This invention relates to a new nitration system, and a new method for nitration of aromatic compounds.

Aromatic compounds which are nitrated, are most interesting to the fine chemical industry, and are inter alia used as raw materials for pharmaceuticals, dyestuffs, pesticides and explosives.

From an industrial point of view it is desirable to improve and optimize the already known methods for preparing these nitrated aromatic compounds. In connection with this problem, there has lately been an increasing interest in using dinitrogen pentoxide (N ₂ O ₅ ) as a nitrating agent. This is primarily due to the fact that new and more profitable methods for preparing such compounds have been found (EP-295878, US-4.432.902 and US-4.525.252).

A variety of methods are available for nitration of aromatic compounds. However, the direct nitration of a number of aromatic compounds, and in particular some heteroaromatic compounds, give low or no yields at all, and the substitution has to be conducted by initial preparation of suitably activated derivatives. This makes the preparation of these nitro compounds cumbersome.

Nitration of aromatic compounds are today mainly performed by nitration with nitric acid or a mixture of nitric acid and sulphuric acid. Both these systems are strongly acidic. A supposition for these methods to be successful is therefore that the aromatic compounds to be nitrated are stable under acidic conditions. Once the compound has been nitrated by any of these nitration systems, the product is separated from the acid phase and then washed to remove any mineral acids. The major drawbacks of this system have been the instability of

some molecules to the strongly acidic and oxidizing conditions, and the sensitivity of some molecules to water. There is also formed large amounts of waste in the form of spent acid.

Dinitrogen pentoxide in nitric acid is another known nitrating system for nitration of aromatic compounds (US H-447 and DE-2435651). This nitrating system is a more powerful nitrating agent than both 100% HNO ₃ , HNO ₃ /H ₂ SO ₄ and N ₂ O ₅ in H ₂ SO ₄ . However, this nitrating system also does have the same drawback as the methods mentioned above because of the solvent used, and that regeneration of nitric acid still will have to take place.

The nitration systems N ₂ O ₅ in HNO ₃ and HNO ₃ /H ₂ SO ₄ give approximately the same yield and kind of substitution. For deactivated compounds reacting slowly by use of HNO ₃ /H ₂ SO ₄ , it might be advantageous to use N ₂ O ₅ in HNO ₃ .

There are several aromatics not being stable under such conditions as those described above. In these cases nitration by N ₂ O ₅ in aprotic media might be advantageous. Possible advantages by use of N ₂ O ₅ in organic solvents are avoiding strong acids and/or aqueous solutions, which will keep intact groups that are sensitive to acids, and groups that might hydrolyse.

Two examples of aromatic compounds which have not been possible to nitrate in high yields are pyridine and 2-methylpyridine. Ege, S. (Organic Chemistry, D.C. Heath: Lexington, MA, (1984) 1827) found that direct nitration with nitric acid/sulphuric acid only gives 5% of 3- nitropyridine. Further Friedl, F. (Ber. Dtsch. Ges. 72 (1912) 428) has reported that nitration of pyridine by potassium nitrate and fuming sulphuric acid at 330°C gives 15% of 3-nitropyridine. Plazek (Ber. 72 (1939) 577) achieved a yield of 3.6% 2-methyl-5-nitropyridine when nitrating 2-methyipyridine by potassium nitrate and fuming sulphuric acid at 160°.

In order to solve the problems described above, the inventors did examine several nitration systems on aromatic compounds. Among these were NO ₂ ⁺ BF ₄ ^" in liquid S0 ₂ , HNO ₃ in liquid SO _2r N ₂ O ₅ in HNO ₃ and N ₂ O ₅ in CCI ₄ where neither of these systems gave nitration of pyridine. Most surprisingly it was discovered that the nitration system N ₂ O ₅ in liquid SO ₂ gave 60% of 3-nitropyridine using pyridine as substrate. The nitration system N ₂ O ₅ in liquid SO ₂ was further examined, and proved to be surprisingly effective by nitration of substituted and unsubstituted aromatics (including both carbocyclic aromatics and heteroaromatics),in general.

Using liquid sulphur dioxide as a solvent in the nitration processes was by the inventors considered as an interesting alternative to the ordinary solvents used, even if it in the prior art hardly is mentioned. Part of the scepticism for the use of SO ₂ may be connected to the fact that it boils at a relatively low temperature, - 11 °C. It is therefore necessary to cool down the reaction mixture.

Sulphur dioxide was chosen because it is capable of dissolving both organic and inorganic compounds, and it also has high polarity which makes it a good solvent in ionic reactions. Another advantage by performing the nitration processes in SO ₂ is the fact that this makes use of a less acidic medium than HNO ₃ or HNO ₃ /H ₂ SO ₄ . Hydrolysis of ester groups, acid chloride groups, etc. will therefore be minimised.

