The present invention relates to a process for the nitration of aromatic compounds.

Traditional processes for nitrating aromatic compounds employ nitric acid and use sulphuric acid as catalyst [Nitration methods and mechanism, Olah et al VCH, New York, 1989]. Such processes have the advantage of using cheap and readily available reactants. However, these processes suffer from many disadvantages because nitration occurs non-selectively, yields of required products are often low, oxidation by-products may be formed because of the presence of excess nitric acid, the acid mixture is corrosive and hazardous and the large quantities of waste acid are expensive to dispose of or to recycle.

Processes which avoid the use of acids have been developed such as a process which uses nitrogen dioxide in the presence of ozone [J. Chem. Soc. Chem. Commun. 1049-1050, 1991 Suzuki et al] but the nitrogen dioxide/ozone mixture is such a powerful nitrating agent that selective production of mononitrated products is difficult to achieve. Other methods such as nitration using inorganic nitrate/trifluoroacetic anhydride mixtures [J. Org. Chem., 46, 3056, 1981 , Crivello] or molten nitrates [J. Chem. Commun. 966, 1967, Temple] or using alkyl nitrate/polyphosphoric acid [J. Am. Chem. Soc. 1964, Tsang] have been disclosed but generally give non-selective nitration or poor yield of required products. European patent application No. EP-A-0 356 091 discloses a nitration process using an aluminosilicate such as a zeolite or a clay in combination with an acyl nitrate as a nitrating agent in a liquid organic solvent. This process provides higher yields of mononitro products with better para-selectivity than the prior art. For example, toluene was nitrated using benzoyl nitrate in tetrachloromethane in the presence of a mordenite catalyst to give a 99% yield of mononitrotoluene with proportions o:m:p of 32:1 :67. A more specific example of this process in which an activated silicate is reacted with an acyl nitrate generated in situ has also been reported (PCT/PT94/00001 ). In particular, the first step is the formation of an activated mixture of a silicate (montmorilionite aluminosilicate clay modified with a metal nitrate), an acid anhydride and an organic solvent, to which the substrate and then nitric acid are added. The method is more useful for polynitration although it is exemplified by the mononitration of chlorobenzene to give a quantitative yield of chloronitrobenzene with proportions o:m:p of 13:2:85.

Successful use of this process to mononitrate alkylaromatic compounds such as toluene requires high dilution and high temperature and/or long reaction times to obtain quantitative yields with good selectivity [Ace. Chem. Res.19, 121 , 1986, Lazlo; J. Chem. Lett. 1843, 1988, Lazlo; and Tet. Lett. 29, 5657, 1988 Cornelis et al].

Such processes are commercially unattractive because output of the required products would be low and recovery of the products from large volumes of solvents particularly environmentally undesirable halogenated hydrocarbons such as carbon tetrachloride would be expensive. An object of the present invention is to provide a process in which nitrated aromatic compounds, particularly mononitro compounds, may be produced economically in high yields and with good regioselectivity, minimising the amount of oxidised by¬ products and acid waste and avoiding the use of environmentally undesirable solvents.

According to the present invention there is provided a solvent free process for the nitration of an aromatic compound in which the aromatic compound is reacted with nitric acid in the presence of an acid anhydride wherein the process is catalysed by an aluminosilicate catalyst.

The present process has advantages over previously disclosed processes because nitration occurs quickly and regioselectively in high yield. The process also avoids the need to recover product from large volumes of solvent which may be environmentally unacceptable. Additionally, there is no need for an aqueous work up stage to recover the nitrated product. It preferably utilises only a stoichiometric amount of nitric acid and therefore avoids the need for the treatment of a waste inorganic acid stream. The process can also be stoichiometric in acid anhydride thereby minimising the amount of organic acid by-product. This by-product may be recovered, recycled or disposed of.

