An experimental dynamic NMR study of 2-(aryl)-4,5-diphenyl-1H-imidazoles in solution: the evaluation of NH behavior in terms of proton transfer and tautomerism and its application on detecting of special protons and carbons of trisubstituted imidazoles

doi:10.21203/rs.3.rs-2496242/v1

Download PDF

Research Article

An experimental dynamic NMR study of 2-(aryl)-4,5-diphenyl-1H-imidazoles in solution: the evaluation of NH behavior in terms of proton transfer and tautomerism and its application on detecting of special protons and carbons of trisubstituted imidazoles

https://doi.org/10.21203/rs.3.rs-2496242/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

The proof of the tautomerism phenomenon and the exchange of protons bounded to nitrogen and oxygen is possible by evaluating the rate of proton exchange and factors that effect on it. For 2-(aryl)-4,5-diphenyl-1H-imidazoles, scrutiny of proton transfers and tautomerism is possible by evaluation of their proton and carbon spectra. This paper reports results of the studies on ¹H and ¹³C NMR spectra of 2-(aryl)-4,5-diphenyl-1H-imidazoles in solution. We have investigated the dynamic NMR of these compounds based on concentration and introduce a way instead of TOCSY technique for detecting the overlapped signals of protons and carbons of aryl substituent which located in position 2 of imidazole ring.

Dynamic NMR

Proton transfer

Tautomerism

Trisubstituted imidazole

TOCSY

Dynamic NMR is the NMR spectroscopy of samples that undergo physical or chemical changes with time. The timescales studied can be from picoseconds to centuries and the techniques used for their study depend on the timescale. NMR can be used to determine the equilibrium and the rate constants which can be used to calculate the dynamic parameters of the system [1]. Rotation about the C-C single bonds, rotation about partial double bonds, inversion at nitrogen and phosphorus atoms, ring inversions, valence tautomerism, keto-enol tautomerism, intermolecular proton exchange and reactions and equilibrium processes are the cases that can be evaluated by dynamic NMR studies [2]. In 1985, M. Oki published a textbook about applications of dynamic NMR spectroscopy to organic chemistry [3]. After that, researchers turned to the dynamic NMR studies and a variety of experimental and theoretical methods was reported [4–12]. Nowadays, dynamic NMR have been also used in distance degree vector and scalar sequences of corona and lexicographic products of graphs [13], sedimentary rock cores [14], paramagnetic properties [15], intact bodies and heterogeneous systems [16] and drug design [17].

1H-1H TOCSY (TOtal Correlation SpectroscopY also known as HOHAHA (HOmonuclear HArtmann HAhn) is useful for dividing the proton signals into groups or coupling networks, especially when the multiplets overlap (have very similar chemical shifts) or there is extensive second order coupling [18]. TOCSY is usually used in large molecules with many separated coupling networks such as peptides, proteins, oligosaccharides and polysaccharides [19]. If an indication of the number of bonds connecting the protons is required, for example in order to determine the order in which they are connected, a COSY spectrum is preferable [20].

Imidazole is a planar 5-membered aromatic ring. It exists in two equivalent tautomeric forms, because hydrogen atom can be located on either of the two nitrogen atoms [21–23]. Imidazole is a highly polar compound, as evidenced by its electric dipole moment of 3.67D [24]. In the ¹H NMR spectrum of imidazole in dilute solution, a triplet at δ = 7.47 ppm (one proton) related to H₂ and a doublet at δ = 7.70 ppm (two protons) related to H₄ and H₅ with ⁴J_HH =1 Hz are observed. Due to the rapid exchange of N-H, H₄ and H₅ protons are magnetically equal and there is no spin-spin splitting by H₁ in them. The absorption of the N-H proton is broad and only in the concentrated solution of imidazole in benzene, acetone or chloroform appears in the strong field (δ < 1ppm) [25, 26].

Many of nitrogen heterocycles are appropriate cases for dynamic NMR studies. There are reports for 3-methyl-1-phenylpyrazolin-5-one [27], adenine [28], ethenoadenosine [29], N-heterocyclic hydrazones [30], 3-Methyl-1H-pyrazole [31], 2,6-bis(20-pyridyl)-4-hydroxypyridine [32] and 2,6-bis(20-pyridyl)-4-pyridone [32], 2-phenacylpyridine [33], 2-phenacylquinoline [34], 2-(4-pyrrolidinylcinnamoylmethyl)quinolone [35],1,4-di(pyridin-2-yl)buta-1,3-diene-2,3-diol [36] and dimethyl ester of bonellin [37]. In this paper by providing a conclusive evidence, we prove that proton transfer in imidazole molecules is not occurred in dilute and concentrated solutions unless there is a trace amount of protonated solvent, especially water in the solution. When the protonated solvent reaches a certain level (which depends on the pH value of the imidazole derivative), the proton exchange starts, and with dilution of the solution, the exchange rate is increased (Scheme 1).

Materials and apparatus

Chemicals such as 1-2-diketones, ammonium acetate, aldehyde derivatives, chlorosulfonic acid, kaolin nanoparticles, ethanol and acetone were purchased from Fluca, Merck and Aldrich chemical companies. Some of the products are known compounds characterized by comparison of their spectral data (¹H-NMR, IR), TLC and physical data with authentic samples. New products were characterized also by CHN analysis. ¹H and ¹³C NMR spectra were recorded on a Avance BRUKER (DRX- 400 MHz) in acetone-d₆ or DMSO- d₆ as solvent. UV-Vis spectra were taken by a double beam Perkin-Elmer 550S spectrophotometer in the range of 200–400 nm, using acetone as the solvent. IR spectra were determined on a Nicolet Magna series FTIR 550 spectrometer using KBr pellets. The elemental analyses (C, H, N) were obtained from a Carlo ERBA Model EA 1108 analyzer carried out on a Perkin–Elmer 240c analyzer. Thin layer chromatography (TLC) on commercial aluminium-backed plates of silicagel 60 F₂₅₄ was used to monitor the progress of the reactions.

