(12) Patent Application Publication (10) Pub. No.: US 2004/0242932 A1 Earle Et Al

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US 2004O242932A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0242932 A1 Earle et al. (43) Pub. Date: Dec. 2, 2004

(54) AROMATIC SULFONATION REACTIONS (30) Foreign Application Priority Data Oct. 10, 2000 (GB)...... OO24747.8 (76) Inventors: Martyn John Earle, Finaghy Belfast (GB); Suhas Prabhakar Katdare, Publication Classification Belfast (GB) (51) Int. Cl." ...... C07C 39/02 (52) U.S. Cl...... 564/86 Correspondence Address: DRINKER BIDDLE & REATH (57) ABSTRACT ONE LOGAN SQUARE 18TH AND CHERRY STREETS A proceSS for the Sulfonation of an aromatic compound PHILADELPHIA, PA 19103-6996 (US) wherein the aromatic compound and Sulfonating agent are admixed in the presence of an ionic liquid is described. The (21) Appl. No.: 10/398,531 method for the Sulfonation of aromatic compounds in (e.g. water stable) ionic liquids offers advantages over conven (22) PCT Filed: Oct. 5, 2001 tional Sulfonation reactions. These are that no by-products form, the ionic liquid is not consumed, and the Sulfonating (86) PCT No.: PCT/GB01/04427 agent (e.g. SO) is relatively inexpensive. US 2004/0242932 A1 Dec. 2, 2004

AROMATIC SULFONATION REACTIONS fate, or a chloride, bromide or other halide. Other anions include Sulfur containing anions including Sulfate or Sul 0001. The present invention relates to a process for the phite, hydrogenSulfate, oxoanions of metals, Selenium, tel Sulfonation of aromatic compounds. lurium, phosphorus, arsenic, antimony, and bismuth based 0002 The sulfonation of aromatic compounds can be anions. achieved by a number of methods. Classically this involves the reaction of an aromatic compound with oleum, the 0009 More than one ionic liquid or any combination of reaction with sulfur trioxide in various organic solvents. ionic liquids may be used in the present invention. and reaction with sulfuric acid. Fuming sulfuric acid, chlorosulfonic acid, the dioxane adduct of SO, amine 0010) Suitable Process Conditions adducts of SO" are chiefly used as agents for sulfonating 0011 Temperature: ideally 20-100° C. but to include aromatic compounds by introducing a Sulfonic acid group O° C. to 250° C. into the aromatic ring of the compound. However, the use of Such agents for Sulfonation involves various problems. For 0012 Pressure: ideally, atmospheric, but include 1 example, Sulfuric acid or fuming Sulfuric acid, when used, mbar to 100 Bar produce water as a by-product to result in a reduced con version. To obtain high conversions, an excess of the Sul 0013 Time: ideally 24–48 hours, can be 1 minute to 1 fonating agent needs to be used, consequently producing a month. large amount of waste acid. On the other hand, use of chlorosulfonic acid SUBSTITUTE SHEET (RULE 26) pro 0014. In one embodiment the process uses neutral ionic duces waste hydrochloric acid. The adducts of SO with liquids such as emimHSO and emimEtOSO as now dioxane or an amine with SO are less reactive Sulfonating shown agents, and although the adduct produces little waste acid, they cause problems with amine Salt/dioxane disposal. HSO 0003. According to one aspect of present invention, there is provided a process for the Sulfonation of an aromatic |-- NS compound wherein the aromatic compound and Sulfonating f HsCOSOs) agent are admixed in the presence of an ionic liquid. Nu-N2N4. -- M 0004. The method for the Sulfonation of aromatic com pounds in (e.g. water stable) ionic liquids offers advantages over conventional Sulfonation reactions. These are that no 0.015 as media for the sulfonation reaction, and the use of by-products formed, the ionic liquid is not consumed and the Sulfur trioxide alone as the Sulfonating agent, as there would Sulfonating agent (e.g. SO or CISOH) is relatively inex be no by-products from the reaction (as shown in the pensive. following reaction: 0005 Room temperature ionic liquids have been used to great effect as solvents for a number of reactions, for example Friedel-Crafts reactions, isomerisations of fatt acid derivatives, 7 dimerisation reactions of alkenes. Diels-Alder reactions and hydrogenation reactions." 0006 Ionic liquids consist of two components, which are a positively charged cation and a negatively charged anion. Generally, any compound that meets the criterion of being a R = H, CH, Cl, Ph, OCH Salt (consisting of an anion and cation) and is fluid at or near 21 R’= CHs the reaction temperature or exists in a fluid State during any X = HSO4, HCOSO Stage of the reaction may be defined as an ionic liquid. N X 0007. The cation for the present process is preferably a SOH 1,3-dialkylimidazolium cations. Other cations for this pro ceSS are other Substituted pyridinium or alkyl- or poly 0016. The sulfonation reactions of aromatic compounds alkylpyridinium, alkyl imidazolium, imidazole, alkyl or using Sulfur trioxide were found to be Successful in two poly-alkylimidazolium, alkyl or polyalkylpyrazolium, types of Sulfate based ionic liquids. These were with ionic ammonium, alkyl or polyalkyl ammonium, alkyl or poly liquids containing the hydrogensulfate or ethylsulfate anion, alkyl phosphonium cations. and with a 1-ethyl-3-methylimidazolium cation. The results 0008. The anion for the present process is preferably a of the Sulfonation of benzene and toluene are shown in Table nitrogen containing anion, Such as nitrate, nitrite, alkylsul 1.