In a preferred embodiment of the present invention the process comprises solvent free nitration of an aromatic compound in which the aromatic compound is nitrated using an aluminosilicate catalyst which has been treated with nitric acid and an acid anhydride.

By solvent free it is meant that no additional organic solvent is added to the reaction mixture.

It is believed that the nitric acid and acid anhydride react with each other in situ to form an acyl nitrate and this acts as a nitrating agent for the aromatic compound. The aromatic compound may be a monocyclic or polycyclic aromatic hydrocarbon, for example benzene, naphthalene, anthracene and biphenyl, and may contain one or more heteroatoms. Examples of suitable aromatic compounds containing one or more heteroatoms include pyridine, quinoline, furan, benzofuran, thiophene, benzthiophene, indole, carbazole, imidazole, benzimidazole and thiazole. The aromatic compound may optionally be substituted by one or more substituents, preferably substituents selected from alkyl, especially C^e-aikyl and more preferably methyl, ethyl and propyl; alkoxy, especially C _1-6 -alkoxy and more preferably methoxy and ethoxy; halogen; cyano; nitro; phenyl; hydroxy; amino; formyl; and acyl. Especially preferred substituents are selected from -F, -Cl, -Br, d. ₆ -alkyl, Cι.6-alkoxy and phenyl. The process is particularly suitable for the nitration of a benzene which carries one or two substituents,

for example fluorobenzene, chlorobenzene, bromobenzene, toluene, ethylbenzene, iso- propylbenzene, tert-butylbenzene, 2-chlorofluorobenzene, 2-fluoroanisole, 2-fluorotoluene, 2-bromotoluene, 3-fluorotoluene, 1 ,2-difluorobenzene and 2-bromofluorobenzene. The concentration of the nitric acid is preferably from 10% to 100%, more preferably 70% or more because the water present in the nitric acid undesirably hydrolyses the acid anhydride. Dilute nitric acid requires more acid anhydride in the reaction mixture and increases the amount organic acid by-product compared with a more concentrated nitric acid. Especially preferred nitric acid concentrations are from 70% to 98%. The acid anhydride may be symmetrical or unsymmetrical and may be an anhydride of an alkyl or aryl carboxylic or sulphonic acid. Suitable acid anhydrides include anhydrides of alkanoic acids, for example C ₂ . ₈ -alkanoic acids, especially acetic, propionic, butanoic and trifluoroacetic acids; anhydrides of C ₆ . ₉ -cycloalkanoic acids, for example cyclohexanecarboxylic acid; anhydrides of arylenecarboxylic acids, for example C ₆ . ₁₂ - arylenecarboxylic acids, especially benzoic acids; and anhydrides of thio acids, for example acetic thioanhydride, propionic thioanhydride and acetic benzoic thioanhydride. The acid anhydride is preferably an anhydride of an alkanoic acid, especially acetic anhydride because it is cheap and readily available.

The ratio of aromatic compound/nitric acid/acid anhydride is preferably from 1 :1 :1 to 1 :1 :500, especially 1 :1 :1 but with enough additional acid anhydride for mononitration of the aromatic compound and to destroy any additional water present. Use of stoichiometric amounts of nitric acid has the advantage of minimising the amount of waste nitric acid requiring treatment and/or disposal and lowers the amount of oxidation by-products. Accordingly, it is preferred that the molar ratio of nitric acid : aromatic compound is 1 :1. The aluminosilicate catalyst is preferably a zeolite or a clay, more preferably a zeolite, especially a zeolite which has a rigid three-dimensional pore structure. The pores are of molecular dimensions and it is believed that the nitration reaction occurs in the confined space of the pores which induces shape selectivity and affects the regioselectivity, particularly the para-selectivity, of the reaction. Generally the bigger the pore dimension the greater the tendency to form ortho and/or meta isomers it is thus preferred that the pore dimension is 0.7 μm or less, more preferably 0.7nm or less. Within the pores are acid sites which catalyse the reaction and the number of acid sites is determined by the Si/AI ratio and the nature of the counterbalancing cations. A Si/AI ratio of from 2 to 1000 is preferred. Preferred zeolites are zeolites with medium to large pore sizes, such as X, Y, ZSM-5, ZSM-11 , ZSM-12, Mordenite and β types (available from PQ Zeolites, Holland). Typical Si/AI ratios are from 2:1 to 80:1. The cation-forms which are most preferred are H ⁺ , Fe ³⁺ , Al ³⁺ , ammonium, substituted ammonium, rare earth cations and other cations capable of generating acidity. In one particular embodiment the zeolite is H ⁺ β zeolite or another cation exchanged β zeolite for example, Fe ³⁺ β and Al ³⁺ β.