Preparation of 2,4,5- trisubstituted imidazoles

2-(aryl)-4,5-diphenyl-1H-imidazole derivatives obtained via the procedure described in our previous work through three component reaction of aromatic aldehyde (1mmol), 1,2-diketone (1mmol), ammonium acetate (6mmol) and optimized amount of kaolin sulfonic acid (0.055) as a solid catalyst under conventional heating condition in the absence of solvent (Scheme 2) [38]. In the fallowing, the physical and spectral data of the products are presented.

Spectral data

2,4,5-triphenyl-1H-imidazole (lophine) (1): white solid. mp/°C: 273–275 (Lit. 275–276 [39]). λ_max (CHCl₃)/nm: 338 (π→π^*), 212 (n→π^*). ῡ_max (KBr)/cm^− 1: 3430 (N-H), 3050 (= C-H), 1600 − 1400 (C = C and C = N), 768 and 699 (= C-H bending OOP of monosubstituted phenyl rings). ¹H NMR in low concentration (Acetone-d₆)/ppm: δ_H = 11.75 (1H, s, NH), 8.2 (2H, d, ³J_HH = 7.6Hz), 7.6 (4H, d, ³J_HH = 7.2Hz), 7.48(2H, “t”, ³J_HH = 7.2Hz), 7.42–7.25(7H, m). ¹³C NMR in low concentration (DMSO-d₆)/ppm: δ_C = 145.98, 136.00, 130.79, 129.15, 129.00, 128.95, 128.88, 128.73, 127.64, 125.66.

2-(4-methyl-phenyl)-4,5-diphenyl-1H-imidazole (2): white solid. mp/°C: 229–231 (Lit. 230–233 [40]). λ_max (Acetone)/nm: 338 (π→π^*), 212 (n→π^*). ῡ_max (KBr)/cm^− 1: 3420 (N-H), 3028 (= C-H), 2863 (-C-H), 1600 − 1400 (C = C and C = N), 1384 (CH₃ bending), 824 (= C-H bending OOP of parasubstituted phenyl ring), 767 and 696 (= C-H bending OOP of monosubstituted phenyl rings). ¹H NMR in high concentration (Acetone-d₆)/ppm: δ_H = 11.66 (1H, s, NH), 8.018 (2H, d, ³J_HH = 8.4Hz), 7.65 (2H, d, ³J_HH = 7.6Hz), 7.56 (2H, d, ³J_HH = 7.6Hz), 7.45–7.2 (8H, m), 2.385 (3H, s). ¹³C NMR in low concentration (Acetone-d₆)/ppm: δ_C = 163.52, 150.41, 145.91, 142.41, 130.62, 129.42, 129.03, 122.48, 120.21, 119.50, 20.52.

2-(4-methoxy-phenyl)-4,5-diphenyl-1H-imidazole (3): white solid. mp/°C: 231–233 (Lit. 230–231 [41]). λ_max (CHCl₃)/nm: 343 (π→π^*), 218 (n→π^*). ῡ_max (KBr)/cm^− 1: 3420 (N-H), 3057 (= C-H), 2839 (-C-H), 1611 − 1400 (C = C and C = N), 1384 (CH₃ bending), 1266 and 1027 (ArC-OCH₃), 824 (= C-H bending OOP of parasubstituted phenyl ring), 767 and 696 (= C-H bending OOP of monosubstituted phenyl rings). ¹H NMR in low concentration (Acetone-d₆)/ppm: δ_H = 11.66 (1H, s, NH), 8.018 (2H, d, ³J_HH = 8.8Hz), 7.6 (2H, d, ³J_HH = 6.8Hz), 7.35 (2H, “t”, ³J_HH = 6.8Hz), 7.28 (2H, “t”, ³J_HH = 6.8Hz), 6.93 (2H, d, ³J_HH = 8.8Hz), 3.85 (3H, s). ¹³C NMR in high concentration (Acetone-d₆)/ppm: δ_C = 169.75, 160.10, 146.02, 133.80, 133,70, 133.25, 129.35, 129.17, 128.29, 127.85, 126.96, 126.74, 123.51, 114.01, 113.65, 54.78.

2-(4-chloro-phenyl)-4,5-diphenyl-1H-imidazole (4): white solid. mp/°C: 262–264 (Lit. 260–262 [42]). λ_max (CHCl₃)/nm: 343 (π→π^*), 218 (n→π^*). ῡ_max (KBr)/cm^− 1: 3425 (N-H), 3063 (= C-H), 1602 − 1400 (C = C and C = N), 729 (C-Cl), 832 (= C-H bending OOP of parasubstituted phenyl ring), 766 and 696 (= C-H bending OOP of monosubstituted phenyl rings). ¹H NMR in low concentration (Acetone-d₆)/ppm: δ_H = 11.77 (1H, s, NH), 8.15 (2H, d, ³J_HH = 7.6Hz), 7.731 (2H, d, ³J_HH = 7.2Hz), 7.55 (2H, d, ³J_HH = 7.6Hz), 7.4–7.25 (6H, m). ¹³C NMR in low concentration (DMSO-d₆)/ppm: δ_C = 144.89, 133.22, 129.65, 129.25, 128.94, 128.92, 128.90, 128.88, 128.86 127.31.

