Multicomponent green synthesis, spectroscopic and structural investigation of multi-substituted imidazoles. Part 1

2.1 Synthetic procedures

In order to determine the most appropriate reaction conditions and to evaluate the catalytic efficiency of the ionic liquid diethyl ammonium hydrogen sulfate (DEAHS) [53], an initial model study was carried out on the synthesis of 1,2,4,5-tetrasubstituted imidazoles. Among the tested solvents were methanol, ethanol, DMF and DMSO; a solvent-free system was also investigated. Condensation of benzil, benzaldehyde, ethanolamine, and ammonium acetate to form 2-(2,4,5-triphenyl-1H-imidazol-1-yl)ethanol (2a) was found to be significantly more facile under solvent-free conditions and proceeded to give the highest yield in a relatively very short time, Table 1.

Additionally, we sought to evaluate the generality of this process for the synthesis of a broad range of derivatives with a variety of substituents on the phenyl ring at the 2-position of the imidazole ring, Scheme 1. Thus, reactions of benzil (10 mmol), with various aromatic aldehydes (10 mmol) bearing electron releasing groups (such as hydroxyl, mono- and di-methoxy, or dimethyl amino substituents), ethanolamine (11 mmol) and ammonium acetate (10 mmol), were carried out in the presence of diethylammonium hydrogen sulfate (0.5 g, 3 mmol) as catalyst (Table 1). The yields of all the products so obtained were very good to excellent. Furthermore, the reactions proceeded without the formation of any side products, such as 2,4,5-trisubstituted imidazoles, which are normally observed as an impediment to efficient synthesis under the influence of other strong acids [19, 20]. An earlier report of the preparation of (2a) used a similar preparative route, but with l-proline triflate as the catalyst [54].

The yield and reaction time for the formation of 2a has been recorded using different catalysts as listed in Table 2 and the results represented graphically in Fig. 1. While it is obvious that reaction temperatures will have a significant effect on reaction times, the data in Table 1 clearly confirm that DEAHS is indeed a highly efficient catalyst in terms of both yield and reaction time when compared to other type of catalysts that have been used.

Fig. 1:

Dependence of the yield and time of reaction on the catalyst type.

Hydrogen bond formation between the carbonyl group of the starting aldehyde and the catalyst DEAHS makes the carbonyl very susceptible to nucleophilic attack by an ammonia molecule generated from the ammonium acetate starting material. The resulting intermediate readily loses a water molecule to produce the imine I (Scheme 2). Similarly the catalyst promotes an additional condensation reaction of one of the carbonyl groups from benzil with the aminoethanol reactant to furnish the imine II. DEAHS also catalyzes nucleophilic attack by the imine I on the second carbonyl group in imine II followed by protonation to form the intermediate cation III. This in turn undergoes an intramolecular cyclization to give the unstable cyclic cation IV which eliminates water and then loses a proton to yield the target products 2a–2j. All products were fully characterized by spectroscopic methods such as IR, ¹H NMR, ¹³C NMR and the structures of 2a, 2c and 2j were determined by X-ray crystallography (see below).

Scheme 2:

General mechanism for the multi-component synthesis.

2.2 Spectroscopic properties

The IR spectra of all of the compounds showed definitive broad bands in the frequency range 3568–3144 cm^–1 for the OH stretching vibration of the ethanolic OH groups of all nine compounds. The phenolic OH stretches for 2b and 2c could not be distinguished separately from these vibrations. In addition, C–H stretching modes were found in the range 3084–3053 cm^–1 while the C=N stretching mode of the imidazole unit was observed in a relatively narrow range 1601–1603 cm^–1 for 2a–2h with the corresponding vibration for the dimethylamino substituted derivative 2i appearing at 1610 cm^–1 while that for the 4-nitro derivative 2j appeared at 1595 cm^–1. The stretching vibrations of the nitro group of 2j were observed at 1537 cm^–1 (asymmetrical) and 1338 cm^–1 (symmetrical). Clearly the nature of the substituent on the 2-benzene ring has a noticeable effect on the vibrational spectra.

