Synthesis and structure of some azolium salts - Pham Van Thong

Vietnam Journal of Chemistry, International Edition, 55(2): 248-253, 2017 DOI: 10.15625/2525-2321.2017-00454 248 Synthesis and structure of some azolium salts Pham Van Thong, Nguyen Hien, Nguyen Son Ha, Nguyen Thi Thanh Chi * Faculty of Chemistry, Hanoi National University of Education Received 8 December 2016; Accepted for publication 11 April 2017 Abstract The reactions between benzimidazole, imidazole, or 1,2,4-triazole with either benzyl chloride or isopropyl bromide yielded 6 azolium salts, namely 1,3-dibenzylimidazolium chloride (M1), 1,3-dibenzylbenzimidazolium chloride (M2), 1,3-dibenzyl-1,2,4-triazolium chloride (M3), 1,3-diisopropylimidazolium bromide (M4), 1,3- diisopropylbenzimidazolium bromide (M5), and 1,3-diisopropyl-1,2,4-triazolium bromide (M6). These salts can be further used as the starting compounds for the synthesis of complexes based on N-heterocyclic carbenes for various applications. The structures of M1÷M6 have been unambiguously determined by means of IR and 1H NMR spectroscopic methods. Keywords. N-heterocyclic carbenes, azoles, azolium salts. 1. INTRODUCTION In the past few years, transition metal complexes of N-heterocyclic carbene ligands (NHCs) have found vast application in molecular catalysis, material science, and medicine [1, 2]. Recently, researchers have also coupled their photo emissivity with anti-cancer activity and demonstrated their potential use towards lifesaving chemo-theranostic treatment [3]. In particular, palladium(II) complexes bearing carbine ligands derived from imidazolium precursors have been successfully developed as highly active precatalysts for C-C coupling reactions such as Mizoroki – Heck and Suzuki – Miyaura cross-coupling as well as CO-olefin copolymerization [4, 5]. Among many ways to synthesize NHC complexes, in-situ deprotonation of azolium salts with a basic metal precursor is one of the most widely used method due to its simplicity and efficiency [6, 7]. In this article, we describe the synthesis and structural characterization of some azolium salts that may be used as precursors for the synthesis of NHC complexes. 2. EXPERIMENTAL 2-1. Synthesis of the azolium salts Synthesis of 1,3-dibenzylimidazolium chloride (M1): A 5 M aqueous solution of NaOH (2.0 mL, 10 mmol) was added to a suspension of imidazole (680 mg, 10 mmol) in CH3CN (10.0 mL). The resulting mixture was stirred at RT for 30 minutes to give a clear solution. To the obtained solution was added benzyl chloride (1.20 mL, 10 mmol). The reaction mixture was held at reflux for 1 day. Another portion of benzyl chloride (1.5 mL, 14 mmol) was added to the reaction mixture and the mixture was stirred under reflux for a further day. After removing the volatiles under reduced pressure, CHCl3 (30 mL) was added to the residue and the resulting suspension was filtered over celite. The remaining solid was washed with CHCl3 (3 × 10 mL), and the solvent of the filtrate was removed in vacuo under reduced pressure to give a spongy solid, which upon washing with ethyl acetate (2 x 10 ml) afforded the desired azolium salt as a white powder. Yielded: 2.28 g (80 %). Synthesis of 1,3-dibenzylbenzimidazolium chloride (M2): M2 was prepared starting from benzimidazole (1.18 g, 10 mmol) and 2.7 mL benzyl chloride (24 mmol) following the procedure used for the preparation of M1. Yielded: 2.51 g (75 %). Synthesis of 1,3-dibenzyl-1,2,4-triazolium chloride (M3): M3 was prepared starting from 1,2,4- triazole (690 mg, 10 mmol) and benzyl chloride (2.5 mL, 22 mmol) following the procedure used for the preparation of M1. Yielded: 2.23 g (78 %). Synthesis of 1,3-diisopropylimidazolium