2-(4-N,N-dimethylamino)-4,5-diphenyl-1H-imidazole (5): white solid. mp/°C: 257–259 (Lit. 259–262 [40]). λ_max (Acetone)/nm: 338 (π→π^*), 225 (n→π^*). ῡ_max (KBr)/cm^− 1: 3422 (N-H), 3034 (= C-H), 2882 (-C-H), 1613 − 1400 (C = C and C = N), 1359 (CH₃ bending), 1200 (C-N), 819 (= C-H bending OOP of parasubstituted phenyl ring), 767 and 696 (= C-H bending OOP of monosubstituted phenyl rings) .¹H NMR in low concentration (Acetone-d₆)/ppm: δ_H = 13 − 9 (1H,s, NH), 8.00 (2H, d, ³J_HH = 9.2Hz), 7.6 (4H, d, ³J_HH = 7.2Hz), 7.35 (4H, “t”, ³J_HH = 7.2Hz), 7.275 (2H, “t”, ³J_HH = 7.2Hz), 6.80 (2H, d, ³J_HH = 9.2Hz), 3.00 (6H, s). ¹³C NMR in low concentration (Acetone-d₆)/ppm: δ_C = 150.76, 146.86, 134.01, 131.20, 128.22, 127.79, 126.75, 126.31, 118.90, 119.99, 39.52.

2-(4-hydroxy)-4,5-diphenyl-1H-imidazole (6): white solid. mp/°C: 265–267 (Lit. 265–267 [43]). λ_max (Acetone)/nm: 318 (π→π^*), 218 (n→π^*). ῡ_max (KBr)/cm^− 1: 3422 (N-H and O-H), 3032 (= C-H), 1608 − 1400 (C = C and C = N), 1240 (Ar-O), 837 (= C-H bending OOP of parasubstituted phenyl ring), 768 and 697 (= C-H bending OOP of monosubstituted phenyl rings). ¹H NMR in high concentration (Acetone-d₆)/ppm: δ_H = 12.40 (1H, s, NH), 9.71 (1H, s, OH), 8.88 (2H, d, ³J_HH = 8.8Hz), 7.6–7.1 (10H, m), 6.83 (2H, d, ³J_HH = 8.8Hz). ¹³C NMR in low concentration (Acetone-d₆)/ppm: δ_C = 159.61, 135.14, 132.98, 129.61, 129.30, 128.55, 127.91, 126.24, 107.00, 103.36.

2-(4-isopropyl)-4,5-diphenyl-1H-imidazole (7): white solid. mp/°C: 252–253 (Lit. 253–255 [44]). λ_max (Acetone)/nm: 337 (π→π^*), 216 (n→π^*). ῡ_max (KBr)/cm^− 1: 3422 (N-H), 3054 (= C-H), 1601 − 1400 (C = C and C = N), 1385 (CH₃ bending), 838 (= C-H bending OOP of parasubstituted phenyl ring), 768 and 697 (CH bending OOP of monosubstituted phenyl rings). ¹H NMR in low concentration (Acetone-d₆)/ppm: δ_H = 11.63 (1H, s, NH), 8.05 (2H, d, ³J_HH = 8.0Hz), 7.8–7.2 (12H, m), 3.26 (1H, sep, ³J_HH = 6.8Hz), 1.30 (6H, d, ³J_HH = 6.8Hz). ¹³C NMR in low concentration (Acetone-d₆)/ppm: δ_C = 149.7, 146.13, 128.87, 128.49, 128.29, 127.87, 127.00, 126.62, 126.22, 125.36, 33.79, 23.40.

2-(4-nitro)-4,5-diphenyl-1H-imidazole (8): red solid. mp/°C: 240–242 (Lit. 239–242 [45]). λ_max (CHCl₃)/nm: 300 (π→π^*), 245 (n→π^*). ῡ_max (KBr)/cm^− 1: 3406 (N-H), 3032 (= C-H), 1604 − 1400 (C = C and C = N), 1514 and 1339 (ArN = O), 1107 (C-N), 854 (= C-H bending OOP of parasubstituted phenyl ring).¹H NMR in high concentration (Acetone-d₆)/ppm: δ_H = 12.65 and 12.55 (1H, NH and OH), 8.46–8.25 (8H, m), 8.00-7.8 (6H, m). ¹³C NMR (Acetone-d₆)/ppm: δ_C = 144.65. 142.93, 142.24, 141.37, 135.28, 132.82, 132.29, 132.06, 129.50, 128.78, 128.42, 128.16, 127.95, 125.93, 124.14.

2-(3-nitro)-4,5-diphenyl-1H-imidazole (9): yellow solid. mp/°C: 308–309 (Lit. 311–312 [4464]). λ_max (CHCl₃)/nm 310 (π→π^*), 240 (n→π^*). ῡ_max (KBr)/cm^− 1: 3427 (N-H), 3060 (= C-H), 1600 − 1400 (C = C and C = N), 1525 and 1348 (ArN = O), 1301 (C-N), 913 and 767 & 700 (= C-H bending OOP of metasubstituted phenyl ring), 767 and 700 (= C-H bending OOP of monosubstituted phenyl rings). ¹H NMR in high concentration (DMSO-d₆): δ_H = 13.11 (1H, s, NH), 8.96 (1H, s), 8.51 (1H, d, ³J_HH = 7.6Hz), 8.21 (1H, d, ³J_HH = 7.6Hz), 7.79 (1H, “t”, ³J_HH = 7.6Hz), 7.56 (1H, d, ³J_HH = 7.6Hz), 7.53 (2H, d, ³J_HH = 7.6Hz), 7.47 (2H, “t”, ³J_HH = 7.6Hz), 7.4 (1H, “t”, ³J_HH = 7.6Hz), 7.32 (2H, “t”, ³J_HH = 7.6Hz), 7.24 (1H, “t”, ³J_HH = 7.6Hz). ¹³C NMR in high concentration (DMSO-d₆)/ppm [42]: δ_C = 148.3, 143.4, 137.7, 134.7, 131.8. 131.2, 130. 6, 130. 4, 129.2, 128.7, 128.4, 128.3, 128.1, 127.1, 126.8, 122.6, 119.4.