In the nitration system N ₂ O ₅ in SO ₂ , other aprotic, organic solvents, for instance chloroform, may also be present. The reactants may be added to the reaction mixture as a solution dissolved in this additional organic solvent. A deciding factor when choosing an additional solvent or solvents is that the reactants are soluble in the medium.

The yields obtaining when using the present nitration system (N ₂ 0 ₅ in S0 ₂ ) do depend on the reaction temperature. In a wide temperature range from -100°C to 0°C nitrated products are formed. However, the optimal temperature during the reaction depends on the compound being nitrated. For certain occasions it might be advantageously to perform the nitration reaction at increased pressure and temperature.

The concentration of N ₂ O ₅ in SO ₂ is not critical for the performance of this nitration reaction. However, it is found practically to use a concentration within the range 0.5 - 1.0 M.

What is critical is the concentration ratio between N ₂ O ₅ and the substrate being nitrated. For instance, when nitrating pyridine to 3-nitropyridine a ratio of 2:1 gave good yields. For toluene the ratio between N ₂ O ₅ and the substrate give influence to the division of mononitrated and dinitrated toluene. The ratio N^O _g /toluene being 1 :1 and 2:1 give rise to the product mixture mononitrotoiuene/dinitrotoluene 14:1 and 1 :2.5, respectively. The ratio dinitrogen pentoxide : substrate, should therefore be valued in each occasion because the determination of this condition is important for the product yield and the product mixture obtained.

The present invention comprises a nitration system, comprising dinitrogen pentoxide dissolved in liquid sulphur dioxide.

The invention further comprises a process for nitration of aromatic compounds according to the general formula (I)

where A is either of the groups -CR ₅ =CR ₆ - , -S-, or -N=CFt ₇ -; and R, - R ₇ are independent of each other, and being hydrogen. C.-C _j -aikyl.

C _j -C ₄ -alkoxy or C.-C^-alkyloxycarbonyi; and where R _τ and \ , or F^ and R ₃ may together with the carbon atoms they are combined with, form an aromatic ring containing 6 carbon atoms. The process further comprises application of the nitration system dinitrogen pentoxide in sulphur dioxide, and performing the nitration reaction within the temperature range -100 to 0°C, and for a period of 1 - 8 hours.

The expression C.-C ₄ -alkyl refers to alkyl groups containing from one to four carbon atoms, and are for instance methyl, ethyl, propyl, isopropyl, n-butyi or tert-butyl.

The expression C.-C ₄ -alkoxy refers to alkoxy groups containing from one to four carbon atoms, and are for instance methoxy, ethoxy, prαpoxy. isopropoxy. butoxy, isobutoxy, sec- butoxy and tert-butoxy.

The expression O.-C ₄ -a!kyioxycarbonyl refers to alkyl carboxylate groups, where the alkyl part are defined like the C.-C ₄ -alkyl groups above.

A preferred feature of the invention is nitration of pyridine by the nitration agent N ₂ O _c in SO-,,

at -40°C to -25°C for a period of about 4 hours.

Another preferred feature of the invention is nitration of 2-methyl- or 4-methylpyridine, or dimethyl- or diethyl isophtalate by the nitration agent N ₂ 0 ₅ in SO ₂ , at -78 to -11 °C for a period of about 4 hours.

In the following the invention will be further explained by examples. The examples are to be considered as illustrating and not limiting for the present invention.

Example 1

Nitration of various aromatic compounds by the nitration system N ₂ O ₅ in liquid S0 ₂ . The substrates chosen, the temperature, the reaction time, the products obtained and the yields thereof are shown in Table 1.

General procedure for nitration with N ₂ O ₅ in liquid SO-,.

The nitration mixture was prepared by addition of dinitrogen pentoxide (2.7 g, 25 mmol) to sulphur dioxide (25 ml) at -78°C. The substrate (12.5 mmol) was then added slowly. The mixture was heated to -11°C for a period of two hours and stirred for another two hours. The reaction mixture was poured over ice. The aqueous solution was extracted with CH ₂ CI ₂ . The organic phase was washed with water, saturated NaHC0 ₃ solution, and again with water, before being dried over Na ₂ SO ₄ and evaporated.

For the N-containing heteroaromatic compounds the following procedure was also carried out during the work-up of the products. Saturated NaHCO ₃ solution was added to the aqueous solution until basic. The basic solution was extracted with CH ₂ CI ₂ and the organic phase was washed with water, dried and evaporated.

