b School of Science, Xi'an Jiaotong University, Xi'an 710049, China
Nitration is a very important reaction in organic chemistry because many nitro aromatics can be used as pharmaceuticals intermediates to afford aromatic amines by reduction. Traditional nitration reagents are composed of nitric acid [1], nitrosyl sulfuric acid [2], benzoyl nitrate [2], ethyl nitrate [2], acetone cyanohydrin nitrate [2], inorganic nitrates [2], N-nitropyridinium salt [2], nitronium tetrafluoroborate [2], nitrosyl chloride [2], nitrogen oxide [2], trimethylsilyl nitrate [3] and nitrating mixtures [2] such as nitric acid-sulfuric acid, nitric acid-acetic acid, nitric acid-acetic anhydride, metal nitrates-acetic anhydride, potassium nitrate or nitric acid and boron trifluoride monohydrate [4] as the nitrating agents. Although the above reagents give some specificity in nitration, new nitration reagents are still needed for the selective nitration of some aromatic compounds. Urea nitrate has been used as a well documented nitration reagent for aromatic compounds [5, 6]. Surprisingly, though, its thio-substituted counterpart, thiourea nitrate (1, TN), has never been utilized for the nitration of aromatic compounds. Because urea and thiourea share similar structures, yet are not completely interchangeable [7], we decided to explore the potential of 1 for nitration of various aromatic compounds. Crystallized TN could be easily prepared from thiourea and nitric acid according to (Scheme 1) [8] and should be stored properly [9, 10, 11].
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| Scheme 1.Preparation of thiourea nitrate (TN). | |
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| Scheme 2.Nitration of aromatic compounds using TN. | |
Melting points were taken on an X-1 digital melting point apparatus and are uncorrected. Mass spectra were measured on an HP5988A instrument by direct inlet at 70 eV. All materials were obtained from commercial suppliers and used as received.
To a three-necked flask (250 mL) equipped with a magnetic stirrer and thermometer was added thiourea (20 g, 0.26 mol) and water (120 mL), the reaction mixture was stirred while heated to 55-60 ℃ to ensure the complete dissolution of the thiourea in the water. The reaction mixture was then allowed to cool down to 45- 50 ℃. At the first appearance of the crystal-like solid, nitric acid (69%, 30 mL) was added dropwise to the solution, while keeping the reaction temperature below 45 ℃ with an ice-water bath. The stirring was continued until the reaction cooled down below 10 ℃. The crystals thus obtained were collected by filtration, washed with a small amount of ice water, and then dried under vacuo to give a white solid as the desired product (29.5 g, 80.6%), mp 148- 149 ℃ [12].
Sulfuric acid (98%, 25 mL) was added to a three-necked flask (50 mL) equipped with a magnetic stirrer and thermometer then cooled down below 0 ℃ with a salt-ice bath. While keeping the temperature below 0 ℃, aromatic compound (0.02 mol) was added to the mixture, followed by slow addition of thiourea nitrate 1 (2.8 g, 0.02 mol). After the addition of 1 was complete, the mixture was allowed to warm up to room temperature and then stirred for an additional 0.2-5 h (Table 1) at room temperature. The reaction mixture was slowly poured onto ice water (250 mL). The aqueous layer was extracted with ethyl acetate (3× 50 mL). The combined ethyl acetate layer was washed with saturated brine (25 mL) and water (25 mL) and then dried (anhydrous Na2SO4). After evaporation of the solvent, a brown residue was obtained. The content of the crude product was determined by LC-MS. The crude product was purified by column chromatography [12].
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Table 1 Nitration of aromatic compounds using TN. Ar–H→Ar–NO2. |
The reaction of 1 in 98% sulfuric acid with benzene (entry 1) was first explored with high yield. Encouraged by this good result, we further investigate the nitration of TN with other aromatic compounds bearing different substituted groups on the benzene ring (entries 2-12). The substituted groups were chosen according to their electronic properties, which include strongly electron withdrawing groups (entry 2), activating groups (in entries 3, 4, 5, 6, 8, 9, 10, 11) and deactivating groups (in entry 4, 5, 7, 12). We found that mono-nitrations were obtained in excellent yield for unsubstituted benzene (entry 1). Di-nitration was also obtained in excellent yields for nitrobenzene (entry 12). The mono-nitrated products were also obtained for entries 2-11. Moreover in all of the monosubstituted substrates (entries 2, 3, 6), only the p-substituted nitro compounds were obtained regioselectively. Interestingly, the nitration of acetanilide (entry 9) with TN ended up without any undesired starting material. Introducing a methyl or a methoxy group at the para position of the acetylamino group could improve the nitration yields (entries 10-11). In the cases of aldehyde groups, the reaction of TN with substituted aromatic aldehyde gave relatively poor yields (entries 4, 7). The results of nitration are summarized in Table 1.
When nitrating with TN, it is difficult to mono-nitrate aromatic substrates with electron withdrawing groups. This is the opposite of nitrating with urea nitrate [5] or guanidinium nitrate [2], in which it is difficult to mono-nitrate aromatic substrates with electron donating groups. In the two extreme examples with good yield shown in entry 1 and entry 12, the substrates bears no group or one moderately deactivating group on the aromatic ring, respectively. Aromatic substrates with electron withdrawing groups are very suitable for the nitration with TN (entry 12). Electron donating groups as activating group on the benzene are also quite suitable for the nitration with TN (entry 9).
Traditional mechanisms of nitration include high temperature reaction and free radicals on electrophilic aromatic substitution or single-electron transfer (SET) on aromatic hydrocarbons [13]. However, neither of these mechanisms could completely explain the nitration result with TN. Therefore, we proposed that a different, complex mechanism might exist in the nitration process of TN due to the difference between the volume of the sulfur atom in thiourea and the oxygen atom in urea. S is bulkier and more polarizable than O, which makes the TN behave differently in the SET process (Scheme 3).
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| Scheme 3.Nitration with TN via plausible intermediate. | |
In conclusion, a series of aromatic compounds bearing moderately activating, activating, weakly deactivating and strongly deactivating groups have been nitrated with TN in different yields to give the corresponding nitro compounds. TN offers advantages in ease of preparation, low cost, and simple handling in the nitration of aromatic substrates, making it a plausible alternative for nitrating aromatic compounds, especially when traditional nitration reagents are less successful.
The authors are grateful to Fundamental Research Funds for the Central Universities (2011), and Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, PR China (2011) for the financial support. We would also like to express our appreciation for grammatical checking by Professor Norbert Haider in Vienna University, Austria.
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