2-(2-nitro)-4,5-diphenyl-1H-imidazole (10): yellow solid. mp/°C: 229–231 (Lit. 230–231 [45]). λ_max (CHCl₃)/nm: 315 (π→π^*), 250 (n→π^*). ῡ_max (KBr)/cm^− 1 3398 (N-H), 280 (= C-H), 1601 − 1400(C = C and C = N), 1528 and 1351 (ArN = O), 769 (= C-H bending OOP of orthosubstituted phenyl ring), 769 and 696 (= C-H bending OOP of monosubstituted phenyl rings). ¹H NMR in high concentration (Acetone-d₆)/ppm: δ_H = 12.00 (1H, s, NH), 8.03 (1H, d, ³J_HH = 8.0Hz), 7.85 (1H, d, ³J_HH = 8.0Hz), 7.79 (1H, “t”, ³J_HH = 8.0Hz), 7.67 (1H, “t”, ³J_HH = 8.0Hz), 7.6 (2H, d, ³J_HH = 7.6Hz), 7.55 (2H, d, ³J_HH = 7.6Hz), 7.44 (2H, “t”, ³J_HH = 7.6Hz), 7.4 (1H, “t”, ³J_HH = 7.6Hz), 7.3 (2H, “t”, ³J_HH = 7.6Hz), 7.25 (1H, “t”, ³J_HH = 7.6Hz). ¹³C NMR in high concentration (Acetone-d₆)/ppm [42]: δ_C = 148.2, 140.9, 137.4, 134.6, 132.0, 130.5, 129.7, 129.4, 128.7, 128.6, 128.2, 128.1, 127.9, 126.9, 126.6, 123.9, 123.3.

2-(2-Methoxy-phenyl)-4,5-diphenyl-1H-imidazole (11): White solid. mp/°C: 210–212 (Lit. 210–211 [45]). λ_max (CDCl₃)/nm: 333 (π→π^*), 218 (n→π^*). υ_max (KBr)/cm^− 1: 3430 (N-H), 3064 (= C-H), 2970 (-C-H), 1600 − 1400 (C = C and C = N), 1389 (CH₃ bending), 1252 and 1018 (ArC-OCH₃), 764 (= C-H bending OOP of orthosubstituted phenyl ring), 764&693 (= C-H bending OOP of monosubstituted phenyl rings). ¹H NMR in high concentration (DMSO-d₆)/ppm: δ_H = 11.888 (1H, s, NH), 8.033 (1H, d, ³J_HH = 7.6Hz), 7.515 (2H, d, ³J_HH = 7.6Hz), 7.5–7.3 (6H, m), 7.226 (2H, “t”, ³J_HH = 7.6Hz), 7.23 (1H, “t”, ³J_HH = 7.6Hz), 7.15 (1H, d, ³J_HH = 7.6Hz), 7.04 (1H, “t”, ³J_HH = 7.6Hz), 3.908 (3H, s). ¹³C NMR in low concentration (Acetone-d₆)/ppm: δ_C = 164.74, 163.81, 143.06, 141.22, 140.65, 136.45, 136.38, 128.48, 127.78, 122.82, 119.44, 102.53, 60.26.

2-(2-Methyl-phenyl)-4,5-diphenyl-1H-imidazole (12): white solid. mp/°C: 205–207 (Lit. 204–206 [46]). λ_max (Acetone)/nm: 320 (π→π^*), 212 (n→π^*). υ_max (KBr)/cm^− 1: 3429 (N-H), 3063 (= C-H), 2968 (-C-H), 1600 − 1400 (C = C and C = N), 1389 (CH₃ bending), 764 (= C-H bending OOP of orthosubstituted phenyl ring), 764 and 694 (= C-H bending OOP of monosubstituted phenyl rings). ¹H NMR (Acetone-d₆)/ppm: δ_H = 11.65 (1H, s, NH), 7.77 (1H, dd, ³J_HH = 7.6Hz, ⁴J_HH = 4.0Hz), 7.69 (2H, d, ³J_HH = 8.0Hz), 7.56 (2H, d, ³J_HH = 8.0Hz), 7.43 (2H, “t”, ³J_HH = 8.0Hz), 7.4–7.28 (6H, m), 7.23 (1H, “t”, ³J_HH = 8.0Hz), 2.73 (3H, s). ¹³C NMR (Acetone-d₆)/ppm: δ_C = 146.58, 137.15, 136.77, 136.03, 131.83, 131.30, 130.53, 128.95, 128.76, 128.68, 128.29, 128.24, 127.79, 127.72, 127.39, 126.47, 125.83, 21.21.

2-(3-hydroxy)-4,5-diphenyl-1H-imidazole (13): white solid. mp/°C: 258–260 (Lit. 258–260 [46]). λ_max (Acetone)/nm: 345 (π→π^*), 215 (n→π^*). ῡ_max (KBr)/cm^− 1 3500 − 3100 (N-H and O-H), 3060 (= C-H), 1600 − 1400 (C = C and C = N), 1229 (Ar-O), 873, 766 and 695 (= C-H bending OOP of metasubstituted phenyl ring), 766 and 695 (= C-H bending OOP of monosubstituted phenyl rings) .¹H NMR (Acetone-d₆)/ppm: δ_H = 9–14 (1H, brs, NH), 8.6 (1H, brs, OH), 7.635 (1H, s,), 7.6 (4H, d, _3JHH = 7.6Hz), 735 (4H, “t”, _3JHH = 7.6Hz), 7.35–7.2 (4H, m), 6.86 (1H, dd, _3JHH = 8.0Hz, _4JHH = 1.6Hz). ¹³C NMR (Acetone-d₆)/ppm: δ_C = 140.16, 136.28, 135.33, 133.44, 132.73, 131.96, 130.25, 129.61, 128.79, 128.57, 127.65, 127.34, 125.61, 125.37, 125.05, 99.57, 92.99.