2.3 Molecular and crystal structures of 2a, 2c and 2j

The molecular structures of the three compounds investigated by X-ray crystallography are shown in Fig. 2 (i–iii). The broad features of the three structures are sufficiently similar to be discussed together. Each molecule comprises a central imidazole ring substituted at N1 with a CH₂CH₂OH unit which generally lies almost orthogonal to the imidazole ring, Table 3. The imidazole ring also carries an aromatic ring on each C atom with a substituted benzene ring on the C2 carbon atom for all but 2a and simple phenyl substituents on C4 and C5. The relative inclinations of these benzene rings to the central imidazole ring are also detailed in Table 3 which clearly shows that the benzene and imidazole rings are not co-planar in any of the molecules.

Fig. 2:

The molecular structures of (i) 2a; (ii) 2c; (iii) the two unique molecules in the asymmetric unit of 2j (crystallographic atom numbering and displacement ellipsoids drawn at the 50% probability level; H atoms as spheres with arbitrary radii).

The C2 benzene ring substituents differentiate the three molecules, starting with the prototypical compound 2a with a simple phenyl ring in the 2-position. 4-Hydroxy substitution is found in the C2 benzene ring of 2b, while 2j has a nitro substituent at the 4-position of the C21…C26 benzene rings of each of the two unique molecules. These are distinguished in the atom numbering by leading 1 and 2 characters; the two molecules differ principally in the inclination of the benzene rings at C2, C4 and C5 relative to the imidazole ring, (vide supra, Table 3). Also for 2j, the planes of the nitro groups are inclined at 12.52(11)° for molecule 1 and 4.3(3)° for molecule 2 to the planes of the benzene ring to which they are bound.

4.1 Synthesis of diethyl ammonium hydrogen sulfate (DEAHS)

Diethylamine (22.2 g, 0.3 mol) was added into a 250 mL three-necked flask with a magnetic stirrer. Then 29.4 g (0.3 mol) concentrated sulfuric acid (98%) was slowly added dropwise to the flask at room temperature then heated to 80°C for 12 h. The product was washed with diethyl ether three times to remove traces of non-ionic material. The residue was dried under vacuum using a rotary evaporator to obtain the clear viscous product, diethyl ammonium hydrogen sulfate. Yield 98%, pH 1.6 [53].

4.2 General method for the synthesis of 1,2,4,5-tetrasubstituted imidazoles

Benzil (10 mmol), an aldehyde (1a–1j) (10 mmol), ammonium acetate (10 mmol) and ethanolamine (11 mmol) were added to diethylammonium hydrogen sulfate (0.5 g, 3 mmol) in an oil bath at room temperature. The resulting mixtures were heated to 100°C for the time reported in Table 4. Reaction progress was monitored by TLC until completion after 15–35 min. The reaction mixtures were washed with water and the resulting solid products were purified in all cases by recrystallization from ethanol.

4.3 Spectroscopic properties of 2a–2j

4.4 X-ray structure determinations

Crystallographic data for 2a, 2c, and 2j are detailed in Table 5. Diffraction data for 2a were collected at Baku Estate University on a Bruker APEXII CCD diffractometer using graphite-monochromatized MoK_α radiation (λ=0.71073 Å). Data for 2c and 2j were obtained at the University of Otago on an Agilent SuperNova (Dual, Cu at zero, Atlas) diffractometer using a mirror monochromator and CuK_α radiation (λ=1.54184 Å). The Bruker data collection was controlled by Apex2 [60] software with cell refinement and data reduction performed using Saint [60]. Multi-scan absorption corrections were applied using Sadabs [61]. For 2c and 2j these processes were all controlled by CrysAlisPro [62]. The structures were all solved with Shelxs [63] and refined by full-matrix least-squares on F² using Shelxl-2014 [64] and Titan2000 [65]. All non-hydrogen atoms were assigned anisotropic displacement parameters. The H atoms of the hydroxyl groups for all three molecules were located in difference Fourier maps and their coordinates refined with atomic displacement parameters set to 1.5×U_eq(O). All other H atoms were positioned geometrically and refined using a riding model with d(C–H)=0.95 Å for aromatic and 0.99 Å for CH₂ with U_iso=1.2×U_eq(C) and 0.98 Å, U_iso=1.5×U_eq(C) for CH₃ atoms. All molecular plots and packing diagrams were drawn using Mercury [66]. Other calculations were performed using Platon [67] and tabular material was produced using WinGX [68].

CCDC 1024500 (2a) 1024501 (2b) and 1024505 (2j) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data_request/cif.