TABLE 1. The sulfonation of aromatic compounds with SOs, in ionic liquids. Aromatic Ionic Temp. / Time/ Compound Liquid Eq-SO C. h. Product(s) % Yield Benzene emim HSO O42 8O 18 CH-SOH 99 0.5 eq Benzene ComimOTf 1.1 25 1 CH-SOH 99 US 2004/0242932 A1 Dec. 2, 2004

TABLE 1-continued The sulfonation of aromatic compounds with SOs, in ionic liquids. Aromatic Ionic Temp. / Time/ Compound Liquid Eq-SO C. h. Product(s) % Yield Toluene mim HSO O.25 25 8 2-HC-CH-SOH 25 3 eq 4-HC-CH-SOH 74 Toluene emim HSO O.25 8O 30 2-HC-CH-SOH 29 3 eq 4-HC-CH-SOH 71 Toluene emim HSO O.25 8O 5 2-HC-CH-SOH 32 0.8 eq 4-HC-CH-SOH 67 Toluene emim HSO O.25 8O 30 2-HC-CH-SOH 32 0.8 eq 4-HC-CH-SOH 67 Toluene emim EtOSO O.25 8O 5 2-HC-CH-SOH 44 0.75 eq 4-HC-CH-SOH 55 Toluene emim EtOSO, 0.25 8O 18 2-HC-CH-SOH 43 0.75 eq 4-HC-CH-SOH 56 Toluene Comim IOTf 1.1 25 1 2-HC-CH-SOH 22 0.50 eq 2-HC-CH-SOH 77

0.017. The Sulfonation of benzene proceeds smoothly to a catalyst for the reaction, as the Sulfur trioxide and arene give benzeneSulfonic acid in almost quantitative yield, in the were in excess over the ionic liquids used, and gave 98-99% ionic liquid emim HSO' as shown in scheme 2. yields. 0018 Scheme 2: Proposed Mechanism for the Sulfona 0020. The Sulfonylation of toluene with chlorosulfuric tion of Aromatic in Ionic Liquids acid in the ionic liquid bmimNTf) was investigated and compared with a similar reaction in dichloromethane. See NSN HSO4. SO Her FIG. 1 and Table 2 The reaction in dichloromethane gave Hsc:1 N21 YCH, predominantly the Sulfonyl chloride product, whereas in the ionic liquid, the Sulfonic acid was the major product. In O O general, the o-, p-Selectivities were higher in the ionic liquid, f=\ and for the formation of the sulfonyl chloride product. Nsa NS Ho1ino1 ino HsC1 NY Not, O CH2 DCM O -- OFSFO (bmim) NTf R Her 20° C. OH SOOH SOOH --