2-(3-Methoxy-phenyl)-4,5-diphenyl-1H-imidazole (14): white solid. mp/°C: 265–266 (Lit. 266–268 [40]). λ_max (CDCl₃)/nm: 333 (π→π^*), 215 (n→π^*). υ_max (KBr)/cm^− 1: 3438 (N-H), 3056 (= C-H), 2924 (-C-H), 1600 − 1400 (C = C and C = N), 1383 (CH₃ bending), 1250 and 1025 (ArC-OCH₃), 841, 769 and 696 (= C-H bending OOP of metasubstituted phenyl ring), 769 and 696 (= C-H bending OOP of monosubstituted phenyl rings). ¹H NMR in low concentration (Acetone-d₆)/ppm: δ_H = 11.30 (1H, s, NH), 8.403 (1H, dd, ³J_HH = 7.8Hz, ⁴J_HH = 1.6Hz), 7.57(4H, d, ³J_HH = 6.4Hz), 7.4–7.2(6H, m), 7.293(1H, d, ³J_HH = 8.0Hz), 7.1 (1H, “t”, ³J_HH = 8.0Hz), 4.026 (3H, s). ¹³C NMR in low concentration (Acetone-d₆)/ppm: δ_C = 144.37, 143.39, 141.81, 135.92, 135.04, 131.72, 131.34, 129.64, 129.06, 128.53, 128.28, 125.88, 125.82, 124.19, 120.88, 120.18, 113.03, 59.79.

2-(3,4-dimethoxy phenyl)-4,5-diphenyl-1H-imidazole (15): white solid. mp/°C: 215–217 (Lit. 213–216 [47]). λ_max (Acetone)/nm: 337 (π→π^*), 212 (n→π^*). ῡ_max (KBr)/cm^− 1: 3413 (N-H), 3062 (= C-H), 1600 − 1400 (C = C and C = N), 1363 (CH₃ bending), 1250 and 1031 (ArC-OCH₃). ¹H NMR in low concentration (Acetone-d₆)/ppm: δ_H = 11.05 (1H, s, NH), 8.29 (1H, d, ³J_HH = 8.4Hz), 7.57 (4H, d, ³J_HH = 6.8Hz), 7.34 (4H, “t”, ³J_HH = 6.8Hz), 7.3 (2H, “t”, ³J_HH = 6.8Hz), 4.026 (3H, s), 3.882 (3H, s). ¹³C NMR in low concentration (DMSO-d₆)/ppm: δ_C = 166.51, 161.02, 162.70, 154.05, 148.50, 142.00, 137.53, 132.40, 131.50, 123.22, 120.69, 116.96, 59.95, 59.72.

2-(1-naphthyl)-4,5-diphenyl-1H-imidazole (16): yellow solid. mp/°C: 215–217 (Lit. 215 [48]). λ_max (Acetone)/nm: 350 (π→π^*), 230 (n→π^*). ῡ_max (KBr)/cm^− 1: 3426 (N-H), 3053 (= C-H), 1672 − 1400 (C = C and C = N), 770 and 695 (= C-H bending OOP of monosubstituted phenyl rings). ¹H NMR in high concentration (Acetone-d₆)/ppm: δ_H = 11.84 (1H, s, NH), 9.37 (1H, d, ³J_HH = 8.4Hz), 8.0-7.9 (3H, m), 7.75 (2H, d, ³J_HH = 7.2Hz), 7.7–7.5 (5H, m), 7.7–7.5 (5H, m), 7.7–7.5 (6H, m). ¹³C NMR in high concentration (DMSO-d₆)/ppm: δ_C = 145.90, 134.65, 134.10, 133.25, 130.83, 130.7, 129.85, 129.67, 129.48, 129.22, 128.98, 128.75, 128.32, 128.19, 127.78,, 127.50, 127.46, 127.27, 126.96, 126.66, 125.72.

2-(2-naphthyl)-4,5-diphenyl-1H-imidazole (17): yellow solid. mp/°C: 272–274 (Lit. 273–276 [40]). λ_max (Acetone)/nm: 350 (π→π^*), 230 (n→π^*). ῡ_max (KBr)/cm^− 1: 3428 (N-H), 3055 (= C-H), 1600 − 1400 (C = C and C = N), 755 and 698 (= C-H bending OOP of monosubstituted phenyl rings). ¹H NMR in high concentration (Acetone-d₆)/ppm: δ_H = 12.878 (1H, s, NH), 8.610 (1H, s), 8.34 (1H, d, ³J_HH = 8.4Hz), 8.13 (1H, d, ³J_HH = 8.4Hz), 7.96 (1H, “t”, ³J_HH = 7.6Hz), 7.47 (2H, d, ³J_HH = 6.8Hz), 7.65–7.5 (4H, m), 7.44 (2H, “t”, ³J_HH = 7.6Hz), 7.4 (1H, “t”, ³J_HH = 7.6Hz), 7.3 (2H, “t”, ³J_HH = 7.6Hz), 7.25 (1H, “t”, ³J_HH = 7.6Hz). ¹³C NMR in low concentration (Acetone-d₆)/ppm: δ_C = 173.65, 172.02, 157,70, 153.76, 148.41, 136.03, 135.58, 135.88, 134.29, 131.6, 129.15, 124.69, 122.43, 120.47.

Bis[3-hydroxy-4-4,5-diphenyl imidazole-yl]methane (18): brown solid. mp/°C: 244–247. λ_max (CHCl₃)/nm: 333 (π→π^*), 218 (n→π^*). ῡ_max (KBr)/cm^− 1 3500 − 3100 (N-H), 3052 (= C-H), 2922 (-C-H), 1604 − 1400 (C = C and C = N), 1442 (CH₂ bending), 1260 (Ar-O), 765 and 695 (= C-H bending OOP of monosubstituted phenyl rings). ¹H NMR (Acetone-d₆)/ppm: δ_H = 13.05 (2H, s, NH), 12.79 (2H, s, OH), 7.97 (2H, s), 7.5-7.0(20H, m), 6.92(2H, d, ³J_HH = 8.0Hz), 6.60 (2H, d, ³J_HH = 8.0Hz). ¹³C NMR (Acetone-d₆)/ppm: δ_C = 153.07, 136.19, 136.08, 131.80, 130.66, 129.05, 127.76, 126.32, 124.24, 123.38, 120.08, 115.67, 41.70. Anal. Calcd for C₄₃H₃₂N₄O₂ (%): C 81.132, H 5.031, N 8.805. Found: C 84.89, H 5.069, N 8.807.