bromide (M4): A mixture of imidazole (680 mg, 10 mmol) and K2CO3 (760 mg, 11 mmol) was suspended in acetonitrile (8 mL) and stirred at ambient temperature for 1 h. To the suspension was added isopropyl bromide (2.1 mL, 20 mmol). The reaction mixture was stirred under reflux conditions for 24 VJC, 55(2), 2017 Nguyen Thi Thanh Chi et al. 249 hours followed by the addition of the second portion of isopropyl bromide (3.3 mL, 30 mmol). The reaction mixture was stirred under reflux for an additional 48 h. After removing the volatiles under reduced pressured, CHCl3 (20 mL) was added to the residue and the resulting suspension was filtered over celite. The remaining solid was washed with CHCl3 (3×10 mL), and the solvent of the filtrate was removed under reduced pressure to give a spongy solid, which upon washing with ethyl acetate afforded the desired product as a white powder. Yielded: 2.23 g (85 %). Synthesis of 1,3-diisopropylbenzimidazolium bromide (M5): M5 was prepared starting from benzimidazole (1.18 g, 10 mmol) and isopropyl bromide (5.4 mL, 50 mmol) following the procedure used for the preparation of M4. Yielded: 2.21 g (78 %). Synthesis of 1,3-diisopropyl-1,2,4-triazolium bromide (M6): M6 was prepared starting from 1,2,4- triazole (0.69 g, 10 mmol) and isopropyl bromide (3.3 mL, 30 mmol) following the procedure used for the preparation of M4. Yielded: 1.76 g (75 %). 2.2. Instrumentation Analytical thin-layer chromatography was performed with commercial glass plates coated with 0.25 mm silica gel (Merck, Kieselgel 60 F254). The studied compounds were visualized under UV-light at 254 nm. The IR spectra were recorded on an IMPACK-410 NICOLET spectrometer in KBr discs in the range 400-4000 cm-1 at Faculty of Chemistry, Hanoi National University of Education. The 1H NMR spectra were recorded on a Bruker AVANCE III 500 MHz, all at 298-300 K, with TMS as the internal standard at Faculty of Chemistry - VNU University of Science. 3. RESULTS AND DISCUSSION Normally, azolium salts are prepared by alkylation of azoles with alkyl halide [8]. According to this method, 1,3-dibenzylazolium chloride (M1÷M3) and 1,3-diisopropylazolium bromide (M4÷M6) were synthesized by alkylating three azoles, benzimidazole, imidazole, and 1,2,4-triazole, with 75÷85 % isolated yields. Table 1 summarizes the results of some selected experiments. Scheme 1 shows the synthetic procedure of M2 and M4 as two typical examples. The synthetic procedure of M1÷M6 undergoes three stages as shown in the diagram (2) for M2 and M4. Scheme 1: Synthesis of 1,3-dibenzylazolium chloride (M2) and 1,3-diisopropylazolium bromide (M4) Table 1: Some selected experiments of producing M1÷M6 Compound Molar ratio of azole:R-X Solvent (v/v) Base Temp. (oC) Time (h) Yield (%) M1 1:2.4 acetonitrile-water (5:1) NaOH 85÷90 30 50 1:2.4 acetonitrile-water (5:1) NaOH 85÷90 50 80 M2 1:2.4 acetonitrile-water (5:1) NaOH 85÷90 50 75 M3 1:2.2 acetonitrile-water (5:1) NaOH 85÷90 50 78 M4 1:3.0 acetonitrile-water (5:1) NaOH 85÷90 50 20 1:5.0 acetonitrile NaOH 85÷90 72 25 1:5.0 acetonitrile K2CO3 85÷90 48 60 1:5.0 acetonitrile K2CO3 85÷90 72 85 M5 1:5.0 acetonitrile K2CO3 85÷90 72 78 M6 1:3.0 acetonitrile K2CO3 85÷90 72 75 VJC, 55(2), 2017 Synthesis and structure of some azolium salts. 