Spectroscopic and theoretical characterization of 2-(4

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 151 (2015) 965–979

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Spectroscopic and theoretical characterization of 2-(4-methoxyphenyl)4,5-dimethyl-1H-imidazole 3-oxide K.B. Benzon a, Hema Tresa Varghese a,⇑, C. Yohannan Panicker b, Kiran Pradhan c, Bipransh Kumar Tiwary d, Ashis Kumar Nanda c, C. Van Alsenoy e a

Department of Physics, Fatima Mata National College, Kollam, Kerala, India Department of Physics, TKM College of Arts and Science, Kollam, Kerala, India Department of Chemistry, University of North Bengal, Siliguri, West Bengal, India d Department of Biotechnology, University of North Bengal, Siliguri, West Bengal, India e Department of Chemistry, University of Antwerp, B2610 Antwerp, Belgium b c

h i g h l i g h t s

g r a p h i c a l a b s t r a c t

IR, Raman spectra and NBO analysis

were reported. The wavenumbers are calculated

theoretically using Gaussian09 software. The wavenumbers are assigned using PED analysis. Molecular docking is reported.

a r t i c l e

i n f o

Article history: Received 27 October 2014 Received in revised form 1 July 2015 Accepted 3 July 2015 Available online 4 July 2015 Keywords: DFT Imidazole FTIR FT-Raman Molecular docking Hyperpolarizability

a b s t r a c t The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of 2 -(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide have been investigated experimentally and theoretically. Gauge-including atomic orbital 1H NMR chemical shifts calculations were carried out and compared with experimental data. The HOMO and LUMO analysis is used to determine the charge transfer within the molecule. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. The calculated geometrical parameters are in agreement with that of similar derivatives. Molecular electrostatic potential was performed by the DFT method. Mulliken’s net charges have been calculated and compared with the atomic natural charges. First and second hyperpolarizability are calculated in order to find its role in non-linear optics. Molecular docking is also reported. Ó 2015 Elsevier B.V. All rights reserved.

1. Introduction Imidazole is an aromatic heterocyclic with ‘‘1,3-diazole’’ and is classified as an alkaloid. Imidazole ring system is present in

⇑ Corresponding author. E-mail address: [email protected] (H.T. Varghese). http://dx.doi.org/10.1016/j.saa.2015.07.020 1386-1425/Ó 2015 Elsevier B.V. All rights reserved.

important biological building blocks, such as histidine and the related hormone histamine. Imidazole can serves as a base and as a weak acid. Many drugs contain an imidazole ring, such as antifungal drugs and nitroimidazole [1–3]. Imidazole and its derivatives are widely used as intermediates in synthesis of organic target compounds including pharmaceuticals [4–10], agrochemicals, dyes, photographic chemicals, corrosion inhibitors, epoxy curing agents, adhesives and plastic modifiers [11]. Various biologically active

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K.B. Benzon et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 151 (2015) 965–979

synthetic compounds have five-membered nitrogen-containing heterocyclic ring in their structures [12]. Structural frameworks have been described as privileged structures and in particular, nitrogen containing polycyclic structures has been reported to be associated with a wide range of biological activity [13,14]. The high therapeutic properties of the imidazole related drugs have encouraged the medicinal chemists to synthesize a large number of novel chemotherapeutic agents [15]. Imidazole drugs have broadened scope in remedying various dispositions in clinical medicines. Medicinal properties of imidazole include anticancer, b-lactamase inhibitors, carboxypeptidase inhibitors, hemeoxygenase inhibitors, anti-aging agents, anticoagulants, anti-inflammatory, antibacterial, antifungal, antiviral, anti-tubercular, anti-diabetic and anti-malarial [16–21]. Imidazole and its derivatives are reported to be physiologically and pharmacologically active and find applications in the treatment of several diseases [22]. In the present work, IR and Raman spectra of the title compound are reported both experimentally and theoretically. The NBO analysis, molecular electrostatic potential, first and second hyperpolarizability and 1H NMR studies are also reported. Due to the different potential biological activity of the title compound, molecular docking of the title compound is also reported. 2. Experimental details 2-(4-Methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide was synthesized via a solvent free procedure. 1 mmol (0.101 g) of 3-(hydroxyimino) butan-2-one was mixed with 1 mmol (0.136 g) of 4-methoxybenzaldehyde and 5 mmol (0.385 g) of ammonium acetate in an agate mortar and grinded thoroughly with a pestle into an intimate mixture. The mixture was then transferred to a test tube and heated to 115–120 °C in an oil bath for 20 min with constant shaking. Reaction progress was monitored by thin-layer chromatography (TLC) using 0.25 mm Merck Aluminum silica gel 60-F254 precoated plates. After 20 min, a black solution resulted, which on cooling formed a black sticky precipitate. To the black precipitate was then added a small volume of diethyl ether when a brown precipitate separated. The precipitate was washed with 15 ml of ethyl acetate to yield the pure product. The FT-IR spectrum (Fig. 1) was recorded using KBr pellets on a DR/Jasco FT-IR 6300 spectrometer. The spectral resolution was 2 cm1. The FT-Raman spectrum (Fig. 2) was obtained on a Bruker RFS 100/s, Germany. For excitation of the spectrum the emission of Nd:YAG laser was used, excitation wavelength 1064 nm, maximal power 150 mW, measurement on solid sample. The spectral resolution after apodization was 2 cm1. 1H and 13C NMR were recorded in dmso-d6 on a Bruker Avance 300 spectrometer. The electrospray mass spectrum was recorded on a MICROMASS QUATTRO II triple quadruple mass spectrometer. The ESI capillary was set at 3.5 kV and cone voltage was 40 V. Melting Point (uncorrected) 138–140 °C. ESI m/z found for (C12H14N2O2): 218.2 (M+1). 3. Computational details Calculations of the title compound were carried out with Gaussian09 [23] program using the HF/6-31G(6D, 7F), B3LYP/6-31G(d)(6D, 7F) and B3LYP/SDD(6D, 10F) basis sets to predict the molecular structure and vibrational wave numbers. Molecular geometry was fully optimized by Berny’s optimization algorithm using redundant internal coordinates. Harmonic vibrational wave numbers are calculated using the analytic second derivatives to confirm the convergence to minima on the potential energy surface. The wave number values computed at the Hartree– Fock level contain known systematic errors due to the negligence

of electron correlation [24] and a scaling factor value of 0.8929 is used for the wavenumbers obtained by HF method. The DFT hybrid B3LYP functional and SDD methods tend to overestimate the fundamental modes; therefore scaling factor of 0.9613 has to be used for obtaining a considerably better agreement with experimental data [24–27]. The Stuttgart/Dresden effective core potential basis set (SDD) [28] was chosen particularly because of its advantage of doing faster calculations with relatively better accuracy and structures [29]. Then wavenumber calculations were employed to confirm the structure as minimum points in energy. Parameters corresponding to optimized geometry (SDD) of the title compound (Fig. 3) are given in Table 1. The absence of imaginary wavenumbers on the calculated vibrational spectrum confirms that the structure deduced corresponds to minimum energy. The assignments of the calculated wavenumbers are aided by the animation option of GAUSSVIEW program, which gives a visual presentation of the vibrational modes [30]. The potential energy distribution (PED) is calculated with the help of GAR2PED software package [31]. The 1H NMR data were obtained from the DFT method using the basis set B3LYP/6-31G(d)(6D, 7F). The HOMO– LUMO energy is calculated by B3LYP/SDD(6D, 7F) method.

4. Results and discussion 4.1. IR and Raman spectra The observed IR and Raman bands and calculated (scaled) wavenumbers and assignments are given in Table 2. In the following discussion phenyl ring is designated as PhI, imidazole ring as RingII and the experimentally observed IR, Raman bands are compared with the values given by B3LYP/SDD(6D, 10F) values. In aromatic compounds the N–H stretching vibration appears in the region 3400 ± 40 cm1 [32]. In the present case, the band at 3567 cm1 in IR, 3558 cm1 in Raman and 3566 cm1 (SDD) is assigned as N–H stretching modes. N–H group show deformation bands at 1510–1500, 1400–1300 and 740–730 cm1 [33]. According to literature, if N–H is a part of a closed ring [32,34] the C–N–H deformation band is absent in the region 1510– 1500 cm1. For the title compound the C–N–H deformation band is assigned at 1255 cm1 (IR), 1259 cm1 (Raman) and 1256 cm1 theoretically (SDD). The out-of-plane N–H deformation is expected in the region 650 ± 50 cm1 [32] and the bands at 486 cm1 in the IR spectrum 473 cm1 in Raman spectrum and 472 cm1 theoretically (SDD) are assigned as this mode. Mary et al. [35] reported tN– H at 3546 cm1 (SDD) and 3547 cm1 (IR). Minitha et al. [36] reported tN–H at 3469 cm1, dN–H at 1300 cm1 and cN–H at 455 cm1. Kim et al. reported [37] N–H deformation bands at 549, 1484 cm1 in the Raman spectrum and at 556, 1495 cm1 theoretically for benzimidazole and Malek et al. [38] reported modes at 1394, 680 cm1 theoretically as N–H deformation modes. The wavenumbers of the vibrational modes of the methoxy group are known to be influenced by a variety of interesting interaction such as electronic effects, inter-molecular hydrogen bonding [39] and Fermi resonance. Electronic effects such as back donation and induction mainly caused by the presence of oxygen atom adjacent to CH3 group can shift the position of C–H stretching and bending modes [40,41]. In the spectra of methyl esters the overlap of the region in which both asymmetric stretching [32] tasCH3 absorb with a weak to medium intensity (2985 ± 25 and 2970 ± 30 cm1) is not large and regularly seen above 3000 cm1. For the title compound the SDD values of tasCH3 groups are 3063, 2996 cm1. The symmetrical stretching mode tsCH3 is expected in the range 2920 ± 80 cm1 in which all the three C–H bonds extend and contract in phase [32]. The band calculated at 2914 (SDD) cm1 is assigned as this mode. For the title compound


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Fig. 1. FT-IR spectrum of 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide.

the bands observed at 3063 cm1 in the IR spectrum and at 2998 cm1 in Raman spectrum are assigned as the methyl stretching bands. Two bending vibrations can occur within a methyl

group. With methyl esters the overlap of the regions in which methyl asymmetric deformations are active (1460 ± 25 and 1450 ± 15 cm1) is quite strong, which leads to many coinciding

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Fig. 2. FT-Raman spectrum of 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide.

wavenumbers [32]. This is obvious, not only for the asymmetric deformations, but also for the symmetric deformations [32] which are in the range 1380 ± 15 cm1. The SDD calculations give 1460, 1455 and 1426 cm1 as asymmetric and symmetric CH3 deformation modes for the title compound. The methyl rocking

wavenumbers are expected in the regions [32] 1100 ± 95 and 1080 ± 80 cm1. In the present case the bands calculated at 1148, 1106 cm1 (SDD), 1152, 1116 cm1 (IR) and 1149, 1115 cm1 (Raman) are assigned as rocking modes of the methyl groups. According to literature [40,32], asymmetric and symmetric

969


Corresponding to the tN–O mode, for the title compound, bands are observed at 1184 cm1 in the IR spectrum, at 1186 cm1 in the Raman spectrum and the SDD calculations give the tN–O mode at 1182 cm1. Ring with nitrogen directly on the ring absorb strongly at 1330–1260 cm1 due to stretching of the phenyl carbon–nitrogen bond [52]. Sandhyarani et al. [53] reported tC–N at 1318 cm1 for 2-mercaptobenzothiazole. For the title compound tC–N is assigned at 1247, 1129, 938 cm1 theoretically (SDD), 1248, 1135, 926 cm1

Fig. 3. Optimized geometry (SDD) of 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide.

C–O–C stretching modes are expected in the ranges 1200–1000 cm1 and 1050–900 cm1. The SDD calculations give 1221 and 978 cm1 as asymmetric and symmetric C–O–C stretching vibrations, respectively. The bands observed at 1219 cm1 (IR) and 1222 cm1 (Raman) was assigned as C–O–C stretching vibrations. Klimentova et al. [42] reported the asymmetric and symmetric C–O–C stretching vibrations in the range, 1214–1097 cm1. Castaneda et al. [43] reported the methoxy vibrations at 1252, 1190, 1172, 1028 and 1011 cm1 theoretically. The methyl stretching vibrations are expected in the region 3010–2900 cm1 (asymmetric) and 2950–2850 cm1 (symmetric) [32]. In the present case the SDD calculations give tasMe stretching vibrations at in the range 3036–2979 cm1 (SDD), 3009, 2960 cm1 (IR) and 3037, 3029, 3011, 2964 cm1 (Raman). The symmetric stretching modes of the methyl group are calculated to be at 2933, 2916 cm1 (SDD), 2922 cm1 (IR) and 2925 cm1 (Raman). The methyl esters the overlap of the region in which methyl asymmetric deformations are active (1460 ± 25 and 1450 ± 15 cm1) is quite strong, which leads to many coinciding wave numbers [32]. For the title compound, the bands were calculated at 1458, 1455, 1450, 1435 cm1 (SDD), 1442 cm1 (IR) and 1446 cm1 (Raman). The symmetric deformation modes of the methyl group are assigned at 1405, 1387 cm1 theoretically (SDD) and observed at 1384 cm1 (Raman). Most of the investigated molecules display the first methyl rock [32] in the region 1150 ± 35 cm1. The other methyl rocking modes are expected in the region [32] 1035 ± 55, 990 ± 50 and 925 ± 30 cm1. The SDD calculations give these rocking modes in the range 1046, 1035, 972, 938 cm1 (SDD). Experimentally these bands are observed at 1045, 1039, 958, 926 cm1 (Raman) and 1032, 961, 924 cm1 (IR). According to Socrates [33] the C@C stretching is expected around 1600 ± 50 cm1. In the present case the corresponding mode is observed at 1653 cm1 (IR), 1647 cm1 (Raman) and assigned at 1630 cm1 (SDD) respectively. Felfoldi et al. [44] reported the C@C stretching vibrations at 1625 cm1 theoretically. For the nitrone group, one would expect the emergence of bands in the vibration spectrum typical of stretching vibrations tC@N and tN–O. However, the identification of band tC@N is easy, while the assignment of band tN–O is frequently unjustified and erroneous [45]. Early reviews of the chemistry of nitroxide radical report that tN–O lies between 1340 and 1380 cm1 [46] or near 1350 cm1 [47], with other published values lying between 1310 cm1 for 3-car bamoyl-2,2,5,5-tetramethyl-3-pyrrolin-1-yloxyl and 1370 cm1 for tert-butyl-pheny nitroxide. The accepted band position of tN–O is considerably less than tN@O (1600–1500 cm1) [48] but greater than tN–O in oximes (965–930 cm1) [49] in accordance with its bond and a half character [50]. Rintoul et al. [51] reported the tN– O at 1431 cm1 (Raman), 1428 cm1 (IR) and 1433 cm1 (DFT). More concrete justification comes from the labeling studies with 15 N of the nitrone group in the 3-imidazoline-3-oxides.

Table 1 Optimized geometrical parameters (B3LYP/SDD) of 2-(4-methoxyphenyl)-4,5dimethyl-1H-imidazole 3-oxide, atom labeling according to Fig. 3. Bond lengths (Å)

Bond angles (°)

C1–C2 C1–C6 C1–H7 C2–C3 C2–H8 C3–C4 C3–O11 C4–C5 C4–H9 C5–C6 C5–H10 C6–C16 C12–O11 C12–H13 C12–H14 C12–C15 C16–N17 C16–N18 N17–O20 N17–C21 N18–H19 N18–C22 C21–C22 C21–C23 C22–C24 C23–H25 C23–H26 C23–H27 C24–H28 C24–H29 C24–H30

C2–C1–C6 C2–C1–H7 C6–C1–H7 C1–C2–C3 C1–C2–H8 C3–C2–H8 C2–C3–C4 C2–C3–O11 C4–C3–O11 C3–C4–C5 C3–C4–H9 C5–C4–H9 C4–C5–C6 C4–C5–H10 C6–C5–H10 C1–C6–C5 C1–C6–C16 C5–C6–C16 C3–O11–C12 O11–C12–H13 O11–C12–H14 O11–C12–H15 H13–C12–H14 H12–C12–H15 H14–C12–H15 C6–C16–N17 C6–C16–N18 N17–C16–N18 C16–N17–O20 C16–N17–C21 O20–N17–C21 C16–N18–H19 C16–N18–C22 H19–N18–C22 N17–C21–C22 N17–C21–C23 C22–C21–C23 N18–C22–C21 N18–C22–C24 C21–C22–C24 C21–C23–H25 C21–C23–H26 C21–C23–H27 H25–C23–H26 H25–C23–H27 H26–C23–H27 C22–C24–H28 C22–C24–H29 C22–C24–H30 H28–C24–H29 H28–C24–H30 H29–C24–H30

1.3959 1.424 1.0889 1.4127 1.0857 1.4094 1.3956 1.4049 1.0855 1.4186 1.0845 1.4527 1.4569 1.0918 1.0988 1.0988 1.3679 1.391 1.3511 1.4176 1.0085 1.4001 1.383 1.4923 1.4988 1.097 1.0951 1.097 1.0991 1.0939 1.0991

Dihedral angles (°) 121.2 117.9 120.9 119.7 121.4 118.6 119.7 115.5 124.8 120.1 121.0 118.8 120.8 121.1 118.1 118.1 120.8 121.1 118.6 105.3 111.2 111.2 109.7 109.7 109.6 127.8 126.2 112.0 127.3 109. 8 122.9 124.5 110.4 125.1 108.5 119.6 133.0 106.5 122.2 131.3 110.6 111.2 110.6 109.0 106.5 109.0 111.8 110.6 111.9 107.5 107.8 107.6