2-(4-N,N-dimethylamino phenyl)4,5-di(4-flouro phenyl)-1H-imidazole (19): off-white solid. mp/°C: 269–271. λ_max (Acetone)/nm: 285 (π→π^*), 245 (n→π^*). ῡ_max (KBr)/cm^− 1: 3397 (N-H), 3066 (= C-H), 2912 (-C-H), 1649 − 1400 (C = C and C = N), 1363 (CH₃ bending), 1221 (C-N), 1221 (Ar-F), 835 (= C-H bending OOP of parasubstituted phenyl rings). ¹H NMR (Acetone-d₆)/ppm: δ_H = 12.35 and 11.978 (1H, s, NH), 7.87 (2H, d, ³J_HH = 8.4Hz), 7.495 (4H, “t”, ³J_HH = 6.8Hz, ³J_HF = 6.8Hz), 7.199 (4H, “t”, ³J_HH = 6.8Hz, ⁴J_HF = 5.6Hz), 6.77(2H, d, ³J_HH = 8.4Hz), 2.970 (6H, s). ¹³C NMR (Acetone-d₆)/ppm: δ_C = 172.52, 162.00 (d, ¹J_C−F =245.0 Hz), 150.77, 146,94, 130.6 (d, ³J_C−F =8.0 Hz), 126.76, 118,52, 115.82 (d, ²J_C−F =20.0 Hz), 112.35, 100.01, 21.51. Anal. Calcd for C₂₃H₁₈N₃F₂ (%): C 73.60, H 5.061, N 11.20. Found: C 73.26, H 5.311, N 11.678.

2-(4-chloro phenyl)4,5-di(4-flouro phenyl)-1H-imidazole (20): gray solid. mp/°C: 270–273 (Lit. 273–276 [47]). λ_max (Acetone)/nm: 315 (π→π^*), 245 (n→π^*). ῡ_max (KBr)/cm^− 1: 3434 (N-H), 3081 (= C-H), 1607 − 1400 (C = C and C = N), 1224 (Ar-F), 835 (= C-H bending OOP of parasubstituted phenyl rings). ¹H NMR (Acetone-d₆)/ppm: δ_H = 12.9 (1H, s, NH), 8.1 (2H, d, ³J_HH = 8.8Hz), 7.7–7.4 (6H, m), 7.3 (2H, “t”, ³J_HH = 6.8Hz), ³J_HF = 6.8Hz), 7.15 (2H, “t”, ³J_HH = 6.8Hz, ³J_HF = 6.8Hz). ¹³C NMR (DMSO-d₆)/ppm [38]: δ_C = 162.2 (d, ¹J_C−F =242.0 Hz), 161.3 (d, ¹J_C−F =242.0 Hz), 144.7, 135.6, 131.5, 130.8 (d, ⁴J_C−F =2.0 Hz), 130.0 (d, ³J_C−F =9.0 Hz), 129.1, 128.8 (d, ³J_C−F =9.0 Hz), 128.5, 127.9, 125.1 (d, ⁴J_C−F =2.0 Hz), 124.7, 114.6 (d, ²J_C−F =21.0 Hz), 113.2 (d, ²J_C−F =21.0 Hz).

By surveying of ¹H and ¹³C NMR spectra, it is offered very interesting information about the behavior of hydrogen atom attached to nitrogen of imidazole.

In the number of products (Entries 2, 3, 6, 7, 8, 9, 10, 11, 12, 15, 17 and 20), the phenyls substituted in 4 and 5 positions of imidazole ring (we call them Ph^a and Ph^b), are chemical non-equivalent as shown in Fig. 1-a in the case of 10. It seems that in these derivatives, proton exchange not occur and the corresponding protons of Ph^a and Ph^b are recorded in different chemical shifts. However, another set of products (Entries 1, 4, 5, 13, 14, 16, 18 and 19), showed a different behavior as shown in Fig. 1-b in the case of 5. In these derivatives, the nucleus of Ph^a and Ph^b are chemical equivalent. In other words, in these derivatives the proton exchange occurs which eventually leads to the symmetry of the structures (there is only a hybrid structure) and their ¹H NMR spectrum make no difference between the corresponding protons of Ph^a and Ph^b (Fig. 1-b). Similarly, such a behavior is observed in ¹³C NMR spectra of imidazole derivatives.

Studies conducted on the substituent effects (induction, resonance, electron-releasing or electron- withdrawing and the Van der Waals radii parameters) not justified the behavior of the NH proton but we found several points by studying the proton and carbon spectra of trisubstituted imidazoles:

(1) Two spectra from a derivative at different times

It is found that the two ¹H NMR spectra of an imidazole derivative which obtained at different times are different. As shown in Fig. 2-c, in the case of 20, the proton exchange caused that the imidazole structure have been existed in two tautomeric forms. However, its ¹H NMR spectrum which obtained in another time (Fig. 2-d) results no proton transfer and tautomerism.

(2) Disturbance of a number of signals

In a large number of ¹H and ¹³C NMR spectra, the proton and carbon peaks of aryl group which substituted in position 2 of imidazole ring were sharp. However, the proton and carbon peaks of the Ph^a and Ph^b were broadened and showed disturbed appearance (Fig. 3e-f).

(3) Comparison of ¹H NMR and ¹³C NMR spectra of a derivative: It is also found that for a derivative for example in the case of 10, the ¹H NMR spectrum shows no proton transfer and tautomerism (Fig. 4-g) while the ¹³C NMR spectrum shows (The number of peaks in the ¹³C NMR spectrum shows that the Ph^a and Ph^b are equivalent) (Fig. 4-h).

