The synthesis of 1,3-Bis-[2,6-bis-(1-methylethyl)-phenyl]-1H-imidazolium chloride

Application

1,3-Bis (2,6-Diisopropylphenyl) imidazolium chloride (IPr. HCl) is white to orange to brown powder, crystals, crystalline powder and/or chunks (figure 1) [1]. 1,3-Bis (2,6-diisopropylphenyl) imidazolium chloride is used in organic synthesis, as well as a pharmaceutical intermediate and it is used as a reagent in the synthesis of N-heterocyclic carbene (NHC) Copper (I) complexes bearing dipyridylamine ligands which exhibit interesting luminescent properties and are potential candidates for organic light-emitting diode applications (OLED). 1,3-Bis(2,6-Diisopropylphenyl)imidazolium chloride is also used as a reagent in the synthesis of 5,6-Dimethyl-9-Oxo-9H-xanthene-4-acetic acid methyl ester; the methyl ester derivative of the drug Vadimezan [2]. Moreover, it is an imidazolium salt that is active against all stages of Trypanosoma Cruzi and may represent a promising candidate for treatment of Chagas disease [3].

Figure 1 The appearance of IPr.HCl

Synthesis of 1,3-Bis-[2,6-bis-(1-methylethyl)-phenyl]-1H-imidazolium chloride

The synthesis routes of IPr.HCl were shown as following:

Scheme 1 Synthesis route of IPr.HCl

A 1000 mL round bottom flask was charged with methanol (500 mL), 2,6-diisopropylaniline (63.8 mL, 340 mmol), glyoxal (40 wt% in water, 19 mL, 170 mmol), and formic acid (1 mL). The resulting mixture was allowed to stir for 3 hours at room temperature. The yellow precipitate was filtered, washed with cold methanol and dried in vacuo overnight (70%, 44.2 g, 238 mmol). A 5 L round bottom flask was charged with the yellow precipitate (200 g, 532 mmol) and ethyl acetate (2 L) and the resulting mixture was stirred until the yellow precipitate was dissolved. The solution was cooled to 0° C. A 500 mL Erlenmeyer flask was charged with paraformaldehyde (20.7 g, 690 mmol), HCl (4N in dioxane, 212 mL, 851 mmol). This solution was stirred for 10 minutes, then added. The resulting mixture was then stirred for 2 hours at room temperature. The precipitate was filtered, dissolved in methanol (200 mL) and 15.0 g of sodium bicarbonate was added. The solution was stirred for 1 hour or until there was no more carbonation. The solution was filtered to remove the solids and the product was reprecipitated with 250 mL of diethyl ether, collected by filtration, washed with diethyl ether and dried in vacuo to obtain IPr.HCl (scheme 1) with 70% yield [4].

Simpler route is shown as following with the same reagents, but the yield is lower.

37.6 g (100 mmol) of bis(2,6-Diisopropylphenyl)diazabutadiene, 1.68 g (100 mmol) of formaldehyde solid, 160 mL of toluene were added to a 500 mL three-neck round bottom flask. Stirred refluxed at 50° C. for 1 h until most of the formaldehyde dissolved. The reaction mixture was cooled to 40° C. and a solution of HCl in dioxane 58 mL (100 mmol, 1.723 mol/L) was added with a syringe. The color of the solution changed from yellow to red to brown with the development of a white solid. The reaction was stirred and refluxed at 40° C. for 40 h, suction filtered and washed three times with THF to give a pink solid mass. About 40 mL of anhydrous ethanol was added to dissolve, and the solvent was removed and to get a powder, then washed three times with THF to obtain 21.94 g of an off-white powder IPr.HCl with 51.7% yield.

References

[1]  https://polypeptideskfo.weebly.com/blog/what-is-13-bis26-diisopropylphenylimidazolium-chloride

[2] https://www.alfa.com/en/catalog/H27150/

[3] https://www.trc-canada.com/product-detail/?B426655

[4] https://www.ambeed.com/products/250285-32-6.html