250 The first step involves the deprotonation of benzimidazole with a strong or moderate base such as NaOH or K2CO3, respectively. This can be achieved easily at room temperature. The deprotonated benzimidazole is then sufficiently nucleophilic to attack the primary carbon of the alkyl halide to generate the corresponding benzimidazolium salt. Prolonging the reaction time and increasing the temperature are necessary to improve the efficiency of this step. Subsequently, in our next experiments (table 1), we conducted all reactions at 85÷90 oC in extended times (30÷72 hours). Additionally, the alkyl halides were also used in excess compared with the reaction molar ratio of azole:alkyl halides (1:2). Nevertheless, the alkyl halides should not be too excessively used in the synthesis of M3 and M6 in order to prevent creating the undesired 1,2,4-triankyl-1,2,4- triazolium. In the reactions of benzyl chloride with azoles, using a mixture of polar solvents (CH3CN and H2O) and a strong base such as NaOH gave 1,3- dibenzylazolium chloride salts (M1÷M3) with high isolated yields (75÷80 %). However, the conversion decreased in the case of isopropyl bromide when a strong base such as NaOH was used. The decreased yield in the N-alkylation of the azoles with secondary alkyl halides was due to the tendency of the latter to undergo elimination reaction in the presence of a strong base. Therefore, we carried out the reaction of azoles with excess isopropyl bromide in the presence of K2CO3 as a relatively weak base for 3 days. To our pleasure, the alkylation furnished 1,3-diisopropylazolium bromide salts (M4÷M6) as a white powder in much better yields (75÷85 %) (table 1, entries 4, 5, and 6). Generally, the reaction yields in the synthesis of benzimidazolium salts are lower than those of imidazolium salts. An obvious reason is the presence of the fused electron-withdrawing phenyl ring that reduces the reactivity of benzimidazole. The purity of the synthesized compounds M1÷M6 was examined preliminary by thin layer chromatography. The results showed that they have adequate purity for further characterization with spectroscopic methods. Several physical properties of M1÷M6 are listed in table 2. The data reveal that M1÷M6 are well soluble in both normal organic solvents such as chloroform, acetonitrile, alcohols, DMSO, and water, but only slightly soluble in acetone. Almost all of the azolium salts are white solids, except for M3 which has an orange color. Table 2: Form, color and solubility of M1÷M6 Comp. Form Color Solubility (at 30 oC) water ethanol acetone chloroform acetonitrile DMSO M1 powder white soluble soluble slightly soluble soluble soluble soluble M2 needles white lightly soluble soluble slightly soluble soluble soluble soluble M3 needles orange soluble soluble slightly soluble soluble soluble soluble M4 needles white soluble soluble slightly soluble soluble soluble soluble M5 needles white soluble soluble slightly soluble soluble soluble soluble M6 needles white soluble soluble lightly soluble soluble soluble soluble The structures of M1÷M6 were elucidated by IR and 1H NMR spectroscopic methods. Main bands in the IR spectra are listed in table 3. The IR spectrum of M2 is shown in figure 1 as an illustrative example. Table 3: Main bands in IR spectra of M1÷M6, cm-1 Compound νOH νCH aromatic νCH aliphatic ν(C=C, C=N) δCH aliphatic ν(C-C, C-N) δCH aliphatic M1 3395 3059 2986; 2846 1659; 1558; 1498 1450; 1357 1204; 1149; 1080 822; 717 M2 3429; 3364 3100; 3036 2951; 2850 1608; 1555; 1454 1423; 1373 1335; 1280; 1184 822; 760 M3 3472; 3391 3051 2980 1624; 1566; 1450 1435; 1350 1203; 1141; 1076 818; 721 M4 3445 3062 2940; 2800 1585; 1454 1408; 1340 1246; 1130 880 M5 3464 3070 2978 1628; 1555; 1462 1381; 1331 1281; 1184; 1146 856; 763 M6 3499 3100; 3040 2982; 2850 1635; 1566; 1516 1416 1300; 1234; 1184 891 VJC, 55(2), 2017 Nguyen Thi Thanh Chi et al. 251 Figure 1: IR spectrum of M2 The IR spectra of M1÷M6 show characteristic bands for the present functional groups in the azolium salts. For example, in the IR spectrum of M2 (Fig. 1), those bands at around 1555÷1609 