In the continuation of studies, we focused on another point. More precision in the ¹H NMR spectra of these two categories, showed that in the first group (with nonequivalent Ph^a and Ph^b), the peak of the NH proton is sharp and the peak of the protons of water in the solvent (δ = 3.00 ppm for water in acetone-d₆ and δ = 3.4 ppm for water in DMSO-d₆) is in high intensity and has undergone any change (Fig. 5i). However, in the second category (with equivalent Ph^a and Ph^b), both of them are broadened (Fig. 5j). Sometimes even the peak of NH is quite removed. More focusing on the ¹H NMR spectra was appeared another point. In a large number of ¹H NMR spectra, the proton peaks of aryl group which substituted in position 2 of imidazole ring were sharp. But the proton peaks of the Ph^a and Ph^b were broadened and showed disturbed appearance; In these case, the NH peaks are broadened and the peak intensity of the water in the solvent is reduced (Fig. 5k).

According to the above description, it was argued that, the water in the deuterated solvent causes the exchange of NH proton of the imidazole molecules. To substantiate this argument, solutions with different concentration of 11, were prepared and the ¹HNMR spectra were obtained for each of them. The results of dynamic NMR study are shown in Fig. 6. As shown in this figure, when the concentration is high, proton exchange is very slow; so the both peaks of NH proton and the protons of water are sharp. The protons of the Ph^a and Ph^b are chemical nonequivalent and their peaks are clear and sharp (Fig. 6m-o). By reducing the concentration, the proton exchange rate is increased. So the peak of NH proton is broadened and the peak intensity of the water is reduced. The peaks of the protons of the Ph^a and Ph^b are broadened and disturbed (Fig. 6o-s). Finally, in the high dilution, the proton exchange is so fast that the peaks of NH proton and the protons of water are very broadened and the protons of the Ph^a and Ph^b are chemical equivalent and their peaks are clear and sharp (Fig. 6t).

As mentioned above, dynamic NMR studies of 2,4,5-tisubstituted imidazoles indicate that the behavior of the protons of Ph^a and Ph^b depends on the amount of water in the deuterated solvent (concentration of the sample). As shown in Fig. 7, the results of this study can be used to detection of proton signals of aryl group (which located in position 2 of imidazole ring) which formed a second order spectrum with other protons. Dynamic NMR studies of 2,4,5-tisubstituted imidazoles in this term can be replaced by TOCSY technique. In high concentrations (Fig. 7v), apart from H_a, all the protons of aryl group, are detected. By diluting the sample, the NH protons are able to exchange. So the peaks of the protons of the Ph^a and Ph^b are disturbed and the peak of H_a is appeared (Fig. 7w).

In this paper by providing a conclusive evidence, we introduce a way based on dynamic NMR studies of 2-(aryl)-4,5-diphenyl-1H-imidazoles instead of TOCSY technique for detecting of special protons and carbons. We prove that proton transfer in imidazole molecules not occur in dilute and concentrated solutions unless there is some protonated solvent, especially water in the solution. When the protonated solvent reached a certain level, the proton exchange starts, and with dilution of the solution the exchange rate is increased.

Acknowledgments

The authors are grateful to University of Kashan for supporting this work by Grant No. 159189/30.

Ethical Approval: This declaration is not applicable.

Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Authors' contributions: This declaration is not applicable.

Funding: This declaration is not applicable.

Availability of data and materials: This declaration is not applicable.