o O O HC CH y \ | (A) (B) HsC1 NstNe1 N YCH, HO11n || YO1 11a. || YO

R SOCI SOCI

21 HC CH Sy (C) (D) SOH 0021 FIG. 1: The reaction of toluene with chlorosulfuric -- acid. f V HSO) HC1 NstS-YoH, 2N TABLE 2 The products and isomer ratios in the reaction of chlorosulfuric acid with toluene, in DCM 0.019 AS can be seen, the sulfonation reaction proceeds and bmim INTFlat 20 C. to give the expected products with benzene and toluene (Table 1). Benzene is sulfonated to benzene sulfonic acid in % Yield % Yield 99% yield in emimHSO and ComimOTf). The sul Solvent (A) + (B) (A/(B) (C) + (D) (C)/(D) fonation of toluene proceeded to give isomeric mixtures of DCM 15 1.4 85 18 toluenesulfonic acids, as shown in Table 1. The best para to (bmim NTf, 8O 2.1 2O 3.0 ortho isomer ratio was obtained in ComimOTf) at 25 C. In Several cases, the ionic liquids were found to function as US 2004/0242932 A1 Dec. 2, 2004

0022. The reaction of 1,2,4-trichlorobenzene with chlo from the flask and analysed by NMR (CDC1, 300 MHz). rosulfuric acid gave rise to a 40 to 60 mixture of the This showed that the reaction was complete and gave 77% corresponding chlorosulfonate and sulfonic acid at 150 C. of p-toluenesulfonic acid and 22% o-toluenesulfonic acid. in the ionic liquid (bmimNTf). The chlorosulfonate inter The products were isolated from the ionic liquid by Kugel mediate Sublimes out of the reaction vessel during the rohr distillation at 1 mmHg. This gave colourless solid reaction. Addition of SOCl, followed by heating at 150° C. (bp=200° C. at 1 mmHg). The structures were confirmed by for 24 hours resulted in the conversion of the Sulfonic acid NMR analysis and were in accordance with authentic mate to the chlorosulfonate (FIG. 2). This reaction is the first step rial. in the synthesis of the insecticide Tetradafion(R) (2,4,4,5- tetrachlorodiphenylsulfone). The yield in synthesis of the EXAMPLE 2 2,4,5-trichlorochlorobenzenesulfonyl chloride WS improves by using a 1:1 mixture of Sulfuryl chloride and 0027 (Chloro)sulfonation of Toluene chlorosulfuric acid. This gave a 55% yield of the 2,4,5- 0028. In a 50 cm round bottomed flask, equipped with a trichlorochlorobenzenesulfonyl chloride. magnetic Stirrer and reflux condenser and ice bath, was