Zeolite structures are negatively charged and contain cations to counter balance the negative charge. These counterbalancing cations may be exchanged for other cations using methods which are known in the art. For example, Na ⁺ β zeolite may be cation exchanged to H ⁺ β zeolite by refluxing the Na ⁺ form in ammonium acetate followed by 5 calcination. Other cation exchange methods are described in EP 0 629 599.

The process is preferably performed at a temperature of from -80°C to 120°C, more preferably at from -30°C to 50°C and especially at from 0°C to 30°C.

We have surprisingly found that the order of the mixing of the components can have a marked effect upon the regioselectivity of the nitration. For good para-selectivity it 0 is preferred that the aluminosilicate catalyst (for example a zeolite) is mixed with the nitric acid, followed by the acid anhydride, followed by the aromatic compound. We have found that this order of addition of reagents also gives good regioselectivity when the process is used for the nitration of an aromatic compound with more than one substituent. For example, when a 1 ,2-disubstituted benzene is nitrated using the preferred order of s addition of reagents it is found that good yields of either the 4- or 5- nitro compound are formed (i.e. para to one of the substituents on the benzene) with only minor quantities of the 6- and 3- nitro compounds (i.e. ortho to the substituents on the benzene).

The reaction is continued until complete as judged by an appropriate analytical technique such as gas chromatography and the reaction products are isolated by any o convenient means such as filtration followed by distillation or direct distillation of the reaction mixture.

We have also found that the aluminosilicate catalyst may be recycled. Accordingly, a further feature of the present invention provides a process for regeneration of an aluminosilicate catalyst which has been used in the nitration process of the present 5 invention, in which the catalyst used in the nitration process is heated to leave an essentially dry catalyst. This catalyst is suitable for re-use in the nitration process of the present invention.

Any convenient method can be used to heat the catalyst to leave an essentially dry catalyst, for example evaporation or heating in a distillation apparatus. o The catalyst regeneration process is preferably performed by heating the catalyst at a temperature of from 20°C to 600°C, more preferably at from 25°C to 400 °C.

It is preferred that the aluminosilicate catalyst is regenerated from a reactant mixture formed by the nitration process of the present invention by distilling the reactant mixture to leave an essentially dry catalyst. It is especially preferred that the distillation is 5 carried out below atmospheric pressure (i.e under vacuum) because this lowers the temperature required for catalyst regeneration.

In a preferred embodiment of the catalyst regeneration process, the aluminosilicate catalyst is regenerated from the reactant mixture formed by the nitration process by vacuum distillation which is performed in two stages. The first stage distillation 0 is carried out at a pressure of from 10 to 50 mmHg (this removes by-product organic acid,

for example acetic acid, and unreacted aromatic compound) and the second stage distillation is carried out at a lower pressure, preferably of from 0.1 to 5 mmHg (this removes the nitroaromatic compounds). An especially preferred pressure for the first stage distillation is 20 to 30 mmHg and for the second stage distillation is 0.2 to 2 mmHg. It is preferred that each distillation independently is carried out at a temperature of from 20°C to 150°C, more preferably at from 25°C to 100°C.

