1-Fluoro-2,5-dimethoxy-4-nitrobenzene

Abstract

1-Fluoro-2,5-dimethoxy-4-nitrobenzene was synthesized in 90% yield by the reaction of commercial 2-fluoro-1,4-dimethoxybenzene with nitric acid. The structure was confirmed by X-ray crystallography. The new title compound was characterized by ¹H and ¹³C-NMR, elemental analysis, EI-MS and FT-IR.

1. Introduction

2-Fluoro-1,4-dimethoxybenzene (3) is available from Apollo Scientific (CAS Number: 82830-49-7) and sold by Sigma-Aldrich in the UK at £277.20 for 100 g. Nitration would give a suitably activated aromatic for facile nucleophilic aromatic substitution. Given the reaction of 1,4-dimethoxybenzene with nitric acid is reported to give 2,3-dinitro-1,4-dimethoxybenzene (2) in high yields of 76–90%, depending on the publication source [1,2,3], the analogous reaction with compound 3 was expected to give some 2-fluoro-1,4-dimethoxy-3-nitrobenzene (4) (Scheme 1). The fluoro-group was expected to direct nitration ortho and para to give 2-fluoro-1,4-dimethoxy-3-nitrobenzene (4) and 1-fluoro-2,5-dimethoxy-4-nitrobenzene (5). The 3-nitro isomer (4) was intended as a substrate for the synthesis of alicyclic ring-fused benzimidazolequinone anti-tumour agents [4,5,6], however nitration was selective giving only isomer (5) in high yield. Herein, is described the first available preparation and analytical characterization of 1-fluoro-2,5-dimethoxy-4-nitrobenzene (5).

2. Results and Discussion

Treating 2-fluoro-1,4-dimethoxybenzene (3) with nitric acid (Honeywell Chemicals, 64–66%) over 10 minutes at 0 °C gave 1-fluoro-2,5-dimethoxy-4-nitrobenzene (5) in 90% yield (Scheme 2). This is the first reported synthesis and characterisation of (5), even though alleged commercial sources exist [7]. X-ray crystallography confirmed the location of the substitution (Figure 1 & Supplementary Materials). There were two chemically identical molecules in the asymmetric unit and there were no significant intermolecular interactions in the solid state.

The fluoro-substituent was found to be overwhelmingly para-directing, in contrast to the nitro-group of the intermediate 1,4-dimethoxy-2-nitrobenzene (1), which directs the electrophile to the adjacent position to give 2,3-dinitro-1,4-dimethoxybenzene (2) in the analogous nitration of 1,4-dimethoxybenzene (Scheme 1). Nitro-groups are well-known to participate in adjacent group coordination and reactions, especially under strong acidic conditions that also favour their protonation [8].

3. Materials and Methods

3.1. General Information

All of the chemicals were obtained from commercial sources and used without purification. Nitric acid was 64–66% (w/v) in water. Melting point was measured on a Stuart Scientific melting point apparatus SMP1 (Cole-Parmer, Staffordshire, UK). Infrared spectrum was recorded using a Perkin-Elmer Spec 1 with ATR attached. ¹H-NMR spectra were recorded using a JEOL ECX 400 MHz instrument equipped with a DEC AXP 300 computer workstation (JEOL Ltd., Tokyo, Japan). The chemical shifts were recorded in ppm relative to tetramethylsilane. ¹³C-NMR data were collected at 100 MHz with complete proton decoupling. NMR assignment was supported by DEPT and ¹H-¹³C-NMR correlation. GC-MS analysis was performed on an Agilent 6890 Series GC System equipped with an Agilent 5975 Inert Mass Selective Detector (EI) and a DB-1, 30 m, ID 0.25 mm, FD 0.25 µm column (Agilent Technologies, Santa Clara, CA., USA). Helium was used as carrier gas at a flow rate of 2.4 mL/min. The injector was heated to 160 °C and the oven temperature was increased from 150 to 180 °C at the rate of 22 °C/min and was then further increased to 320 °C at 40 °C/min. Elemental analysis was carried out on a Exeter Analytical CE-440 analyzer (Exeter Analytical, Coventry, UK). An Oxford Diffraction Xcalibur system was used to collect X-ray diffraction data at room temperature (Rigaku Oxford Diffraction, Oxford, UK). The crystal structures were solved using ShelxT and refined using ShelxL 2016/6 within the Oscail package (Patrick McArdle, Galway, Ireland) [9,10,11].

3.2. Synthesis of 1-Fluoro-2,5-dimethoxy-4-nitrobenzene (5)

2-Fluoro-1,4-dimethoxybenzene (3) (16.00 g, 0.10 mol) was slowly added to a stirred solution of HNO₃ (64–66%, 143 mL) at 0 °C. The solution was stirred for 10 min, poured onto ice water (600 mL), and stirred for 30 min. The precipitate was collected, washed with water, and dried to give 1-fluoro-2,5-dimethoxy-4-nitrobenzene (5) (18.63 g, 90%) as yellow solid; mp 116–118 °C; GC-EIMS m/z: 201 [M]⁺ (100), 154 (48), 141 (39), 125 (65), 97 (68), 95 (48), 69 (34); ν_max (neat, cm⁻¹) 3073, 2974, 2944, 1640, 1506 (NO₂), 1450, 1351 (NO₂), 1285, 1223, 1194, 1081, 1024; δ_H (400 MHz, CDCl₃) 3.90 (s, 3H, Me), 3.92 (s, 3H, Me), 6.88 (d, J 12.2 Hz, 1H, 6-H), 7.62 (d, J 9.2 Hz, 1H, 3-H); δ_C (100 MHz, CDCl₃) 57.0, 57.3 (both Me), 103.0 (d, J 24.8 Hz, 6-CH), 111.4 (d, J 3.8 Hz, 3-CH), 134.4 (4-C), 141.1 (d, J 11.4 Hz, C), 149.0 (d, J 9.5 Hz, C), 155.8 (d, J 255.5 Hz, 1-C). Anal. Calcd for C₈H₈FNO₄: C, 47.77; H, 4.01; N, 6.96. Found: C, 47.67; H, 3.92; N, 6.79.

Crystal Data for C₈H₈FNO₄ (M = 201.15 g/mol): monoclinic, space group Cc, a = 7.9538(6) Å, b = 13.5379(11) Å, c = 16.0790(13) Å, α = 90°, β = 89.983(6)°, γ = 90°, V = 15588.1(3) ų, Z = 8, T = 298.4(4) K, μ(MoKα) = 0.138 mm⁻¹, Dcalc = 1.543 g/cm³, 6792 reflections measured (−10 ≤ h ≤ 9, −18 ≤ k ≤ 17, −20 ≤ l ≤ 9), 3164 unique (Rint = 0.0214) which were used in all calculations. The structure was refined as an inversion twin. The final R1 was 0.0755 (I > 2σ(I)) and wR2 was 0.1838 (all data).