Next Article in Journal
Gold-Catalyzed Synthesis of 2-Sulfenylspiroindolenines via Spirocyclizations
Previous Article in Journal
Dimethyl 2,2′-[Carbonylbis(azanediyl)](2S,2′S)-bis[3-(4-hydroxyphenyl)propanoate]
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Short Note

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

1
School of Chemistry, National University of Ireland Galway, University Road, Galway, H91 TK33, Ireland
2
Department of Pharmacy, School of Life Sciences, Pharmacy and Chemistry, Kingston University, Penrhyn Road, Kingston upon Thames KT1 2EE, UK
*
Author to whom correspondence should be addressed.
Molbank 2018, 2018(1), M984; https://doi.org/10.3390/M984
Submission received: 31 January 2018 / Revised: 13 February 2018 / Accepted: 18 February 2018 / Published: 20 February 2018
(This article belongs to the Section Structure Determination)

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.

Graphical Abstract

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); νmax (neat, cm−1) 3073, 2974, 2944, 1640, 1506 (NO2), 1450, 1351 (NO2), 1285, 1223, 1194, 1081, 1024; δH (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); δC (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) Å3, 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).

Supplementary Materials

The following are available online: https://www.mdpi.com/1422-8599/2018/1/M984/s1. 1H and 13C-NMR spectra, EI-MS, and crystal data and structure refinement of the title compound 5. CCDC 1819149 also contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html.

Acknowledgments

We thank the Irish Research Council (IRC) for a Government of Ireland Postgraduate Scholarship for M. Sweeney.

Author Contributions

M. Sweeney was the only experimentalist, who obtained, and analysed all data, apart from the X-ray crystallography, which was performed by P. McArdle. F. Aldabbagh directed the research and wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

  1. Taleb, A.; Alvarez, F.; Nebois, P.; Walchshofer, N. An improved methodology for the preparation of 4,7-dimethoxy-1H-benzimidazole, a key intermediate in the synthesis of 1-alkyl-1H-benzimiadzole-4,7-diones. Heterocycl. Commun. 2006, 12, 111–114. [Google Scholar] [CrossRef]
  2. Hammershøj, P.; Reenberg, T.K.; Pittelkow, M.; Nielsen, C.B.; Hammerich, O.; Christensen, J.B. Synthesis and properties of 2,3-Dialkynyl-1,4-benzoquinones. Eur. J. Org. Chem. 2006, 12, 2786–2794. [Google Scholar] [CrossRef]
  3. Gurry, M. The benign synthesis of bioactive heterocycles using photochemistry and hydrogen peroxide with hydrohalic acids. Ph.D. Thesis, NUI Galway, Galway, Ireland, 2016. [Google Scholar]
  4. Lynch, M.; Hehir, S.; Kavanagh, P.; Leech, D.; O’Shaughnessy, J.; Carty, M.P.; Aldabbagh, F. Synthesis by radical cyclization and cytotoxicity of highly potent bioreductive alicyclic ring fused [1,2-a]benzimidazolequinones. Chem. Eur. J. 2007, 13, 3218–3226. [Google Scholar] [CrossRef] [PubMed]
  5. Fahey, K.; O’Donovan, L.; Carr, M.; Carty, M.P.; Aldabbagh, F. The influence of the aziridinyl substituent of benzimidazoles and benzimidazolequinones on toxicity towards normal and Fanconi anaemia cells. Eur. J. Med. Chem. 2010, 45, 1873–1879. [Google Scholar] [CrossRef] [PubMed]
  6. Sweeney, M.; Gurry, M.; Keane, L.-A.J.; Aldabbagh, F. Greener synthesis using hydrogen peroxide in ethyl acetate of alicyclic ring-fused benzimidazoles and anti-tumour benzimidazolequinones. Tetrahedron Lett. 2017, 58, 3565–3567. [Google Scholar] [CrossRef]
  7. Chemspace. Available online: https://chem-space.com (accessed on 24 January 2018).
  8. Laali, K.K. Nitro and nitroso transformations in superacids. Coord. Chem. Rev. 2000, 210, 47–71. [Google Scholar] [CrossRef]
  9. Sheldrick, G.M. SHELXT—Integrated space-group and crystal-structure determination. Acta Crystallogr. A 2015, 71, 3–8. [Google Scholar] [CrossRef] [PubMed]
  10. Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Crystallogr. C. 2015, 71, 3–8. [Google Scholar] [CrossRef] [PubMed]
  11. McArdle, P. Oscail, a program package for small-molecule single-crystal crystallography with crystal morphology prediction and molecular modelling. J. Appl. Crystallogr. 2017, 50, 320–326. [Google Scholar] [CrossRef]
Scheme 1. Expected nitration based upon similar literature reaction [1,2,3].
Scheme 1. Expected nitration based upon similar literature reaction [1,2,3].
Molbank 2018 m984 sch001
Scheme 2. Preparation of 1-fluoro-2,5-dimethoxy-4-nitrobenzene (5).
Scheme 2. Preparation of 1-fluoro-2,5-dimethoxy-4-nitrobenzene (5).
Molbank 2018 m984 sch002
Figure 1. One of the two molecules in the asymmetric unit of the X-ray crystal structure of 1-fluoro-2,5-dimethoxy-4-nitrobenzene (5), 40% ellipsoids.
Figure 1. One of the two molecules in the asymmetric unit of the X-ray crystal structure of 1-fluoro-2,5-dimethoxy-4-nitrobenzene (5), 40% ellipsoids.
Molbank 2018 m984 g001

Share and Cite

MDPI and ACS Style

Sweeney, M.; McArdle, P.; Aldabbagh, F. 1-Fluoro-2,5-dimethoxy-4-nitrobenzene. Molbank 2018, 2018, M984. https://doi.org/10.3390/M984

AMA Style

Sweeney M, McArdle P, Aldabbagh F. 1-Fluoro-2,5-dimethoxy-4-nitrobenzene. Molbank. 2018; 2018(1):M984. https://doi.org/10.3390/M984

Chicago/Turabian Style

Sweeney, Martin, Patrick McArdle, and Fawaz Aldabbagh. 2018. "1-Fluoro-2,5-dimethoxy-4-nitrobenzene" Molbank 2018, no. 1: M984. https://doi.org/10.3390/M984

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop