ultrasound assisted synthesis of imidazolium salts: an efficient way to ionic liquids

Ultrasonics Sonochemistry xxx (2014) xxx–xxx

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Ultrasonics Sonochemistry

journal homepage: www.elsevier .com/locate /u l tson

Ultrasound assisted synthesis of imidazolium salts: An efficient way toionic liquids

http://dx.doi.org/10.1016/j.ultsonch.2014.10.0281350-4177/� 2014 Elsevier B.V. All rights reserved.

⇑ Corresponding author. Tel.: +40 232 201278; fax: +40 232 201313.E-mail address: [email protected] (C. Moldoveanu).

Please cite this article in press as: G. Zbancioc et al., Ultrasound assisted synthesis of imidazolium salts: An efficient way to ionic liquids, Ultrasonchem. (2014), http://dx.doi.org/10.1016/j.ultsonch.2014.10.028

Gheorghita Zbancioc, Ionel I. Mangalagiu, Costel Moldoveanu ⇑‘‘Al. I. Cuza’’ University of Iasi, Organic Chemistry and Biochemistry Department, 11 Carol Bd, 700506 Iasi, Romania

a r t i c l e i n f o

Article history:Received 12 February 2014Received in revised form 23 October 2014Accepted 27 October 2014Available online xxxx

Keywords:UltrasoundEnvironmentally friendly methodsN-Alkylation1,3-DiazoleReaction mechanismIonic liquids

a b s t r a c t

In this study a straightforward and efficient approach concerning synthesis of 1,3-diazole derivativesunder ultrasound (US) irradiation as well as under conventional thermal heating (TH) is presented.N-alkylation under US irradiation may be considered environmentally friendly in terms of higher yields,smaller amounts of solvent used and an overall energy efficiency due to a substantial reduction of reac-tion times. A comparative study of ultrasound vs. conventional conditions has been performed. Overall,the use of US proved to be more efficient than TH. A possible explanation concerning the different behav-ior of imidazole and benzimidazole in the N1-alkylation reactions under US irradiation was proposed.

� 2014 Elsevier B.V. All rights reserved.

1. Introduction

Ultrasound (US) irradiation has gained popularity in organicchemistry in the past decade as a viable reaction alternative toconventional thermal heating (TH). It already offers a versatileand facile pathway in a large variety of syntheses [1–11]. Com-pared with conventional TH, US irradiation brings a substantialdecrease of reaction time, improved yields and high purity of com-pounds as well as simplicity in handling and processing. Also, anincreased selectivity and lower costs of US procedure is a powerfulreason for the use of this alternative. At the same time, by usingsmall amounts of solvents and generating fewer side products,the reactions under US irradiation could be considered environ-mentally friendly [12].

Imidazole and its derivatives have demonstrated fascinatingpotential applications for medicinal chemistry, these includinganticancer activity [13,14], anti-HIV [15,16], antibacterial and anti-fungal activity [17,18] and drugs for treatment of cardiovasculardiseases [19,20]. Moreover, imidazolium salts are potent roomtemperature ionic liquids of current great interest in industry[21,22].

A major drawback in the synthesis of ionic liquids is that reac-tions involved in both imidazole quaternization (first generation of

ionic liquids) and anion metathesis (second generation of ionicliquids) are excessively time consuming. Under conventional TH,the synthesis of the first generation of imidazolium-based ionicliquids can take from a few hours in the case of bromides up to afew days for the chlorides. Given the attractive properties of thesecompounds, finding an alternative way for improving their synthe-sis becomes an important target. Microwave-assisted preparationof first generation ionic liquids in solvent [23] or under solvent-free conditions [24], was hence addressed, starting with 2001. UStechnology was also used prior in preparation of first generationionic liquids [25]. The classic method used for anion metathesisrequires 24–48 h, large amounts of solvents for purification and afew hours of drying under high vacuum. This procedure being alsotime-consuming, the effort of several research groups was focusedto adapt non-conventional methods to synthesize second genera-tion of the ionic liquids [26,27]. Other literature data reportedone-pot synthesis of various imidazolium based second generationionic liquids using classical [28], ultrasound [29], and a combina-tion of the microwave and ultrasound conditions [30].

In previous research work within the imidazole area, we havepresented several contributions concerning the synthesis of imi-dazolium salts [31,32]. Their potential practical applications suchas anticancer agents [33] and ionic liquids [34] were also investi-gated by us. In continuation of our work in this area [31–34], wefocus on developing a straightforward, efficient and environmen-tally friendly method for preparation of imidazolium and benzim-idazolium salts, under US irradiation and conventional TH.

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2. Method

2.1. Apparatus and analysis

All reagents and solvents were purchased from commercialsources and used without further purification. Melting points wererecorded on a MEL-TEMP II apparatus in open capillary tubes andare uncorrected. Analytical thin-layer chromatography wasperformed with commercial silica gel plates 60 F254 (Merck) andvisualized under UV light. The NMR spectra were recorded on aBruker Avance 400 DRX spectrometer operating at 400 MHz for1H and 100 MHz for 13C, or on a Bruker Avance III 500 MHz spec-trometer operating at 500 MHz for 1H and 125 MHz for 13C. Thefollowing abbreviations were used to designate chemical shiftmultiplicities: s = singlet, d = doublet, dd = doublet of doublet,t = triplet, m = multiplet. Chemical shifts were reported in delta(d) units, part per million (ppm) and coupling constants (J) in Hz.Infrared (IR) data were recorded as films on potassium bromide(KBr) pellets on a FT-IR Shimadzu Prestige 8400s spectrophotome-ter. The microanalyses were in satisfactory agreement with the cal-culated values: C, ±0.15; H, ±0.10; N, ±0.30. Ultrasound assistedreactions were carried out using Bandelin Ultrasound reactor(Sonopuls GM 3200), with a nominal power of 200 W and a fre-quency of 20 kHz. The booster horn SH 213 G was fixed tightlyto the ultrasonic converter. The titanium flat probe tip TT13 (diam-eter: 12.7 mm; length: 7 mm) was fixed tightly to the booster horn.The titanium probe tip was immersed in the used solvent.

Compound 3a was initially synthesized by Makaev [22]. Syn-thesis and optical spectral characteristics of compounds 5a-f and50a-cwere first reported by us [31,32].

2.2. General procedure for N-alkylation under TH and US irradiation

2.2.1. General procedure for the synthesis of N1-alkylated imidazolederivatives 3a-d andN1-alkylated benzimidazole derivatives 30a-dunder conventional TH and US irradiation

50 mmol of imidazole derivative (as indicated in Table 1),0.2 mL triethylamine and 50 mmol acrylic acid derivative were dis-solved in 60 mL toluene. The mixture was refluxed using an oilbath for 26 h (for 3a-d) and 36 h (30a-d). After the completion ofthe reaction (TLC), the solvent was removed under vacuum andthe obtained imidazole derivatives were separated with a goodgrade of purity. For further purification this derivatives can be crys-tallized (if solid) from an appropriate solvent. Analytically pure

Table 1Amounts of imidazole and acrylic acid derivatives involved in the synthesis of N1-alkylated imidazole derivatives.

Compound Imidazole derivative Acrylic acid derivative

TH (g) US (g) TH (g/mL) US (g/mL)

3a Imidazole Acrylonitrile3.40 0.34 2.65/3.25 0.27/0.33

3b Imidazole Ethyl acrylate3.40 0.34 5.00/5.45 0.50/0.55

3c Imidazole Methyl acrylate3.40 0.34 4.30/4.50 0.43/0.45

3d Imidazole Acrylamide3.40 0.34 3.55 0.36

30a Benzimidazole Acrylonitrile5.90 0.59 2.65/3.25 0.27/0.33

30b Benzimidazole Ethyl acrylate5.90 0.59 5.00/5.45 0.50/0.55

30c Benzimidazole Methyl acrylate5.90 0.59 4.30/4.50 0.43/0.45

30d Benzimidazole Acrylamide5.90 0.59 3.55 0.36

Please cite this article in press as: G. Zbancioc et al., Ultrasound assisted synthchem. (2014), http://dx.doi.org/10.1016/j.ultsonch.2014.10.028

samples were obtained after 48 h of drying in vacuum oven at60 �C under reduced pressure.

Under US irradiation, 5 mmol of imidazole derivative (as indi-cated in Table 1), 0.02 mL triethylamine and 5 mmol acrylic acidderivative (as indicated in Table 1) in 4 mL solvent [toluene (forobtaining 3a-d) and dimethylformamide (DMF) (for obtaining30a-dX)], were placed in the reaction vessel and exposed to US irra-diation for an appropriate time as is presented in Table 3. Once theirradiation cycle was completed, the reaction tube was removedfrom the reactor, and processed as indicated above for TH.

2.2.2. General procedure for the N1-alkylation of imidazole under USirradiation in the presence of a radical scavenger, TEMPO

Under US irradiation, 5 mmol of imidazole (0.34 g), 0.02 mL tri-ethylamine, 5 mmol acrylonitrile (0.27 g, 0.33 ml) and 7.5 mmol2,2,6,6-Tetramethylpiperidin-1-yl)oxy (TEMPO) (1.17 g) in 4 mLtoluene were placed in the reaction vessel and exposed to US irra-diation for 2 h. After two hours of US irradiation, the GC–MS shows12% conversion of the imidazole to the desired product 3a.

2.2.3. General procedure for the synthesis of imidazolium salts 5a-l andbenzimidazolium salts 50a-l under conventional TH and US irradiation

10 mmol of N1-alkylated imidazole derivative (as listed inTable 2) was dissolved in 20 mL of acetone. A solution of 12 mmolactivated halogeno-derivative in 10 mL of acetone was added dropwise under stirring. The reaction mixture was then refluxed usingan oil bath, for appropriate time as is presented in Table 5. Theobtained salt was filtered under vacuum and washed with 5 mLof diethyl ether. For future purification these salts can be crystal-lized from an appropriate solvent. Analytically pure samples wereobtained after 48 h of drying in vacuum oven at 60 �C and reducedpressure.

Under US irradiation, 5 mmol of imidazole derivative (asindicated in Table 2) and 6 mmol of activated halogeno-derivative(as indicated in Table 2) in 10 mL of acetone, were placed in thereaction vessel and exposed to US irradiation for an appropriatetime, as is presented in Table 5. The reaction vessel was cooledto 20 �C using a circulating bath in order to prevent the acetoneevaporation. Once the irradiation cycle was completed, thereaction tube was removed from the reactor, and processed asindicated above for TH.

The structure of compounds was proved by elemental and spec-tral analysis [IR, MS, 1H NMR, 13C NMR, 2D-COSY, 2D-HETCOR(HMQC), long range 2D-HETCOR (HMBC)], and were in accordancewith the proposed structure (Scheme 1).

2.2.3.1. 3-(1H-imidazol-1-yl)propanenitrile (3a). Transparent liquid;5.875 g, 97% using TH; 0.588 g, 97% using US; IR (KBr): �v/cm�1:3099, 3068, 3039 (C–Harom), 2983, 2972 (C–Haliph), 2250 (CN),1512, 1456, 1419 (C–Carom); 1H NMR (400 MHz, CDCl3): dppm:2.82 (2H: H7, t, J6,7 = 6.4 Hz), 4.25 (2H: H6, t, J6,7 = 6.4 Hz), 7.03(1H: H5, s), 7.09 (1H: H4, s), 7.56 (1H: H2, s); 13C NMR (100 MHz,CDCl3): dppm: 20.55 (C7), 42.41 (C6), 116.89 (C5), 118.79 (CN group),130.23 (C4), 137.08 (C2); Anal. calcd. C6H7N3: C, 59.49; H, 5.82; N,34.69; Found: C, 59.44; H, 5.79; N, 34.77.

2.2.3.2. Ethyl 3-(1H-imidazol-1-yl)propanoate (3b). Transparentliquid; 8.241 g, 98% using TH; 0.824 g, 98% using US; IR (KBr): �v/cm�1: 3110, 2981 (C–Harom), 2939 (C–Haliph), 1720 (C@Oester),1506, 1446, 1398 (C–Carom), 1284, 1193 (C–O–C); 1H NMR(400 MHz, CDCl3): dppm: 1.22 (3H: H9, t, J8,9 = 7.2 Hz, CH3 fromOC2H5), 2.75 (2H: H7, t, J6,7 = 6.4 Hz), 4.12 (2H: H8, q, J8,9 = 7.2 Hz,CH2 from OC2H5), 4.24 (2H: H6, t, J6,7 = 6.4 Hz), 6.95 (1H: H5, s),7.00 (1H: H4, s), 7.50 (1H: H2, s); 13C NMR (100 MHz, CDCl3): dppm:14.09 (C9, CH3 from OC2H5), 36.11 (C7), 42.29 (C6), 60.98 (C8, CH2

from OC2H5), 118.97 (C5), 129.39 (C4), 137.30 (C2), 170.55 (COester);

esis of imidazolium salts: An efficient way to ionic liquids, Ultrason. Sono-


Table 2Amounts of N1-alkylated imidazole and activated halogeno-derivatives involved in the synthesis of N3-alkylated imidazolederivatives.

Compound N1-alkylated imidazole derivative Activated halogeno-derivatives

TH (g) US (g) TH (g/mL) US (g/mL)

5a 3a Ethyl bromacetate1.21 0.61 2.01/1.33 1.00/0.67

5b 3a Methyl bromacetate1.21 0.61 1.84/1.14 0.97/0.57

5c 3a 2-Iodoacetamide1.21 0.61 2.22 1.11

5d 3b Ethyl bromacetate1.68 0.84 2.01/1.33 1.00/0.67

5e 3b Methyl bromacetate1.68 0.84 1.84/1.14 0.97/0.57

5f 3b 2-Iodoacetamide1.68 0.84 2.22 1.11

5g 3c Ethyl bromacetate1.54 0.77 2.01/1.33 1.00/0.67

5h 3c Methyl bromacetate1.54 0.77 1.84/1.14 0.97/0.57

5i 3c 2-Iodoacetamide1.54 0.77 2.22 1.11

5j 3d Ethyl bromacetate1.39 0.70 2.01/1.33 1.00/0.67

5k 3d Methyl bromacetate1.39 0.70 1.84/1.14 0.97/0.57

5l 3d 2-Iodoacetamide1.39 0.70 2.22 1.11

50a 30a Ethyl bromacetate1.71 0.81 2.01/1.33 1.00/0.67

50b 30a Methyl bromacetate1.71 0.81 1.84/1.14 0.97/0.57

50c 30a 2-Iodoacetamide1.71 0.81 2.22 1.11

50d 30b Ethyl bromacetate2.18 1.09 2.01/1.33 1.00/0.67

50e 30b Methyl bromacetate2.18 1.09 1.84/1.14 0.97/0.57

50f 30b 2-Iodoacetamide2.18 1.09 2.22 1.11

50g 30c Ethyl bromacetate2.04 1.02 2.01/1.33 1.00/0.67

50h 30c Methyl bromacetate2.04 1.02 1.84/1.14 0.97/0.57

50i 30c 2-Iodoacetamide2.04 1.02 2.22 1.11

50j 30d Ethyl bromacetate1.89 0.95 2.01/1.33 1.00/0.67

50k 30d Methyl bromacetate1.89 0.95 1.84/1.14 0.97/0.57

50l 30d 2-Iodoacetamide1.89 0.95 2.22 1.11

N

N

CO

Y

Z

N

N

CO

Y

Z

12

34

5

67

7a8

9

10 10a

1112

123

45

6

7

3a

89

12a

7a

12

Z=

C N

O

O

7a

Y=

O

9a10

11

1314

Z=

C N

O

O

9a

Y=

O

7a b

O

NH

Ha

8

9a b

O

NH

Ha

10

10a b

O

NH

Ha

1112a b

O

NH

Ha

13

Scheme 1. NMR identification of H and C atoms.

G. Zbancioc et al. / Ultrasonics Sonochemistry xxx (2014) xxx–xxx 3

Please cite this article in press as: G. Zbancioc et al., Ultrasound assisted synthesis of imidazolium salts: An efficient way to ionic liquids, Ultrason. Sono-chem. (2014), http://dx.doi.org/10.1016/j.ultsonch.2014.10.028



Anal. calcd. C8H12N2O2: C, 57.13; H, 7.19; N, 16.66; Found: C, 57.11;H, 7.21; N, 16.63.

2.2.3.3. Methyl 3-(1H-imidazol-1-yl)propanoate (3c). Transparentliquid; 7.400 g, 96% using TH; 0.748 g, 97% using US; IR (KBr): �v/cm�1: 3109, 2999 (C–Harom), 2952, 2920 (C–Haliph), 1728 (C@Oester),1506, 1436 (C–Carom), 1325, 1284, 1199, 1107 (C–O–C); 1H NMR(400 MHz, CDCl3): dppm: 2.76 (2H: H7, t, J6,7 = 6.4 Hz), 3.64 (3H:H8, s, OCH3), 4.23 (2H: H6, t, J6,7 = 6.4 Hz), 6.94 (1H: H5, s), 6.99(1H: H4, s), 7.49 (1H: H2, s); 13C NMR (100 MHz, CDCl3): dppm:34.85 (C7), 41.42 (C6), 51.13 (C8, OCH3), 118.34 (C5), 128.57 (C4),136.50 (C2), 170.22 (COester); Anal. calcd. C7H10N2O2: C, 54.54; H,6.54; N, 18.17; Found: C, 54.58; H, 6.52; N, 18.20.

2.2.3.4. 3-(1H-imidazol-1-yl)propanamide (3d). White crystals(from acetone); 6.610 g, 95% using TH; 0.668 g, 96% using US; mp140–143 �C; IR (KBr): �v/cm�1: 3387, 3290, (N–Hamide), 3144, 3107(C–Harom), 2999, 2924 (C–Haliph), 1668 (C@Oamide), 1514, 1413,1356 (C–Carom); 1H NMR (400 MHz, DMSO): dppm: 2.54 (2H: H7, t,J6,7 = 6.8 Hz), 4.17 (2H: H6, t, J6,7 = 6.8 Hz), 6.86 (1H: H5, s), 6.96(1H: Hb from NH2 group, s), 7.12 (1H: H4, s), 7.42 (1H: Ha fromNH2 group, s), 7.66 (1H: H2, s); 13C NMR (100 MHz, DMSO): dppm:36.47 (C7), 42.19 (C6), 119.26 (C5), 128.21 (C4), 137.20 (C2),171.57 (COamide); Anal. calcd. C6H9N3O: C, 51.79; H, 6.52; N,30.20; Found: C, 51.81; H, 6.50; N, 30.21.

2.2.3.5. 3-(1H-benzo[d]imidazol-1-yl)propanenitrile (30a). Whitecrystals (from acetone); 8.132 g, 95% using TH; 0.788 g, 92% usingUS; mp 94–95 �C; IR (KBr): �v/cm�1: 3091, 3080, 3053 (C–Harom),2972, 2958, 2923 (C–Haliph), 2245 (CN), 1494, 1458, 1382 (C–Carom); 1H NMR (500 MHz, CDCl3): dppm: 2.90 (2H: H9, t,J8,9 = 6.5 Hz), 4.51 (2H: H8, t, J8,9 = 6.5 Hz), 7.35 (3H: H5, H6, H7,m), 7.85 (1H: H4, d, J4,5 = 7.5 Hz), 8.00 (1H: H2, s); 13C NMR(125 MHz, CDCl3): dppm: 18.38 (C9), 40.15 (C8), 109.85 (C7),117.46 (CN group), 119.75 (C4), 121.77 (C6), 122.55 (C5), 133.48(C7a), 143.47 (C2), 143.99 (C3a); Anal. calcd. C10H9N3: C, 70.16; H,5.30; N, 24.54; Found: C, 70.13; H, 5.31; N, 24.56.

2.2.3.6. Ethyl 3-(1H-benzo[d]imidazol-1-yl)propanoate (30b). Trans-parent liquid; 10.476 g, 96% using TH; 1.004 g, 92% using US; IR(KBr): �v/cm�1: 3162, 2983 (C–Harom), 2906 (C–Haliph), 1708(C@Oester), 1616, 1496, 1458, 1363 (C–Carom), 1286, 1166, 1093(C–O–C); 1H NMR (400 MHz, CDCl3): dppm: 1.80 (3H: H11, t,J10,11 = 7.2 Hz, CH3 from OC2H5), 2.85 (2H: H9, t, J8,9 = 6.4 Hz), 4.10(2H: H10, q, J10,11 = 7.2 Hz, CH2 from OC2H5), 4.47 (2H: H8, t,J8,9 = 6.4 Hz), 7.28 (2H: H5, H6, m), 7.41 (1H: H7, dd, J6,7 = 6.4 Hz,J5,7 = 1.2 Hz), 7.93 (1H: H4, dd, J4,5 = 6.8 Hz, J4,6 = 2.0 Hz), 7.98 (1H:H2, s); 13C NMR (100 MHz, CDCl3): dppm: 14.04 (C11, CH3 fromOC2H5), 34.39 (C9), 40.37 (C8), 61.13 (C10, CH2 from OC2H5),109.49 (C7), 120.30 (C4), 122.30 (C5), 123.10 (C6), 133.41 (C7a),143.43 (C2), 143.70 (C3a), 170.65 (COester); Anal. calcd.C12H14N2O2: C, 66.04; H, 6.47; N, 12.84; Found: C, 66.08; H, 6.42;N, 12.86.

2.2.3.7. Methyl 3-(1H-benzo[d]imidazol-1-yl)propanoate (30c). Trans-parent liquid; 9.905 g, 97% using TH; 0.950 g, 93% using US; IR(KBr): �v/cm�1: 3159, 2998 (C–Harom), 2928, 2910 (C–Haliph), 1710(C@Oester), 1606, 1488, 1448, 1324 (C–Carom), 1278, 1156, 1110(C–O–C); 1H NMR (400 MHz, CDCl3): dppm: 2.85 (2H: H9, t,J8,9 = 6.4 Hz), 3.64 (3H: H10, s, OCH3), 4.47 (2H: H8, t, J8,9 = 6.4 Hz),7.30 (2H: H5, H6, m), 7.39 (1H: H7, dd, J6,7 = 6.4 Hz, J5,7 = 1.6 Hz),7.80 (1H: H4, dd, J4,5 = 6.8 Hz, J4,6 = 2.0 Hz), 7.97 (1H: H2, s); 13CNMR (100 MHz, CDCl3): dppm: 33.97 (C9), 40.16 (C8), 51.94 (C10,OCH3), 109.21 (C7), 120.24 (C4), 122.17 (C6), 122.96 (C5), 133.18(C7a), 143.20 (C2), 143.54 (C3a), 170.90 (COester); Anal. calcd.


C11H12N2O2: C, 64.69; H, 5.92; N, 13.72; Found: C, 64.65; H, 5.94;N, 13.75.

2.2.3.8. 3-(1H-benzo[d]imidazol-1-yl)propanamide (30d). Whitecrystals (from acetone); 8.893 g, 94% using TH; 0.851 g, 90% usingUS; mp 149–152 �C; IR (KBr): �v/cm�1: 3348 (N–Hamide), 3180, 3084(C–Harom), 2949 (C–Haliph), 1676, 1616 (C@Oamide), 1491, 1456,1417, 1348 (C–Carom); 1H NMR (400 MHz, DMSO): dppm: 2.64(2H: H9, t, J8,9 = 6.8 Hz), 4.46 (2H: H8, t, J8,9 = 6.8 Hz), 6.96 (1H: Hb

from NH2 group, s), 7.20 (2H: H5, H6, m), 7.39 (1H: Ha from NH2

group, s), 7.63 (2H: H4, H7, m), 8.14 (1H: H2, s); 13C NMR(100 MHz, DMSO): dppm: 35.14 (C9), 40.43 (C8), 110.40 (C7),119.33 (C4), 121.36 (C5), 122.16 (C6), 133.58 (C7a), 143.34 (C3a),144.04 (C2), 171.55 (COamide); Anal. calcd. C11H12N2O2: C, 63.48;H, 5.86; N, 22.21; Found: C, 63.45; H, 5.84; N, 22.25.

2.2.3.9. 1-(2-cyanoethyl)-3-(2-ethoxy-2-oxoethyl)-1H-3-imidazoliumbromide (5a). Transparent liquid; 2.449 g, 85% using TH; 1.383 g,96% using US; All spectral and elemental data are in agreementwith the previously reported one [31].

2.2.3.10. 1-(2-Cyanoethyl)-3-(2-methoxy-2-oxoethyl)-1H-3-imidazo-lium bromide (5b). White crystals (from acetone); 2.248 g, 82%using TH; 1.261 g, 92% using US; mp 129–130 �C; All spectral andelemental data are in agreement with the previously reportedone [31].

2.2.3.11. 3-(2-Amino-2-oxoethyl)-1-(2-cyanoethyl)-1H-3-imidazoli-um iodide (5c). White crystals (from acetone); 2.388 g, 78% usingTH; 1.377 g, 90% using US; mp 164–166 �C; All spectral and ele-mental data are in agreement with the previously reported one[31].

2.2.3.12. 3-(2-Ethoxy-2-oxoethyl)-1-(3-ethoxy-3-oxopropyl)-1H-3-imidazolium bromide (5d). Transparent liquid; 3.151 g, 94% usingTH; 1.592 g, 95% using US; All spectral and elemental data are inagreement with the previously reported one [32].

2.2.3.13. 1-(3-Ethoxy-3-oxopropyl)-3-(2-methoxy-2-oxoethyl)-1H-3-imidazolium bromide (5e). Transparent liquid; 3.083 g, 96% usingTH; 1.542 g, 96% using US; All spectral and elemental data are inagreement with the previously reported one [32].

2.2.3.14. 3-(2-Amino-2-oxoethyl)-1-(3-ethoxy-3-oxopropyl)-1H-3-imidazolium iodide (5f). White crystals (from acetone); 3.214 g,91% using TH; 1.642 g, 93% using US; mp 111–113 �C; All spectraland elemental data are in agreement with the previously reportedone [32].

2.2.3.15. 3-(2-Ethoxy-2-oxoethyl)-1-(3-methoxy-3-oxopropyl)-1H-3-imidazolium bromide (5g). Transparent liquid; 3.051 g, 95% usingTH; 1.542 g, 96% using US; IR (KBr): �v/cm�1: 3083 (C–Harom),2985, 2923 (C–Haliph), 1737 (C@Oester), 1568, 1440, 1375 (C–Carom), 1222, 1168, 1101 (C–O–C); 1H NMR (400 MHz, DMSO):dppm: 1.23 (3H: H12, t, J11,12 = 7.2 Hz, CH3 from OC2H5), 3.05(2H: H7, t, J6,7 = 6.4 Hz), 3.60 (3H: H8, s, OCH3), 4.20 (2H: H11,q, J11,12 = 7.2 Hz, CH2 from OC2H5), 4.50 (2H: H6, t, J6,7 = 6.4 Hz),5.36 (2H: H10, s), 7.84 (1H: H4, s), 7.94 (1H: H5, s), 9.36 (1H:H2, s); 13C NMR (100 MHz, DMSO): dppm: 13.92 (C12, CH3 fromOC2H5), 33.51 (C7), 44.77 (C6), 49.56 (C10), 51.78 (C8, OCH3),61.84 (C11, CH2 from OC2H5), 122.19 (C5), 123.70 (C4), 137.70(C2), 166.75 (C10a, COester), 170.56 (C7a, COester); Anal. calcd. C11-

H17BrN2O4: C, 41.14; H, 5.34; N, 8.72; Found: C, 41.12; H,5.36; N, 8.74.




2.2.3.16. 3-(2-Methoxy-2-oxoethyl)-1-(3-methoxy-3-oxopropyl)-1H-3-imidazolium bromide (5h). Transparent liquid; 2.826 g, 92% usingTH; 1.444 g, 94% using US; IR (KBr): �v/cm�1: 3143, 3083, 3006 (C–Harom), 2956, 2921 (C–Haliph), 1737 (C@Oester), 1631, 1568, 1440,1371 (C–Carom), 1228, 1170 (C–O–C); 1H NMR (400 MHz, DMSO):dppm: 3.04 (2H: H7, t, J6,7 = 6.4 Hz), 3.60 (3H: H8, s, OCH3), 3.73(3H: H11, s, OCH3), 4.50 (2H: H6, t, J6,7 = 6.4 Hz), 5.39 (2H: H10, s),7.85 (1H: H4, s), 7.95 (1H: H5, s), 9.37 (1H: H2, s); 13C NMR(100 MHz, DMSO): dppm: 33.54 (C7), 44.81 (C6), 49.53 (C10), 51.83(C8, OCH3), 52.84 (C11, OCH3), 122.24 (C5), 123.70 (C4), 137.71(C2), 167.27 (C10a, COester), 170.59 (C7a, COester); Anal. calcd.C10H15BrN2O4: C, 39.10; H, 4.92; N, 9.12; Found: C, 39.08; H,4.95; N, 9.10.

2.2.3.17. 3-(2-Amino-2-oxoethyl)-1-(3-methoxy-3-oxopropyl)-1H-3-imidazolium iodide (5i). White crystals (from acetone); 3.052 g,90% using TH; 1.594 g, 94% using US; mp 123–125 �C; IR (KBr):�v/cm�1: 3352 (N–Hamide), 3157, 3111, 3088, 3045 (C–Harom),2982, 2933 (C–Haliph), 1716 (C@Oester), 1672 (C@Oamide), 1597,1560, 1438, 1413, 1392 (C–Carom), 1217, 1168 (C–O–C); 1H NMR(400 MHz, DMSO): dppm: 3.02 (2H: H7, t, J6,7 = 6.6 Hz), 3.63 (3H:H8, s, OCH3), 4.46 (2H: H6, t, J6,7 = 6.6 Hz), 4.96 (2H: H10, s), 7.53(1H: Hb from NH2 group, s), 7.70 (1H: H4, s), 7.78 (1H: H5, s),7.83 (1H: Ha from NH2 group, s), 9.14 (1H: H2, s); 13C NMR(100 MHz, DMSO): dppm: 33.45 (C7), 44.59 (C6), 50.45 (C10), 51.78(C8, OCH3), 121.78 (C5), 123.86 (C4), 137.62 (C2), 166.58 (C10a,COamide), 170.79 (C7a, COester); Anal. calcd. C9H14IN3O3: C, 31.87;H, 4.16; N, 12.39; Found: C, 31.85; H, 4.18; N, 12.36.

2.2.3.18. 1-(3-Amino-3-oxopropyl)-3-(2-ethoxy-2-oxoethyl)-1H-3-imidazolium bromide (5j). Transparent liquid; 2.909 g, 95% usingTH; 1.470 g, 96% using US; IR (KBr): �v/cm�1: 3375 (N–Hamide),3159, 3101 (C–Harom), 2985, 2949 (C–Haliph), 1745 (C@Oester),1674 (C@Oamide), 1618, 1566, 1411, 1375 (C–Carom), 1228, 1166(C–O–C); 1H NMR (400 MHz, DMSO): dppm: 1.22 (3H: H12, t,J11,12 = 7.2 Hz, CH3 from OC2H5), 2.75 (2H: H7, t, J6,7 = 6.4 Hz), 4.18(2H: H11, q, J11,12 = 7.2 Hz, CH2 from OC2H5), 4.45 (2H: H6, t,J6,7 = 6.4 Hz), 5.34 (2H: H10, s), 7.03 (1H: Hb from NH2 group, s),7.62 (1H: Ha from NH2 group, s), 7.86 (1H: H4, s), 7.89 (1H: H5,s), 9.29 (1H: H2, s); 13C NMR (100 MHz, DMSO): dppm: 13.92 (C12,CH3 from OC2H5), 34.73 (C7), 45.34 (C6), 49.54 (C10), 61.83 (C11,CH2 from OC2H5), 122.20 (C5), 123.59 (C4), 137.52 (C2), 166.73(C10a, COester), 170.79 (C7a, COamide); Anal. calcd. C10H16BrN3O3: C,39.23; H, 5.27; N, 13.73; Found: C, 39.21; H, 5.29; N, 13.70.

2.2.3.19. 1-(3-Amino-3-oxopropyl)-3-(2-methoxy-2-oxoethyl)-1H-3-imidazolium bromide (5k). Transparent liquid; 2.775 g, 95% usingTH; 1.388 g, 95% using US; IR (KBr): �v/cm�1: 3416 (N–Hamide),3171, 3115, (C–Harom), 2958, 2924 (C–Haliph), 1742 (C@Oester),1674 (C@Oamide), 1624, 1566, 1417, 1371 (C–Carom), 1232, 1166(C–O–C); 1H NMR (400 MHz, DMSO): dppm: 2.74 (2H: H7, t,J6,7 = 6.4 Hz), 3.73 (3H: H11, s, OCH3), 4.44 (2H: H6, t, J6,7 = 6.4 Hz),5.35 (2H: H10, s), 7.03 (1H: Hb from NH2 group, s), 7.61 (1H: Ha

from NH2 group, s), 7.81 (1H: H4, s), 7.85 (1H: H5, s), 9.27 (1H:H2, s); 13C NMR (100 MHz, DMSO): dppm: 34.76 (C7), 45.35 (C6),49.47 (C10), 52.80 (C11, CH3 from OC2H5), 122.26 (C5), 123.60 (C4),137.53 (C2), 167.24 (C10a, COester), 170.79 (C7a, COamide); Anal. calcd.C9H14BrN3O3: C, 37.00; H, 4.83; N, 14.38; Found: C, 37.03; H, 4.81;N, 14.35.

2.2.3.20. 3-(2-Amino-2-oxoethyl)-1-(3-amino-3-oxopropyl)-1H-3-imidazolium iodide (5l). White crystals (from acetone); 2.982 g,92% using TH; 1.523 g, 94% using US; mp 130–132 �C; IR (KBr):�v/cm�1: 3408, 3313 (N–Hamide), 3198, 3169, 3144, 3055 (C–Harom),2987, 2962 (C–Haliph), 1691, 1670 (C@Oamide), 1614, 1566, 1400(C–Carom); 1H NMR (400 MHz, DMSO): dppm: 2.71 (2H: H7, t,


J6,7 = 6.4 Hz), 4.40 (2H: H6, t, J6,7 = 6.6 Hz), 4.96 (2H: H10, s), 7.03(1H: Hb from NH2 group from 8th position, s), 7.49 (1H: Ha fromNH2 group from 8th position, s), 7.51 (1H: Hb from NH2 group from11th position, s), 7.67 (1H: H4, s), 7.73 (1H: H5, s), 7.81 (1H: Ha

from NH2 group from 11th position, s), 9.10 (1H: H2, s); 13C NMR(100 MHz, DMSO): dppm: 33.62 (C7), 45.08 (C6), 50.39 (C10),121.80 (C5), 123.76 (C4), 137.47 (C2), 166.59 (C10a, COamide),170.70 (C7a, COamide); Anal. calcd. C8H13IN4O2: C, 29.65; H, 4.04;N, 17.29; Found: C, 29.62; H, 4.03; N, 17.32.

2.2.3.21. 1-(2-Cyanoethyl)-3-(2-ethoxy-2-oxoethyl)-1H-benzo[d]imi-dazol-3-ium bromide (50a). White crystals (from acetone); 2.909 g,86% using TH; 1.522 g, 90% using US; mp 157–158 �C; All spectraland elemental data are in agreement with the previously reportedone [31].

2.2.3.22. 1-(2-Cyanoethyl)-3-(2-methoxy-2-oxoethyl)-1H-benzo[d]imidazol-3-ium bromide (50b). White crystals (from acetone);2.593 g, 80% using TH; 1.410 g, 87% using US; mp 161–163 �C; Allspectral and elemental data are in agreement with the previouslyreported one [31].

2.2.3.23. 3-(2-Amino-2-oxoethyl)-1-(2-cyanoethyl)-1H-benzo[d]imi-dazol-3-ium iodide (50c). White crystals (from acetone); 3.134 g,88% using TH; 1.621 g, 91% using US; mp 167–169 �C; All spectraland elemental data are in agreement with the previously reportedone [31].

2.2.3.24. 3-(2-Ethoxy-2-oxoethyl)-1-(3-ethoxy-3-oxopropyl)-1H-benzo[d]imidazol-3-ium bromide (50d). White crystals (fromacetone); 3.544 g, 92% using TH; 1.811 g, 94% using US; mp 149–150 �C; IR (KBr): �v/cm�1: 3140, 3070, 3020 (C–Harom), 2980, 2931(C–Haliph), 1751, 1728 (C@Oester), 1566, 1446, 1398, 1379 (C–Carom),1294, 1197, 1095 (C–O–C); 1H NMR (500 MHz, DMSO): dppm: 1.11(3H: H11, t, J10,11 = 7.0 Hz, CH3 from OC2H5), 1.24 (3H: H14, t,J13,14 = 7.0 Hz, CH3 from OC2H5), 3.10 (2H: H9, t, J8,9 = 6.5 Hz), 4.04(2H: H10, q, J10,11 = 7.0 Hz, CH2 from OC2H5), 4.22 (2H: H13, q,J13,14 = 7.0 Hz, CH2 from OC2H5), 4.82 (2H: H8, t, J8,9 = 6.5 Hz), 5.68(2H: H12, s), 7.70 (2H: H5, H6, m), 8.06 (1H: H4, d, J4,5 = 6.5 Hz),8.18 (1H: H7, d, J6,7 = 6.5 Hz), 9.95 (1H: H2, s); 13C NMR(125 MHz, DMSO): dppm: 13.90 (C11, CH3 from OC2H5), 13.95 (C14,CH3 from OC2H5), 32.82 (C9), 42.74 (C8), 47.54 (C12), 60.54 (C10,CH2 from OC2H5), 61.99 (C13, CH2 from OC2H5), 113.92 (C7),113.97 (C4), 126.71 (C6), 126.81 (C5), 130.55 (C7a), 131.34 (C3a),144.30 (C2), 166.49 (C12a, COester), 170.17 (C9a, COester); Anal. calcd.C16H21BrN2O4: C, 49.88; H, 5.49; N, 7.27; Found: C, 49.85; H, 5.51;N, 7.26.

2.2.3.25. 1-(3-Ethoxy-3-oxopropyl)-3-(2-methoxy-2-oxoethyl)-1H-benzo[d]imidazol-3-ium bromide (50e). White crystals (from ace-tone); 3.304 g, 89% using TH; 1.708 g, 92% using US; mp 136–137 �C; IR (KBr): �v/cm�1: 3128, 3010 (C–Harom), 2980, 2956,2929, 2908 (C–Haliph), 1747, 1724 (C@Oester), 1614, 1564, 1487,1433, 1377, 1352 (C–Carom), 1273, 1220, 1203, 1186 (C–O–C); 1HNMR (500 MHz, DMSO): dppm: 1.12 (3H: H11, t, J10,11 = 7.0 Hz, CH3

from OC2H5), 3.10 (2H: H9, t, J8,9 = 6.5 Hz), 3.76 (2H: H13, s,OCH3), 4.05 (2H: H10, q, J10,11 = 7.0 Hz, CH2 from OC2H5), 4.82(2H: H8, t, J8,9 = 6.5 Hz), 5.67 (2H: H12, s), 7.86 (2H: H5, H6, m),8.06 (1H: H4, d, J4,5 = 6.0 Hz), 8.18 (1H: H7, d, J6,7 = 6.0 Hz), 9.88(1H: H2, s); 13C NMR (125 MHz, DMSO): dppm: 13.90 (C11, CH3 fromOC2H5), 32.80 (C9), 42.73 (C8), 47.44 (C12), 60.55 (C10, CH2 fromOC2H5), 52.91 (C13, OCH3), 113.92 (C7), 113.97 (C4), 126.74 (C6),126.84 (C5), 130.57 (C7a), 131.34 (C3a), 143.82 (C2), 166.99 (C12a,COester), 170.19 (C9a, COester); Anal. calcd. C15H19BrN2O4: C, 48.53;H, 5.16; N, 7.55; Found: C, 48.51; H, 5.17; N, 7.54.




2.2.3.26. 3-(2-Amino-2-oxoethyl)-1-(3-ethoxy-3-oxopropyl)-1H-benzo[d]imidazol-3-ium iodide (50f). White crystals (from acetone);3.306 g, 82% using TH; 1.774 g, 88% using US; mp 112–113 �C; IR(KBr): �v/cm�1: 3348 (N–Hamide), 3165, 3026 (C–Harom), 2983,2910 (C–Haliph), 1716 (C@Oester), 1685 (C@Oamide), 1610, 1562,1485, 1429, 1398 (C–Carom), 1286, 1222, 1188 (C–O–C); 1H NMR(500 MHz, DMSO): dppm: 1.11 (3H: H11, t, J10,11 = 7.0 Hz, CH3 fromOC2H5), 3.08 (2H: H9, t, J8,9 = 6.5 Hz), 4.05 (2H: H10, q,J10,11 = 7.0 Hz, CH2 from OC2H5), 4.78 (2H: H8, t, J8,9 = 6.5 Hz), 5.30(2H: H12, s), 7.63 (1H: Hb from NH2 group, s), 7.69 (2H: H5, H6,m), 7.96 (2H: H4, Ha from NH2 group, m), 8.14 (1H: H7, d,J6,7 = 6.5 Hz), 9.79 (1H: H2, s); 13C NMR (125 MHz, DMSO): dppm:13.93 (C11, CH3 from OC2H5), 32.85 (C9), 42.54 (C8), 48.41 (C12),60.56 (C10, CH2 from OC2H5), 113.67 (C7), 113.80 (C4), 126.54(C6), 126.70 (C5), 130.64 (C7a), 131.58 (C3a), 143.80 (C2), 166.34(C12a, COamide), 170.18 (C9a, COester); Anal. calcd. C14H18IN3O3: C,41.70; H, 4.50; N, 10.42; Found: C, 41.72; H, 4.48; N, 10.44.

2.2.3.27. 3-(2-Ethoxy-2-oxoethyl)-1-(3-methoxy-3-oxopropyl)-1H-benzo[d]imidazol-3-ium bromide (50g). White crystals (fromacetone); 3.267 g, 88% using TH; 1.689 g, 91% using US; mp 150–152 �C; IR (KBr): �v/cm�1: 3128, 3010 (C–Harom), 2980, 2933, 2901(C–Haliph), 1737 (C@Oester), 1564, 1483, 1433, 1363 (C–Carom),1261, 1207 (C–O–C); 1H NMR (500 MHz, DMSO): dppm: 1.25 (3H:H14, t, J13,14 = 7.0 Hz, CH3 from OC2H5), 3.12 (2H: H9, t,J8,9 = 6.5 Hz), 3.60 (3H: H10, s, OCH3), 4.22 (2H: H13, q,J13,14 = 7.0 Hz, CH2 from OC2H5), 4.83 (2H: H8, t, J8,9 = 6.5 Hz), 5.67(2H: H12, s), 7.70 (2H: H5, H6, m), 8.06 (1H: H4, d, J4,5 = 6.5 Hz),8.18 (1H: H7, d, J6,7 = 6.5 Hz), 9.92 (1H: H2, s); 13C NMR(125 MHz, DMSO): dppm: 13.94 (C14, CH3 from OC2H5), 32.61 (C9),42.70 (C8), 47.51 (C12), 51.79 (C10, OCH3), 61.98 (C13, CH2 fromOC2H5), 113.88 (C7), 113.95 (C4), 126.70 (C6), 126.80 (C5), 130.51(C7a), 131.34 (C3a), 143.84 (C2), 166.48 (C12a, COester), 170.64 (C9a,COester); Anal. calcd. C15H19BrN2O4: C, 48.53; H, 5.16; N, 7.55;Found: C, 48.55; H, 5.15; N, 7.53.

2.2.3.28. 3-(2-Methoxy-2-oxoethyl)-1-(3-methoxy-3-oxopropyl)-1H-benzo[d]imidazol-3-ium bromide (50h). White crystals (fromacetone); 3.072 g, 86% using TH; 1.607 g, 90% using US; mp 146–148 �C; IR (KBr): �v/cm�1: 3147, 3037 (C–Harom), 2955, 2935, 2904(C–Haliph), 1743 (C@Oester), 1612, 1570, 1487, 1431, 1373 (C–Carom),1288, 1209, 1186 (C–O–C); 1H NMR (400 MHz, DMSO): dppm: 3.11(2H: H9, t, J8,9 = 6.4 Hz), 3.61 (3H: H10, s, OCH3), 3.78 (3H: H13, s,OCH3), 4.82 (2H: H8, t, J8,9 = 6.4 Hz), 5.66 (2H: H12, s), 7.72 (2H:H5, H6, m), 8.06 (1H: H4, d, J4,5 = 6.8 Hz), 8.17 (1H: H7, d,J6,7 = 6.8 Hz), 9.84 (1H: H2, s); 13C NMR (100 MHz, DMSO): dppm:32.53 (C9), 42.66 (C8), 47.37 (C12), 51.76 (C10, OCH3), 52.88 (C13,OCH3), 113.86 (C7), 113.92 (C4), 126.70 (C6), 126.81 (C5), 130.51(C7a), 131.32 (C3a), 143.83 (C2), 166.98 (C12a, COester), 170.65 (C9a,COester); Anal. calcd. C14H17BrN2O4: C, 47.07; H, 4.80; N, 7.84;Found: C, 47.05; H, 4.78; N, 7.86.

2.2.3.29. 3-(2-Amino-2-oxoethyl)-1-(3-methoxy-3-oxopropyl)-1H-benzo[d]imidazol-3-ium iodide (50i). White crystals (from acetone);3.114 g, 80% using TH; 1.693 g, 87% using US; mp 109–110 �C; IR(KBr): �v/cm�1: 3309, 3252 (N–Hamide), 3165, 3078, 3050 (C–Harom),2943, 2908 (C–Haliph), 1726 (C@Oester), 1689 (C@Oamide), 1610,1564, 1485, 1433, 1404 (C–Carom), 1288, 1226, 1186 (C–O–C); 1HNMR (400 MHz, DMSO): dppm: 3.11 (2H: H9, t, J8,9 = 6.4 Hz), 3.62(3H: H10, s, OCH3), 4.80 (2H: H8, t, J8,9 = 6.4 Hz), 5.29 (2H: H12, s),7.64 (1H: Hb from NH2 group, s), 7.71 (2H: H5, H6, m), 7.93 (2H:H4, Ha from NH2 group, m), 8.15 (1H: H7, d, J6,7 = 6.8 Hz), 9.77(1H: H2, s); 13C NMR (100 MHz, DMSO): dppm: 33.60 (C9), 42.48(C8), 48.35 (C12), 51.76 (C10, OCH3), 113.62 (C7), 113.73 (C4),126.50 (C6), 126.65 (C5), 130.58 (C7a), 131.55 (C3a), 143.78 (C2),


166.29 (C12a, COamide), 170.62 (C9a, COester); Anal. calcd. C13H16IN3-

O3: C, 40.12; H, 4.14; N, 10.80; Found: C, 40.15; H, 4.16; N, 10.78.

2.2.3.30. 1-(3-Amino-3-oxopropyl)-3-(2-ethoxy-2-oxoethyl)-1H-benzo[d]imidazol-3-ium bromide (50j). White crystals (fromacetone); 3.420 g, 96% using TH; 1.728 g, 97% using US; mp 142–143 �C; IR (KBr): �v/cm�1: 3398, 3317 (N–Hamide), 3207, 3136,3078, 3030 (C–Harom), 2995, 2908 (C–Haliph), 1747 (C@Oester),1666 (C@Oamide), 1627, 1564, 1487, 1435, 1413, 1402 (C–Carom),1285, 1220, 1186 (C–O–C); 1H NMR (400 MHz, DMSO): dppm:1.25 (3H: H14, t, J13,14 = 6.8 Hz, CH3 from OC2H5), 2.84 (2H: H9, t,J8,9 = 6.0 Hz), 4.24 (2H: H13, q, J13,14 = 6.8 Hz, CH2 from OC2H5),4.78 (2H: H8, t, J8,9 = 6.0 Hz), 5.66 (2H: H12, s), 7.04 (1H: Hb fromNH2 group, s), 7.59 (1H: Ha from NH2 group, s), 7.71 (2H: H5, H6,m), 8.06 (1H: H4, d, J4,5 = 7.2 Hz), 8.17 (1H: H7, d, J6,7 = 7.2 Hz),9.86 (1H: H2, s); 13C NMR (100 MHz, DMSO): dppm: 13.91 (C14,CH3 from OC2H5), 33.59 (C9), 43.27 (C8), 47.43 (C12), 61.92 (C13,CH2 from OC2H5), 113.82 (C7), 113.91 (C4), 126.62 (C6), 126.73(C5), 130.46 (C7a), 131.32 (C3a), 143.72 (C2), 166.46 (C12a, COester),170.78 (C9a, COamide); Anal. calcd. C14H18BrN3O3: C, 47.20; H,5.09; N, 11.80; Found: C, 47.22; H, 5.06; N, 11.83.