In this specification term "pressure" has an identical meaning to "vacuum". For example, the term "a pressure of 0.2 mm Hg" has the same meaning as "a vacuum of 0.2 mmHg". The aluminosilicate catalyst used in the nitration process may be removed from the reactant mixture formed by the nitration process prior to regeneration of the catalyst. Removal of the catalyst used in the nitration process may be effected by any convenient method, for example by filtration of the reactant mixture. Following removal of the catalyst used in the nitration process, the catalyst may be regenerated using any of the methods hereinbefore described.

When the aluminosilicate catalyst used in the nitration process is removed from the reactant mixture formed by the nitration process, for example by filtration, the nitrated aromatic compound may be purified by distilling off the relatively volatile organic acid by product and any unreacted aromatic compound. It is preferred that the distillation of the reactant mixture is performed under a vacuum of 10 to 50mm Hg, preferably at a temperature of from 20 to 150°C, more preferably at from 25 to 100°C.

The regenerated aluminosilicate catalyst is suitable for re-use in the nitration process without the addition of fresh aluminosilicate catalyst. The term "fresh catalyst' meaning aluminosilicate catalyst which has not been used in the nitration process of the present invention. However, we have found that the yield and regioselectivity of the nitration process of the present invention, when performed using regenerated aluminosilicate catalyst, are improved if a proportion of the regenerated aluminosilicate catalyst is removed and replaced by fresh aluminosilicate catalyst prior to performing the nitration process. It is preferred that a proportion of from 5 to 30% and more preferably from 10 to 20% of the regenerated aluminosilicate catalyst is removed and replaced by fresh aluminosilicate catalyst prior to performing the nitration process.

The invention is illustrated by the following Examples:

Example 1

Nitration of toluene

At 0°C, nitric acid (2.45g at 90%, 35 mmol) was added to zeolite H ⁺ β (1.241 g) (CP806β25 obtainable from PQ Zeolites, Holland) followed by acetic anhydride (5cm ³ ,53 mmol) and toluene (3.1 Og, 34 mmol) in that order. The mixture was stirred for 30 minutes at 0°C and then allowed to warm to room temperature. Analysis indicated that

mononitrotoluenes were obtained in quantitative yield with ortho:meta:para product distribution of 18:3:79. The reactant mixture was then distilled at a pressure of 30mm Hg and a temperature of 30°C to remove acetic acid. The reactant mixture was then further distilled at a pressure of 0.2 mmHg and a temperature of 60°C to give the mononitrotoluene mixture (4.600g) in 100% yield.

Examples 2 to 17

The following general procedure was used for Examples 2 to 13.

Nitric acid (2.45g at 90%, 35mmoi) and dry zeolite H ⁺ β (1.00g) were stirred together at 0°C for 5 minutes. Addition of acetic anhydride (5cm ³ , 53mmol) resulted in an exothermic reaction causing a temporary rise in temperature to ca. 10-15°C. After the reactant mixture had cooled to a temperature below 5°C (approximately 5 minutes), the aromatic compound (35mmol) was added dropwise and the mixture was then allowed to warm to room temperature and stirred for a further 30 minutes. The products of the reaction were obtained by direct vacuum distillation of the mixture, first at 30°C, at a pressure of 30 mmHg, to give the acetic acid by-product and then at 60 to 80°C, at a pressure of 0.2 mmHg, to give the nitrated aromatic compound. The results are tabulated in Tables 1 and 2 below.