cm-1 are characteristic for the (C=C and C=N) vibriations that prove the presence of the benzimidazole frame in M2. The presence of benzyl group is characterized by the characteristic absorption pattern of aliphatic CH at 2850÷2951 cm -1. In addition, the spectrum shows two intense bands at 3429÷3364 cm-1, corresponding to the asymmetric and symmetric stretching vibrations of the O-H group in crystallized water. In the IR spectra of the other salts, similar signals characteristic for water were also observed. This may be because in the process of crystallization, the crystallized azolium salts absorbed water from the solution. Table 3 shows that the IR spectra of M1÷M6 are only slightly changed when the alkyl groups are changed from benzyl to isopropyl or to anion Cl- to Br-. The assignment of the 1H NMR signals is based on their chemical shifts (δ), intensities, spin - spin splitting patterns, and splitting constants (J). The analyzed 1H NMR spectra of M3 and M4 are shown in figure 2 as representative examples. Figure 2: 1H NMR spectra of M3 (a) and M4 (b) For example, in 1H NMR spectrum of M4 (figure 2b), the two protons H5 give rise to a doublet centered at 1.57 ppm with 3J = 7.5 Hz, the two protons H4 give rise to a multiplet centered at 4.90 VJC, 55(2), 2017 Synthesis and structure of some azolium salts. 252 ppm. These indicate that the two isopropyl groups in M4 are equivalent. Two singlets at 10.45 ppm and 7.50 ppm are assigned for the two protons H1 and H2, respectively. Similarly, all signals in the spectra of M1÷M6 are unambiguously assigned. The results are listed in table 4. Table 4: 1H NMR signals in M1÷M6, (ppm), J (Hz) Comp. (Solvent) M1 M2 M3 M4 M5 M6 (D2O) ((CD3)2SO) (CDCl3) (CDCl3) (CDCl3) ((CD3)2SO) H1 8.74 s 10.39 s 12.46 s 10.45 s 11.37 s 10.23 s H2 7.29-7.37 ov 8.00 dd 3J 7.0 4J 3.0 8.33 s 7.50 s 7.76 dd 3J 6.5 4J 3.0 9.36 s H3 - 7.63 dd 3J 7.0 4J 3.0 - - 7.61 dd 3J 6.5 4J 3.0 - H4 5.27 s 5.84 s 5.72 / 5.69 s 4.90 m 5.18 m 4.78 / 4.72 m H5 7.29-7.37 ov 7.56 d 3J 7.5 7.57 / 7.52 dd 3J 7.0 4J 2.0 1.57 d 3J 7.5 1.84 d 3J 6.5 1.54 / 1.52 d 3J 6.5 H6 7.29-7.37 ov 7.43 t 3J 7.5 7.40-7.42 ov 7.36-7.38 ov - - - H7 7.29-7.37 ov 7.39 t 3J 7.5 - - - Table 4 shows signals of all protons in M1÷M6. Particularly, the resonance of the proton H1 in M1÷M6 is shifted downfield in comparison with that in the corresponding azoles [9], indicating the formation of the azolium salts. Besides, the equivalence of protons groups in M1, M2 and M4, M6 shows that the positive charge is relieved on the imidazole or the benzimidazole framework. Basing on the results above, we have determined the structures of all synthesized azolium salts (M1÷ M6) as shown in table 4. 4. CONCLUSION In conclusion, six azolium salts including 1,3- dibenzylimidazolium chloride (M1), 1,3- dibenzylbenzimidazolium chloride (M2), 1,3- dibenzyl-1,2,4-triazolium chloride (M3), 1,3- diisopropylimidazolium bromide (M4), 1,3- diisopropylbenzimidazolium bromide (M5) and 1,3- diisopropyl-1,2,4-triazolium bromide (M6) have been successfully synthesized with good isolated yields. From the reactions between benzimidazole, imidazole, or 1,2,4-triazole with benzyl chloride in the presence of a strong base (NaOH) for 2 days, the azolium salts M1÷M3 were obtained. Under similar conditions but with isopropyl bromide and in the presence of a medium base (K2CO3) for 3 days at 85÷90 oC, the other azolium salts M4÷M6 were successfully synthesized. 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Corresponding author: Nguyen Thi Thanh Chi Faculty of Chemistry Hanoi National University of Education No 136, Xuan Thuy, Cau Giay, Hanoi E-mail: chintt@hnue.edu.vn; Telephone: 0989069204.