2.2.3.31. 1-(3-Amino-3-oxopropyl)-3-(2-methoxy-2-oxoethyl)-1H-benzo[d]imidazol-3-ium bromide (50k). White crystals (fromacetone); 3.285 g, 96% using TH; 1.660 g, 97% using US; mp 132–134 �C; IR (KBr): �v/cm�1: 3335, 3323 (N–Hamide), 3174, 3128,3057, 3024 (C–Harom), 2953, 2904 (C–Haliph), 1743 (C@Oester),1672 (C@Oamide), 1620, 1562, 1485, 1446, 1408 (C–Carom), 1280,1250, 1224, 1188 (C–O–C); 1H NMR (400 MHz, DMSO): dppm:2.84 (2H: H9, t, J8,9 = 6.4 Hz), 3.77 (3H: H13, s, OCH3), 4.78 (2H:H8, t, J8,9 = 6.4 Hz), 5.67 (2H: H12, s), 7.05 (1H: Hb from NH2 group,s), 7.58 (1H: Ha from NH2 group, s), 7.71 (2H: H5, H6, m), 8.06 (1H:H4, d, J4,5 = 6.8 Hz), 8.16 (1H: H7, d, J6,7 = 6.8 Hz), 9.84 (1H: H2, s);13C NMR (100 MHz, DMSO): dppm: 33.58 (C9), 43.28 (C8), 47.36(C12), 52.85 (C13, OCH3), 113.83 (C7), 113.93 (C4), 126.64 (C6),126.75 (C5), 130.47 (C7a), 131.31 (C3a), 143.72 (C2), 166.96 (C12a,COester), 170.78 (C9a, COamide); Anal. calcd. C13H16BrN3O3: C,45.63; H, 4.71; N, 12.28; Found: C, 45.61; H, 4.74; N, 12.31.

2.2.3.32. 3-(2-Amino-2-oxoethyl)-1-(3-amino-3-oxopropyl)-1H-benzo[d]imidazol-3-ium iodide (50l). White crystals (from acetone);3.555 g, 95% using TH; 1.777 g, 95% using US; mp 107–108 �C; IR(KBr): �v/cm�1: 3377, 3309, 3248 (N–Hamide), 3173, 3140, 3086,3022 (C–Harom), 2980, 2943 (C–Haliph), 1693, 1672 (C@Oamide),1610, 1560, 1458, 1410 (C–Carom); 1H NMR (500 MHz, DMSO):dppm: 2.81 (2H: H9, s), 4.74 (2H: H8, s), 5.28 (2H: H12, s), 7.03(1H: Hb from NH2 group from 13th position, s), 7.48 (1H: Ha fromNH2 group from 13th position, s), 7.65 (3H: H5, H6, Hb from NH2

group from 10th position, m), 7.92 (2H: H4, Ha from NH2 groupfrom 10th position, m), 8.12 (1H: H7, s), 9.73 (1H: H2, s); 13CNMR (125 MHz, DMSO): dppm: 33.62 (C9), 43.10 (C8), 48.34 (C12),113.68 (C7), 113.74 (C4), 126.48 (C6), 126.65 (C5), 130.60 (C7a),131.61 (C3a), 143.72 (C2), 166.34 (C12a, COamide), 170.82 (C9a,COamide); Anal. calcd. C12H15IN4O2: C, 38.52; H, 4.04; N, 14.97;Found: C, 38.50; H, 4.01; N, 15.01.

3. Results and discussion

3.1. N1-alkylation of imidazole and benzimidazole

Some preliminary aspects concerning the synthesis of a series ofimidazolium salts have been reported previously by our group[31,32]. The strategy adopted in referenced works, involving theN-alkylation of the acidic nitrogen of the imidazole derivatives(imidazole 1 and benzimidazole 10) via Michael addition to acidderivatives (acrylonitrile 2a and ethyl acrylate 2b) was also



N

NH

imidazole - 1,benzimidazole - 1'

Z toluene, Et3N

2a Z= -CN,2b Z= -COOEt,2c Z= -COOMe,2d Z= -CONH2

N

N

Z

imidazolederivatives :3a Z= -CN,3b Z= -COOEt,3c Z= -COOMe,3d Z= -CONH2

benzimidazolederivatives:3a' Z= -CN,3b' Z= -COOEt,3c' Z= -COOMe,3d' Z= -CONH2

Scheme 2. N1-alkylation of imidazole (1) and benzimidazole (10), with acrylic acid derivatives (2a-d).

Table 3Synthesis of N1-alkylated imidazole derivatives.

Compound Conventional TH Ultrasounds

Reaction time(hour)

Yield(%)

Reaction time(hour)

Yield(%)

3a 26 97 2 973b 26 98 2 983c 26 96 2 973d 26 95 2 9630a 36 95 3 9230b 36 96 3 9230c 36 97 3 9330d 36 94 3 90


employed here using methyl acrylate 2c and acrylamide 2d, asshown in Scheme 2.

This reaction requires boiling at high temperature in a rathertoxic solvent (toluene) using small amounts of triethylamine ascatalyst. Other solvents were also tested with unsatisfactoryresults. Table 3 lists the optimized conditions we employed forthe N1-alkylation reactions.

The N1-alkylation occurs in very good yields under conven-tional TH, the major drawback being the higher reaction time.Therefore, all the reactions were also performed under US irradia-tion. The instrumentation used allowed us to control the pulsesequence, as well as the amplitude (mean percent of the nominalpower) and the irradiation time. All these parameters are expectedto influence the reaction. In our attempt to find the best operatingparameters, we monitored by GC–MS the reaction of imidazole (1)and benzimidazole (10) with acrylonitrile (2a) in toluene. In thecase of the imidazole the reaction was completed after 2 h of irra-diation using 80% of the instrument nominal power. Surprisingly,using the same conditions, in the case of the benzimidazole onlystarting materials left have been obtained and no formation ofthe desired product was observed. Similar results were obtainedunder US irradiation in isopropyl alcohol irrespective of the reac-tion time and even when heated near the boiling point, the latersolvent being used to overcome the solubility issues of benzimid-azole in toluene. That makes the method energetically inefficient

Et3N N

N

+

TH

Et3N+

US

H

N

NH

US

N

N

I

II

N

N H2C CH

Z

Scheme 3. Considerations on the reaction mechanism


and hence inappropriate for the synthesis of benzimidazole saltsby N1-alkylation.

3.2. Reaction mechanism consideration

US vs. THA possible explanation for the different behavior ofimidazole and benzimidazole derivatives observed should relateto the different acidity of the hydrogen atom from the 1-st nitrogenin the two heterocycles, resulting in a different reaction mecha-nism involved under US (radical addition) compared to TH (nucle-ophilic addition). The acidity of the first hydrogen atom frombenzimidazole (pKa = 12.8) is much higher than the acidity of thesame hydrogen atom from imidazole (pKa = 14.5), due to electronwithdrawing effect exerted by the condensed benzene ringattached to imidazole. In the case of TH conditions, assuming anucleophilic addition of imidazolate anion to double bond fromZ-alkene, the formation of reaction intermediate (imidazolateanion, I, Scheme 3) is favored via a heterolytic cleavage of N1–Hbond yielding the desired product. In contrast, a radical additionmechanism that is expected to be favored under US irradiationand relays on the homolytic cleavage of N1–H bond will be inhib-ited by the higher stability of imidazolate anion compared to thecorresponding radical. Inhibiting the formation of imidazolateradical II (Scheme 3), the initial step of the addition, would affectoverall the reaction assumed to occur by radical mechanism andhence explain the experimental observations.

In order to prove the radical mechanism for the N1-alkylationreactions under US irradiation, we performed the reaction in thepresence of a radical scavenger, TEMPO in 1.5:1 ratio to the imid-azole derivative according to the literature data [35]. Consideringthat even in the presence of TEMPO, after two hours of US irradia-tion, GC–MS results show 12% conversion of the imidazole to thedesired product, the nucleophilic addition pathway may not betotally excluded under ultrasound irradiation. Hence, a further stepwas to perform the N1-alkylation of benzimidazole in DMF. Wefound that the reaction takes place in 3 h with yields comparableto those obtained under thermal heating conditions. The bestresults obtained are presented in Table 3.

Concerning the efficiency of US irradiation in the N1-alkylationreaction of imidazole we presume that this efficiency was due to

N

N

Z

Et3N HN

NH2C CH

Z

for N1-alkylation of benzimidazole: US vs. TH.