Table 1 : The Effect of X on the Nitration of C ₆ H ₅ -X

Table 2 : Nitration of

Example X ¹ X ² Reaction Time Yield Product Pro portions ( %)

(min) (%) 3-nitro 4-nitro 5-nitro 6-nitro

11 OCH ₃ F 30 98 trace 92 trace 8

12 CH ₃ F 30 96 trace 10 90 trace

13 Cl F 30 86 trace 33 66 trace

14 Cl F 180 95 trace 33 66 trace

15 CH3 Cl 30 >99 trace 25 75 trace

16 CH3 Br 30 >99 trace 23 77 trace

17 Br F 30 >99 trace 31 63 6

Comparative Example A

To a mixture of nitric acid (0.242g, 2.68 mmol) and acetic anhydride (20 cm ³ ) was added toluene (0.248g, 2.67mmol) and a 5A molecular sieve (0.338g) (available from Aldrich Chemical Company, UK). The reactant mixture was stirred for 3 hours at ambient temperature and then analysed by gas chromatography. The analysis showed a 20% yield of mononitrotoluenes with an ortho:meta:para distribution of 66:0:34.

Example 18 : Nitration of 1 .2-Difluorobenzene

The general procedure used in examples 2 to 17 was followed using 1 ,2- difluorobenzene (3.81 g, 33.4mmol) as the aromatic compound. The reaction gave a 98% yield of 4-nitro-1 ,2-difiuorobenzene, with only minor traces of other nitro isomers.

Comparative Example B

To a mixture of sulphuric acid (98%, 2.51 g) and nitric acid (90%, 2.25g) was added 1 ,2-difluorobenzene (3.78g, 0.33mols). The reaction mixture was then heated to 50°C for 180 minutes. The product of the reaction was isolated by solvent extraction followed by Kugel-Rohr distillation, to give a 72% yield of 4-nitro-1 ,2-difluorobenzene (3.81g).

Examples 19 to 22 : The Nitration of Toluene

Examples 19 to 22 illustrate the effect of the order of addition of reagents of the present invention. In the examples 19 to 22, A is nitric acid (90%, 35 mmol), B is zeolite H ⁺ β (1.00g), C is acetic anhydride (5ml, 53mmol) and D is toluene (35mmol). In each case the reactions were performed at ambient temperature with a reaction time of 30 minutes. The results are shown in Table 3.

Table 3 : The effect of order of addition of reagents

Example Order of Reagent Yield Product Proportions (%) Addition

(%) ortho meta para

19 A-B-C-D >99 18 3 79

20 C-A-B-D >99 24 3 73

21 B-C-A-D >99 25 3 72

22 D-B-C-A >99 35 4 62

Note:

Caution should be exercised in the addition of acetic anhydride to nitric acid to avoid the possibility of forming a detonable reactant mixture. See for example T.A. Brown and J.A.C. Watt, Chemistry in Britain, page 504, 1967 for guidance on safe acetic anhydride / nitric acid mixtures.

Example 23: Recycle of Catalyst

The reactant mixture (zeolite included) from Example 1 was distilled under vacuum, firstly at 30 mmHg, at a temperature of 30°C and then at 0.2 mmHg, at a temperature of 60°C. The first distillation removed the acetic acid and any unreacted toluene and the second distillation removed the nitrotoluenes leaving "dry" catalyst behind in the flask.

The method for Example 1 was repeated except that the "dry" catalyst referred to above was used in place of fresh zeolite H ⁺ β to give >99% conversion of toluene to mono- nitrotoluenes in the ratio of o:m:p of 19:2:79. Further recycling and re-use of the same catalyst gave the results summarised in Table 4.

Table 4: The effect of recycling the catalyst by vacuum distillation.

Cycle Yield 0 m P Time No. (%) (min)

1 >99 18 3 79 30

2 >99 19 2 79 30

3 96 22 3 75 30

4 94 25 3 72 30

5 81 32 3 65 30

6 93 33 3 64 60

7 82 37 3 60 60

8 89 36 3 61 120

9 82 42 3 55 120

Example 24: Nitration of Thiophene

The general procedure of Examples 2 to 17 was followed using thiophene (2.922g, 35 mmol) as the aromatic compound. Following removal of the acetic acid by product by distillation under vacuum, the product of the reaction was removed from the reactant mixture by distillation at a pressure of 0.2 mmHg and a temperature of 63°C to give 3.582g of nitrated thiophene.