C C Cl C Cl C f min NTf SOCl. 150° C. ---bnin INTE, CISO; OH X-SO C C Cl

Cl O.\/ O

C C

C X = OH, Cl

0023 FIG. 2: The sulfonation of trichlorobenzene. added toluene (0.91 g, 10 mmol) and bmimNTf) (1.0 g). Chlorosulfuric acid (2.33 g, 20 mmol) was cautiously added 0024. The products of these reactions can be isolated in and the mixture stirred at 0° C. for 2 hours. The mixture was three Separate ways. Vacuum distillation allows the products analysed by NMR and found to give >95% conversion to to be separated from this ionic liquid, which leaves the ionic products. A similar reaction was performed using 1.0 g of liquid ready for reuse. However, this cannot be used for high molecular weight products because the high temperatures dichloromethane in place of the bmimNTf). The product involved may decompose the product. Solvent extraction and isomer distributions for both reactions are given in Table with ethyl acetate can be used to isolate the organic products 2. from the reaction. The third and most Successful approach is EXAMPLE 3 the use of Steam distillation. Complete Separation of the 0029 (Chloro)sulfonation of 1,2,4-trichlorobenzene organic products from the ionic liquid can be achieved by 0030) In a 50 cm round bottomed flask, equipped with a the addition of water, followed by distillation at 140-160 C. magnetic Stirrer and reflux condenser, was added 1,2,4- at atmospheric pressure. The product can then be separated trichlorobenzene (1.81 g, 10 mmol) and bmimNT? (1.0 from the residual water usually by distillation and drying. g). Chlorosulfuric acid (2.33 g, 20 mmol) was cautiously added and the mixture heated at 150° C. After 24 hours the EXAMPLE 1. mixture was analysed by NMR and found to have given >99% conversion to products. The major products were 0025 Sulfonation of Toluene in ComimOTf identified as 2,4,5-trichlorochlorobenzenesulfonyl chloride 0026. In a round-bottomed flask (25 cm) equipped with (40%) and 2,4,5-trichlorochlorobenzenesulfonic acid (60%) a magnetic Stirrer flea and Stopper, 1-decyl-3-methylimida zolium trifluoromethanesulfonate (0.97g, 2.5 mmol) and EXAMPLE 4 toluene (0.46g, 5.0 mmol) were added. Sulfur trioxide (0.44 0031 (Chloro)sulfonation of 1,2,4-trichlorobenzene g, 5.5 mmol) was cautiously added (carried out in a dry box) 0032). In a 50 cm round bottomed flask, equipped with a and the mixture Stirred for 1 hour. A crude Sample was taken magnetic Stirrer and reflux condenser, was added 1,2,4- US 2004/0242932 A1 Dec. 2, 2004 trichlorobenzene (4.21 g, 25 mmol) and bmimNT? (1.0 1. A proceSS for the Sulfonation of an aromatic compound g). A mixture of chlorosulfuric acid (2.33 g, 20 mmol) and comprising admixing the aromatic compound and a Sul sulfuryl chloride (2.70 g, 20 mmol) was cautiously added fonating agent in the presence of an ionic liquid. and the mixture heated at 150° C. After 48 hours the mixture was analysed by NMR and found to give >95% conversion 2. The process as claimed in claim 1 wherein the cation of to products. The major products were identified as 2,4,5- the ionic liquid is Selected from the group consisting of trichlorochlorobenzenesulfonyl chloride (55%) and 2,4,5- 1,3-dialkylimidazolium, Substituted pyridinium alkyl pyri trichlorochlorobenzenesulfonic acid (40%). The 2,4,5- dinium, poly-alkylpyridinium, alkyl imidazolium, imida trichlorochlorobenzenesulfonyl chloride was isolated by Zole, alkyl imidazolium, poly-alkylimidazolium, alkylpyra Vacuum Sublimation directly from the reaction vessel on a Zolium, polyalkylpyrazolium, ammonium, alkyl Kugelrohr apparatus and the 2,4,5-trichlorochlorobenzene ammonium, polyalkyl ammonium, alkyl phosphonium, Sulfonic acid was isolate as its Sodium Salt, by reaction of the poly-alkyl phosphonium, and combinations thereof. Sublimation residue with an aqueous Solution of Sodium hydrogen carbonate. The ionic liquid (insoluble in this 3. The proceSS as claimed in claim 2 wherein the cation is aqueous Solution) was recovered. 