Ximidazolesalts :5a Z= -CN, X= -Br, Y= -OEt5b Z= -CN X= -Br, Y= -OMe5c Z= -CN, X= -I, Y= -NH25d Z= -COOEt, X= -Br, Y= -OEt5e Z= -COOEt, X= -Br, Y= -OMe5f Z= -COOEt, X= -I, Y= -NH25g Z= -COOMe, X= -Br, Y= -OEt5h Z= -COOMe, X= -Br, Y= -OMe5i Z= -COOMe, X= -I, Y= -NH25j Z= -CONH2

, X= -Br, Y= -OEt5k Z= -CONH2

, X= -Br, Y= -OMe5l Z= -CONH2

, X= -I, Y= -NH2

3, 3'

benzimidazolesalts :5a' Z= -CN, X= -Br, Y= -OEt5b' Z= -CN X= -Br, Y= -OMe5c' Z= -CN, X= -I, Y= -NH25d' Z= -COOEt, X= -Br, Y= -OEt5e' Z= -COOEt, X= -Br, Y= -OMe5f' Z= -COOEt, X= -I, Y= -NH25g' Z= -COOMe, X= -Br, Y= -OEt5h' Z= -COOMe, X= -Br, Y= -OMe5i' Z= -COOMe, X= -I, Y= -NH25'j Z= -CONH2

, X= -Br, Y= -OEt5'k Z= -CONH2

, X= -Br, Y= -OMe5'l Z= -CONH2

, X= -I, Y= -NH2

N

N

Z

XCO

Y4a X= -Br, Y= -OEt4b X= -Br, Y= -OMe4c X= -I, Y= -NH2

N

N

CO

Y

Z

Scheme 4. Quaternization of the N1-alkylated imidazole derivatives (3a-d, 30a-d) with ethyl 2-bromoacetate (4a), methyl 2-bromoacetate (4b) and 2-iodoacetamide (4c).

Table 5Synthesis of imidazolium salts under TH and US conditions.

Compound Meltingpoint (�C)

Conventional TH Ultrasounds

Reactiontime (h)

Yield(%)

Reactiontime (h)

Yield(%)

5a <30 36 85 0.66 965b 129–130 36 82 0.66 925c 164–166 36 78 0.66 905d <30 36 94 0.66 955e <30 36 96 0.66 965f 111–113 36 91 0.66 93


the cavitation, a better homogenization of the reaction mixture andan enhanced mass transfer.

3.3. Quaternization of imidazole and benzimidazole derivatives

In the second stage of our approach, the quaternization(N3-alkylation) of the second nitrogen atom from imidazolederivatives (3a-d, 30a-d) was performed with ethyl (4a) or methylbromoacetate (4b) and iodoacetamide (4c) respectively, as shownin Scheme 4.

Since the quaternization of N1-alkylated imidazole derivativesunder conventional TH condition requires longer reaction times[31,32], we tried to increase the reaction rate and reduce the reac-tion time by performing this reaction under ultrasound irradiationin a double walls reaction vessel which permit the temperaturecontrol by circulating a cooled liquid.

The reaction of imidazole derivatives 3b and 30b with methylbromoacetate was monitored by GC–MS. In order to optimize thereaction conditions, a screening was performed with respect tovarious experimental condition expected to influence the reactiontime (irradiation amplitude, pulse sequence and the temperatureof the cooling liquid), the employed conditions being listed inTable 4.

As we may notice reaction times listed in Table 4, following theconditions employed, suggest the occurrence of different reactionspathways depending on the nature of the heterocycle. In the caseof imidazole derivative the variation of the reaction conditionshas no significant influence over the reaction time, the imidazolederivatives being reactive enough for the reaction with methylbromoacetate to complete in one hour even at �4 �C. When thetemperature was increased at 20 �C the reaction time decreasedto 40 min. Benzimidazole derivative shows a decreased reactivitycomparing with the corresponding imidazole, the quaternizationrequiring higher temperatures and longer reaction times. Attemperatures lower than 5 �C, the quaternization reaction of benz-imidazole derivative requires more than 4 h to complete, at 10 �Cthe reaction completes in 3 h, while at 20 �C took 2 h. Since theN3-alkylation reaction takes place in acetone (boiling point 56 �C)

Table 4Quaternization of the N1-alkylated imidazole derivatives under US irradiation.Screening for optimal reaction conditions.

Compound Instrumentamplitude (%)

Pulse on/pulse off (s/s)

Temperature(�C)

Reactiontime (min)

5e 60 5/5 �4 6050e 60 5/5 �4 >2405e 100 6/4 �4 6050e 100 6/4 �4 >2405e 100 5/5 5 6050e 100 5/5 5 >2405e 100 5/5 10 6050e 100 5/5 10 1805e 100 5/5 20 4050e 100 5/5 20 120


we did not raise the temperature above 20 �C to prevent acetoneevaporation. Having established the optimal reaction condition,we extended this reaction to all previously obtained imidazolederivatives 3a-d and benzimidazole derivatives 30a-d with methyland ethyl bromoacetate and iodoacetamide. The results are pre-sented comparatively (TH versus US irradiation) in Table 5.

In Table 5 we present the best results obtained under US irradi-ation the N3-alkylation reactions are remarkable accelerated, thereaction times decreasing from 36 h to 40 min in the case of theimidazolium salts 5a-l, and from 48 h to 120 min in the case ofthe benzoimidazolium salts 50a-l. We may also notice that underUS irradiation the yields were slightly higher (by 1–7%) and theamount of used solvents was two times less. Consequently, theN3-alkylation reaction under US irradiation could be consideredenvironmentally friendly. An appropriate explanation for the sig-nificant increase of reaction time in the case of benzoimidazolederivatives (in both cases US irradiation and TH), could be relatedto the reactivity: benzoimidazole derivatives have lower reactivitythan imidazole derivatives due to a decrease in the basicity.

Concerning the efficiency of US irradiation in the quaternizationreaction of 1,3-diazole derivatives, we presume that this efficiencywas due to the cavitation, the energy being more efficientlytransmitted to the substrates compared to the reactions performedunder conventional conditions. Also, the collapse of bubblesinduces mechanical stress that could be transmitted to a targetsingle bond, this phenomena being specific to ultrasound action.

5g <30 36 95 0.66 965h <30 36 92 0.66 945i 123–125 36 90 0.66 945j <30 36 95 0.66 965k <30 36 95 0.66 955l 130–132 36 92 0.66 9450a 157–158 48 86 2 9050b 161–163 48 80 2 8750c 167–169 48 88 2 9150d 149–150 48 92 2 9450e 136–137 48 89 2 9250f 112–113 48 82 2 8850g 150–152 48 88 2 9150h 146–148 48 86 2 9050i 109–110 48 80 2 8750j 142–143 48 96 2 9750k 132–134 48 96 2 9750l 107–108 48 95 2 95




Some of the obtained imidazolium salts have melting pointlower than 30 �C and can be considered ionic liquids [21]. Asshown in a previous work [34], one of the synthesized imidazoliumsalts, 5h, was tested as ionic liquid for several cellulosic materials,proving excellent ionic liquid properties. Having in view the struc-tural similarities of other imidazole derivatives, these resultsencourage us to claim that our imidazole will have similar ionicliquid properties, which increases substantially the value of theresults presented within this work.

4. Conclusion

The synthesis of 1,3-diazole derivatives was performed bothunder ultrasound (US) irradiation and under conventional thermalheating (TH). N-alkylation of the imidazole under US gives slightlyhigher yields. In addition, the amount of solvent needed was abouttwo times less compared with conventional TH, whereas the reac-tion times reduce from hours or even days to minutes. Taking intoconsideration these advantages the N-alkylation methods could beconsidered environmentally friendly. Overall, the use of US provedto be more efficient than TH, the efficiency of the former in theN-alkylation reaction of 1,3-diazole being assigned to cavitationeffects. The different behavior of imidazole and benzimidazole inthe N1-alkylation reactions under US irradiation should relate tothe different acidity of the hydrogen atom from the 1-st nitrogenin the two heterocycles and also to their different solubilities.Some of the melting points of the synthesized imidazolium saltsbeing lower than 30 �C encourage us to claim that these com-pounds could be considered ionic liquids.

Acknowledgements

Authors are thankful to CNCS Bucharest, Romania, projectPN-II-TE/0010-79/05.10.2011 (director lect. dr. Costel Moldov-eanu) for financial support and the POSCCE-O 2.2.1, SMIS-CSNR13984-901, No. 257/28.09.2010 Project, CERNESIM, for the NMRexperiments.

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ultrasound assisted synthesis of imidazolium salts: an efficient way to ionic liquids

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