Simple and efficient synthetic procedures were established for the preparation of new energetic covalent compounds, salts, and protonated ionic liquids based on the readily available antimicrobial agent metronidazole. Some of these materials exhibit the desirable properties of energetic materials and energetic ionic liquids, such as low vapor pressure, low melting point, good chemical and thermal stability, and high energetic content. For each of the relevant compounds prepared, thermal stability was determined by differential scanning calorimetry. Some of these compounds may be considered promising precursors of pharmaceuticals such as antimicrobial, antiparasitic, antifungal, antineoplastic agents, or enzyme inhibitors.
Interest in energetic ionic liquids (EILs) has grown exponentially in the last few years as a result of their application in various areas of research such as electrochemistry, separation science, chemical synthesis, and catalysis [
Infrared spectra were recorded directly as liquids or solids (both referred to as “neat”) on a Cary 660 Series FTIR Spectrometer with internal calibration. Only the strongest diagnostic bands are reported. Proton and carbon nuclear magnetic resonance (1H NMR and 13C NMR) spectra were recorded on a Bruker AVANCE-III 500 (500 MHz) spectrometer. Unless otherwise stated, CDCl3 was used as solvent. Elemental analyses were performed on a Perkin Elmer PE2400 elemental analyzer by the USAI-UNAM microanalytical laboratory. Melting points were measured on a Mettler Toledo DSC1 (STAR 11.0) DSC apparatus; decomposition temperature (
Ammonium nitrate (1.90 g, 0.237 mol) is added to a cold (ice-water bath) nitric acid solution (68%, 16.03 g, and 0.16 mol), while stirring. Then sulfuric acid (97%, 27.78 g, and 0.276 mol) is added slowly and the mixture is stirred for 5 min, followed by the portionwise addition of metronidazole (3 g, 17.528 mmol). The reaction mixture is then warmed to room temperature and is stirred for 30 min and then the contents of the reaction mixture are transferred to a separation (or addition) funnel. This mixture is added dropwise to a stirred ice-water mixture (200 g crushed ice; 100 mL water) while at the same time adding, also dropwise, a solution of sodium hydroxide (28.48 g, 0.712 mol) at approximately the same rate. After the addition the empty reaction container and its corresponding funnel are rinsed into the ice-water mixture. The pH is finally adjusted to neutral with the addition of a saturated solution of sodium bicarbonate or 10% HCl solution, as required. The resulting mixture is extracted with CH2Cl2 (
A solution of nitric acid in CH2Cl2 (3.1 mL, 1.53 M) is added dropwise to a stirred solution of compound
Picric acid (0.243 g, 1.061 mmol) is dissolved in a stirred mixture of CH2Cl2 (3 mL) and Et2O (4 mL), to which nitrate ester
To a cooled (0°C) solution of triphenylphosphine (8.43 g, 32.14 mmol) in CH2Cl2 (100 mL) bromine is slowly added (1.65 mL, 32.20 mmol) followed by addition of triethylamine (4.48 mL, 32.14 mmol). To the resulting solution metronidazole is then added in small portions (5.00 g, 29.21 mmol), while stirring. After 5 min the reaction mixture is warmed to room temperature, stirred for further 30 min, and then quenched with water (150 mL) and a saturated solution of aqueous sodium thiosulphate (10 mL). The mixture is then extracted with CH2Cl2 (3 × 50 mL) and the combined extracts are washed with brine (1 × 50 mL) and dried with anhydrous sodium sulfate. The resulting solution is then percolated through a short silica gel column after which the solvent is removed
Azide
Picric acid (0.467 g, 2.038 mmol) is dissolved in Et2O (25 mL) at room temperature and then immediately added to a stirred solution of azide
Herein we report our exploratory work into the transformation of the readily available and inexpensive antimicrobial agent metronidazole (
Metronidazole (
A straightforward procedure for producing PILs is the reaction of a suitable acid with an azo compound to produce a protonated azolium-based salt. It is also possible to produce energetic aprotic ionic liquids wherein the cation is constituted by a fully alkylated quaternary ammonium center. In the present work we favored the simpler PIL pathway to expedite the preparation of a number of nitrate and picrate salts by the direct reaction of HNO3 or picric acid with metronidazole derivatives.
Despite what may seem to be a facile way of producing protonated ILs, it should be noted that there are limitations in the formation of protonated imidazolium nitrate and picrate salts. Smiglak et al. [
Nitrate ester
Oxygen deficiency and DSC data for compounds
Compound | Oxygen deficiency (Ω), % | Melting point °C | Decomposition temperature (1st transition; |
Decomposition temperature |
---|---|---|---|---|
|
−81.4 | 70.5 | 182.9 | — |
|
−114.2 | 55.1 | 87.7 |
222.0 |
|
−48.7 | — | 168.3 | 175.3; 208.7 |
|
−63.0 | 141.9 | 192.8 | 247.9 |
|
−71.0 | — |
144.0 | 225.0 |
|
−77.2 | 124.3; 135.0 |
243.2 | — |
Preparation of nitrate ester
DSC plots of compounds
Having compound
The hydroxyethylene moiety attached to position 1 on the imidazole nucleus of metronidazole should allow for versatile transformations. Thus, we next considered the replacement of the primary alcohol functional group with an azide functional group. This was accomplished initially transforming the primary alcohol into its corresponding bromide, followed by nucleophilic substitution using sodium azide in DMF to give azide
Preparation of azide
The reaction of
Apart from the potential uses of the compounds prepared herein as EMs, it is to be noted that compounds
Five new energetic compounds were prepared in a straightforward and efficient manner from the well-known and readily available antimicrobial metronidazole. Compounds
The author declares that there is no conflict of interests regarding the publication of this paper.
Technical assistance by M.S. Julio C. Cortes (Nutek, S.A. de C.V.), M.S. Atilano Gutiérrez (UAM), and Q. Margarita Portilla (USAI-UNAM), is gratefully acknowledged. The author is grateful to Dr. Bernardo Frontana Uribe and MC. Alejandra Núñez Pineda (CCIQS UAEM-UNAM) for graciously running DSC and TG analyses for compound