When performing the reactions at a constant temperature the reagents were mixed at the chosen temperature. The reaction period depend on the system used.

Table 1. Nitration with N ₂ O ₅ in SO ₂ .

a) 62% 2-methyl-5-nitropyridine and 7% 2-methyl-3-nitropyridine. b) Exothermic reaction. There was neither recovered any substrate nor isolated any nitrated product. c) 32% 2-nitrothiophene and 4% 3-nitrothiophene.

The two first compounds in Table 1 , dimethyl and diethyl isophtalate, represents a deactivated aromatic system which can be nitrated by the "mixed acid" (HNO^H _g SO method although hydrolysis of the esters during work-up of the strongly acidic reaction mixture must be anticipated. As mentioned before, pyridine and 2- and 4-methyipyridine are compounds that hardly can be nitrated at all under standard conditions.

Example 2

Experiments when using the nitration system together with another aprotic, organic solvent like chloroform, were performed. The substrates chosen, the temperature, the reaction time,

the products obtained and the yields thereof are shown in Table 2.

General procedure for nitration with N ₂ O ₅ in liquid SO ₂ and CHCI ₃ .

The experiments were performed according to the general procedure described in example 1 , except for the amount of SO ₂ (20 ml) and the addition of the substrate. The substrate (12.5 mmol) was dissolved in chloroform (5 ml) and then slowly added to the nitration mixture.

Table 2. Nitration with N ₂ O ₅ in SO ₂ /CHCI ₃ .

(The yields are given as isolated product.)

The melting point for the products was measured to be 39.5-40.5°C.

Example 3 Reference example.

To illustrate the exceptional results obtained by using the nitration system according to this invention (N ₂ O ₅ in SO ₂ ), comparing experiments were performed. The nitration systems used as references were N ₂ O ₅ in HNO ₃ , N ₂ O ₅ in CCI ₄ , NO ₂ ⁺ BF ₄ ^' in SO ₂ , HNO ₃ in SO ₂ and HNO ₃ /H ₂ SO ₄ , and the substrates examined were dimethyl and diethyl isophtalate, pyridine and 2-methylpyridine. The results are shown in Table 3.

General procedure for nitration with HNO ₃ and D

The nitration mixture was prepared by addition. of fuming nitric acid (1.52 g/cm ³ , 0.7 ml, 24 mmol) or dinitrogen pentoxide (2.7 g, 25 mmol) to sulphur dioxide (25 ml) at -78°C. The substrate (12.5 mmol) was then added slowly. The mixture was heated to -11°C for a period

of two hours and stirred for another two hours and then poured over ice. Neutralisation (NaHCO ₃ ), extraction (CH ₂ Cl ₂ ), drying (Na _g SO^ followed by evaporation gave the products. If necessary, the product was recrystallised.

The nitrations in other solvents followed this general procedure except for the reaction temperature which was about 20°C.

General procedure for nitration with NO^BF,, ^' .

NO ₂ ⁺ BF ₄ ^" (3,32 g, 25 mmol) was transferred to the reaction flask in a glove-box. SO ₂ (25 ml) was then added to the nitration agent under an atmosphere of nitrogen. Finally the substrate (12,5 mmol) was added slowly at -78°C. The rest of the procedure was as described above for the nitration with N ₂ O ₅ .

Table 3. Comparison of different nitration methods. (The yields are given as isolated product.) (Where nothing else is given, the reactions were performed at -78 ^* C to -1 1 °C.)

a) The reaction was performed at -30°C. b) This result is in accordance with Ege, S., Organic Chemistry, D.C. Heath: Lexington, MA, (1984) 1827. c) KNO ₃ /H ₂ SO ₄ /160°C, Plazek, Ber. 72 (1939) 577.

The nitrated products obtained were:

- dimethyl 5-nitroisophtalate from dimethyl isophtalate,

- diethyl 5-nitroϊsophtalate from diethyl isophtalate,

- 3-nitropyridine from pyridine, and

- a mixture of 91 % 2-methyl-5-nitropyridine and 9% 2-methyl-3-nitropyridine from 2-methylpyridine.

Only one of the six nitration systems in Table 3 gave results which were very different from those already reported and that was the combination of dinitrogen pentoxide and sulphur dioxide. It is evident from Table 3 that we have a new nitration system which gives far better results than the conventional ones. This is especially evident from the results for the pyridines, where direct nitration hardly has been possible at all by the nitration methods previously reported. The results from the nitration of the isophtalate esters show that the N- _j O^SO., system also is applicable for the nitration of other aromatic systems. The method gave excellent yields of the 5-nitroisophtalate esters, and the problems related to hydrolysis of the esters during work-up are solved.