1,3-dialkylimidazolium. 0033. In conclusion, sulfonation of aromatic compounds 4. The process as claimed in claim 1 wherein the anion of using Sulfur trioxide or chloroSulfuric acid in ionic liquids the ionic liquid is Selected from the group consisting of a proceeds efficiently to give the mono-Sulfonated product. nitrogen-containing anions, alkylsulfate; halide, Sulfur-con The ionic liquids could all be reused in further sulfonation taining anions, hydrogensulfate, oxoanions of metals, ions reactions and were not destroyed in the reaction. Separation based on Selenium, tellurium, phosphorus, arsenic, anti of the products was achieved by vacuum distillation, Solvent mony, or bismuth; and combinations thereof. extraction, or most notably, Steam distillation. The reaction 5. The process as claimed in claim 4 wherein the anion is is clean, gives no by-products and is easy to perform. a nitrate, nitrite, alkylsulphate, chloride or bromide. 0034. The present invention also extends to the use of an 6. The proceSS as claimed in claim 1 wherein more than ionic liquid in the Sulfonation of aromatic compounds, as one ionic liquid is present. well as a Sulfonated aromatic compound whenever prepared from a process of the present invention. 7. The process as claimed in claim 1 wherein the Sul fonating agent is Sulfur trioxide or chloroSulfuric acid. REFERENCES 8. The proceSS as claimed in claim 1 wherein the ionic 0035) R. T. Morrison and R. N. Boyd “Organic liquid is selected from the group consisting of emim Chemistry Second Edition”, Allyn and Bacon Inc., HSO), emimEtOSO), bmimNTf), ComimOTf), Boston, 1969. and combinations thereof. 0036) H. R. W. Ansink, H. Cerfontain, H. Journal of 9. The process as claimed in claim 1 wherein the aromatic the Royal Netherlands Chemical Society, 1992, 111, compound is benzene, trichlorobenzene or toluene. 183-187. 10. The process as claimed in claim 1 wherein the reaction products are isolated by Vacuum distillation, Solvent extrac 0037) T. M. Fatum, U. Anthoni, C. Christophersen, tion, or Steam distillation, or a combination of two or more P. H. Nielsen, Hetercycles, 1994, 38, 1619-1625. thereof. 0038 4 O. Eiji, Y. Norio, K. Takayuki, U.S. Pat. No. 5,596,128, 11. The proceSS as claimed in claim 1 for Selective 1997. isomeric Sulfonation of an aromatic compound. 0039) M. J. Earle and K. R. Seddon, Pure and App. 12. The process as claimed in claim 1 providing mono Chem. 2000, in press. Sulfonated product. 0040 °C. J. Adams, M. J. Earle, G. Roberts and K. 13. A Sulfonated aromatic compound obtained by a pro R. Seddon. Chem. Commun. 1998, 2097-2098. ceSS as defined in claim 1. 0041 7 C. J. Adams, M. J. Earle, J. Hamill, C. Lok, 14. The compound as claimed in claim 13 being an G. Roberts and K. R. Seddon, World Patent WO 98 arylsulfonic acid. 07679, 1998. 15. The compound as claimed in claim 14 being benzene Sulfonic acid or toluenesulfonic acid. 0042) (a) B. Ellis, W. Keim and P. Wasserscheid, Chem. Commun. 1999, 337. (b) S. Einloft, H. Olivier 16. The compound as claimed in claim 14 being mono and Y. Chauvin, U.S. Pat. No. 5,550,306, 1996. Substituted. 17-20. (cancelled) 0043 M. J. Earle, P. B. McCormac and K. R. 21. The process as claimed in claim 4 wherein the anion Seddon, Green Chem. 1999, 123-25. of the ionic liquid is a Sulfate or Sulphite. 0044) '(a) T. Fisher, A. Sethi, T. Welton, J. Woolf, 22. The process as claimed in claim 10 wherein the Tetrahedron Lett. 1999, 40, 793-194. (b) C. J. Adams, Solvent extraction is Solvent extraction with a base. M. J. Earle, K. R. Seddon, Chem. Commun. 1999, 23. The compound as claimed in claim 15 being mono 1043-1044. Substituted. 0045 ' Synthesised by heating emim)HSO) in water for 5 days, followed by drying under Vacuum.