenyl)ethanol (5)

Colorless oil. 1H NMR (400 MHz, CDCl3, ppm): δ 7.24–7.19 (m, 2H), 7.10–7.02 (m, 2H), 3.90 (t, J = 6.4 Hz, 2H), 2.92 (t, J = 6.4 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 161.3 (C–F, 1JC–F = 244.7 Hz), 131.4 (C–F, 3JC–F = 4.8 Hz), 128.2 (C–F, 3JC–F = 7.7 Hz), 125.4 (C–F, 2JC–F = 16.4 Hz), 124.1 (C–F, 4JC–F = 3.9 Hz), 115.4 (C–F, 2JC–F = 22.2 Hz), 62.6, 32.7.