G. Binsch, “Unified theory of exchange effects on nuclear magnetic resonance line shapes”. J. Am. Chem. Soc. 1969. 91(6): 1304-1309.
E. Kolehmainen, “Novel applications of dynamic NMR in organic chemistry”. Annu. Reports NMR Spectrosc. 2003. 49: 1.
M. Oki, Applications of Dynamic NMR Spectroscopy to Organic Chemistry, VCH, Deerfield Beach, 1985
W. B. Smith, Magn. Reson. Chem., 1999, 37, 107.
M. Pons and O. Millet, Prog. Nucl. Magn. Reson. Spectrosc., 2001, 38, 267.
J. M. Goodman, P. D. Kirby and L. O. Haustedt, Tetrahedron Lett., 2000, 41, 9879.
E. Kleinpeter, Adv. Mol. Struct. Res., 2000, 6, 97.
R. Marek and A. Lycˇka, Curr. Org. Chem., 2002, 6, 35.
M. Barfield and P. Fagerness, J. Am. Chem. Soc., 1997, 119, 8699.
W. B. Smith, Magn. Reson. Chem., 1999, 37, 103.
H. Gu¨nther, NMR Spectroscopy, Basic Principles, Concepts and Applications in Chemistry, 2nd edn, John Wiley & Sons Ltd, Chichester, 1995, 339.
W. B. Smith and C. A. Amezcua, Magn. Reson. Chem., 1999, 37, 110
Medha Itagi Huilgol, B. Divya & Krishnan Balasubramanian Distance degree vector and scalar sequences of corona and lexicographic products of graphs with applications to dynamic NMR and dynamics of nonrigid molecules and proteins, Theoretical Chemistry Accounts volume 140, Article number: 25 (2021)
Aina Marie LøkkevikBratlandJohn GeorgSeland, Multidimensional dynamic NMR correlations in sedimentary rock cores at different liquid saturationsJournal of Magnetic ResonanceVolume 327, June 2021, 106963
Eugeny N. Zapolotsky & Sergey P. Babailov , Intermolecular dynamics and paramagnetic properties of Tm-Na heterometallic complex with macrocyclic ligand by 23Na dynamic NMR, Journal of Inclusion Phenomena and Macrocyclic Chemistry volume 100, pages149–153 (2021)
Yuuri Tsuboi & Jun Kikuchi, Spatial molecular-dynamically ordered NMR spectroscopy of intact bodies and heterogeneous systems, Communications Chemistry volume 3, Article number: 80 (2020)
Abhinav Dubey, Koh Takeuchi, Mikhail Reibarkh & Haribabu Arthanari, The role of NMR in leveraging dynamics and entropy in drug design, Journal of Biomolecular NMR volume 74, pages479–498 (2020)
P. Sandusky, D. Raftery, “Use of selective TOCSY NMR experiments for quantifying minor components in complex mixtures: application to the metabonomics of amino acids in honey”. Anal. Chem. 2005. 77(8): 2455–2463.
P. Sandusky, D. Raftery, “Use of semiselective TOCSY and the pearson correlation for the metabonomic analysis of biofluid mixtures: application to urine”. Anal. Chem. 2005. 77(23): 7717–7723.
A.M. Weljie, J. Newton, P. Mercier, E. Carlson, C.M. Slupsky. “Targeted profiling: quantitative analysis of 1H NMR metabolomics data”. Anal. Chem. 2006. 78(13): 4430–4442.
Amita Verma, Sunil Joshi, Deepika Singh, Imidazole: Having Versatile Biological Activities, JOURNAL OF CHEMISTRY (JAN 2013)
Bamoniria A, Yaghmaeiyan N. Sci. Iran. C 2018; 25: 1344-1353.
Bamoniri A, Mirjalili B.F, Nazemian S, Mahabadi N.Y. Bulg. Chem. Commun. 2014; 46: 79-84.
D. Christen, J. Griffiths, H. Sheridan, Z. Naturforsch. “The microwave spectrum of imidazole; complete structure and the electron distribution from nuclear quadrupole coupling tensors and dipole moment orientation”. 1981. 36(12): 1378–1385.
J. Torres, L. Lavandrea, P. Cabildo, R.M. Claramunt, J.Elguero, “Synthesis and physicochemical studies on 1,2-bisazolylethanes”. J. Hetrocycl. Chem. 1988. 25(3): 771-782.
D.P. Davies, K.L. Kirk, L.A. Cohen, “New synthesis of 2-nitroimidazoles”. J. Hetrocycl. Chem. 1982. 19(7): 253-256.
E. Kleinpeter and A. Koch, J. Phys. Org. Chem., 2001, 14, 566.
A. Laxer, D. T. Major, H. E. Gottlieb and B. Fischer, J. Org. Chem., 2001, 66, 5463.
J. Ma¨ki, K. D. Klika, R. Sjo¨holm and L. Kronberg, J. Chem. Soc., Perkin Trans. 1, 2001, 1216
G. Giorgi, F. Ponticelli, L. Savini, L. Chiasserini and C. Pellerano, J. Chem. Soc., Perkin Trans. 2, 2000, 2259
J. A. Jimenez, R. M. Claramunt, C. Escolastico and J. Elguero, Struct. Chem., 2000, 11, 7.
E. Murguly, T. B. Norsten and N. Branda, J. Chem. Soc., Perkin Trans. 2, 1999, 2789
E. Kolehmainen, B. Os´mialowski, M. Nissinen, R. Kauppinen and R. Gawinecki, J. Chem. Soc., Perkin Trans. 2, 2000, 2185
E. Kolehmainen, B. Os´mialowski, T. M. Krygowski, R. Kauppinen, M. Nissinen and R. Gawinecki, J. Chem. Soc., Perkin Trans. 2, 2000, 1259
R. Gawinecki, B. Os´mialowski, E. Kolehmainen and R. Kauppinen, J. Phys. Org. Chem., 2001, 14, 201.
B. Os´mialowski, E. Kolehmainen, M. Nissinen, T. M. Krygowski and R. Gawinecki, J. Org. Chem., 2002, 67, 3339.
J. Helaja, F.-P. Montforts, I. Kilpela¨inen and P. H. Hynninen, J. Org. Chem., 1999, 64, 432.
A. Bamoniri and N. Yaghmaeiyan-Mahabadi, Nano kaolin-SO3H as a new efficient and reusable catalyst for one-pot synthesis of 2,4,5-trisubstituted imidazoles under solvent-free conditions, Scientia Iranica C (2018) 25(3), 1344{1353
H. Zang, Q. Su, Y. Mo, B. W. Cheng, S. Jun, Ultrason. Sonochem. 17 (2010) 749-751;
J. Safari, S. Dehghan-Khalili, S. H. Banitaba, J. Chem. Sci. 122 (2010) 437–441;
A.R. Khosropour, Ultrason. Sonochem. 15 (2008) 659-664;
A. Teimouri, A. Najafi Chermahini, J. Mol. Catal. A: Chem. 346 (2011) 39-45;
M, Ashrafi, A, Davoodnia, N, Tavakoli-Hoseini, Bull. Korean Chem. Soc. 34 (2013) 1508-1512;
B. F. Mirjalili, A. Bamoniri, N. Mohaghegh, Current Chem. Lett. 2 (2013) 35-42.
P. Shivaji, B. Swapnil, A. Uddhav, A. Gorakshanath, P. Vikram, J. Chem. Sci. 123 (2011) 421-426;
P. Shivaji, B. Swapnil, A. Uddhav, A. Gorakshanath, P. Vikram, J. Chem. Sci. 123 (2011) 421-426;
J. Safari, S. Dehghan-Khalili, S. H. Banitaba, Synthetic Communications. 41 (2011) 2359–2373;
H. N. Roy, M.M. Rahman, P.K.Pramanick, Ind. J. Chem. 52 (2013) 153-159;

Scheme 1 is available in the Supplementary Files section.

No competing interests reported.

suplementary.rar
Scheme1.jpg
Scheme 1. Proton transfer and tautomerism of imidazole in the presence of water as a protonated solvent

Download PDF

Version 1

posted

You are reading this latest preprint version

An experimental dynamic NMR study of 2-(aryl)-4,5-diphenyl-1H-imidazoles in solution: the evaluation of NH behavior in terms of proton transfer and tautomerism and its application on detecting of special protons and carbons of trisubstituted imidazoles

Status:

Version 1

Abstract

Figures

Introduction

Experimental

Materials and apparatus

Preparation of 2,4,5- trisubstituted imidazoles

Spectral data

Results And Discussion

Conclusion

Declarations

References

Scheme 1

Additional Declarations

Supplementary Files

Status:

Version 1