C6–C1–C2–C3 C6–C1–C2–H8 H7–C1–C2–C3 H7–C1–C2–H8 C2–C1–C6–C5 C2–C1–C6–C16 H7–C1–C6–C5 H7–C1–C6–C16 C1–C2–C3–C4 C1–C2–C3–O11 H8–C2–C3–C4 H8–C2–C3–O11 C2–C3–C4–C5 C2–C3–C4–H9 O11–C3–C4–C5 O11–C3–C4–H9 C2–C3–O11–C12 C4–C3–O11–C12 C3–C4–C5–C6 C3–C4–C5–H10 H9–C4–C5–C6 H9–C4–C5–H10 C4–C5–C6–C1 C4–C5–C6–C16 H10–C5–C6–C1 H10–C5–C6–C16 C1–C6–C16–N17 C1–C6–C16–N18 C5–C6–C16–N17 C5–C6–C16–N18 C3–O11–C12–H13 C3–O11–C12–H14 C3–O11–C12–H15 C6–C16–N17–O20 C6–C16–N17–C21 N18–C16–N17–O20 N18–C16–N17–C21 C6–C16–N18–H19 C6–C16–N18–C22 N17–C16–N18–H19 N17–C16–N18–C22 C16–N17–C21–C22 C16–N17–C21–C23 O20–N17–C21–C22 O20–N17–C21–C23 C16–N18–C22–C21 C16–N18–C22–C24 H19–N18–C22–C21 H19–N18–C22–C24 N17–C21–C22–N18 N17–C21–C22–C24 C23–C21–C22–N18 C23–C21–C22–C24 N17–C21–C23–H25 N17–C21–C23–H26 N17–C21–C23–H27 C22–C21–C23–H25 C22–C21–C23–H26 C22–C21–C23–H27 N18–C22–C24–H28 N18–C22–C24–H29 C21–C22–C24–H28 C21–C22–C24–H30

0.0 179.9 180.0 0.0 0.0 179.9 180.0 0.0 0.0 179.9 179.9 0.0 0.0 179.9 179.9 0.0 180.0 0.0 0.0 180.0 179.9 0.0 0.0 179.9 180.0 0.0 180.0 0.0 0.0 180.0 179.9 61.2 61.2 0.0 179.9 179.9 0.0 0.0 180.0 180.0 0.0 0.0 180.0 179.9 0.0 0.0 179.9 180.0 0.0 0.0 179.9 180.0 0.0 58.7 179.9 58.8 121.2 0.0 121.1 60.5 179.9 119.4 119.5

970


Table 2 Observed IR, Raman bands and calculated (scaled) wavenumbers of 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide and assignments. HF/6-31G(6D, 7F) 1

B3LYP/6-31G(d)(6D, 7F) 1

B3LYP/SDD(6D, 10F) 1

IR

Raman 1

Assignmentsa

1

t(cm )

IRI

RA

t(cm )

IRI

RA

t(cm )

IRI

RA

t(cm )

t(cm )

3532 3058 3042 3036 3000 2986 2946 2937 2932 2930 2892 2868 2864 2845 1663 1624 1582 1563 1503 1488 1482 1476 1473 1466 1464 1456 1453 1428 1423 1413 1376 1327 1282 1266 1238 1204 1188 1167 1157 1140 1139 1105 1081 1069 1064 1063 1015 1010 1002 988 964 885 853 790 756 737 714 692 669 642 593 582 576 533 520 458 427 406 334 320 306 286 279

80.31 22.70 6.13 11.52 23.95 30.33 20.50 16.17 10.29 44.32 25.39 26.01 43.66 47.02 51.95 138.60 9.24 23.77 140.62 67.24 8.87 10.26 27.17 10.61 41.44 3.88 28.41 6.42 3.42 1.12 10.13 2.55 17.45 274.97 19.45 53.06 103.93 1.74 4.88 33.96 2.32 17.66 0.07 8.20 3.39 1.49 65.59 12.66 1.53 3.24 10.02 80.54 30.57 3.31 32.68 12.65 12.91 0.78 11.38 3.94 124.52 28.67 6.51 3.61 6.58 2.50 0.09 6.34 26.93 1.35 8.54 0.57 5.54

28.29 41.30 121.25 72.43 39.93 157.16 105.56 45.72 78.57 47.41 110.54 168.73 123.69 203.59 18.30 801.75 100.61 631.21 108.33 34.85 33.97 45.75 25.76 30.01 22.56 18.39 8.42 11.69 84.71 52.93 68.71 4.67 41.54 15.29 113.69 4.10 40.35 8.34 22.90 1.22 6.68 4.29 0.20 34.96 1.59 6.66 5.58 2.15 3.14 3.16 55.76 0.78 2.70 12.08 12.41 19.63 0.84 5.03 4.53 6.82 0.26 1.36 0.99 0.55 10.90 1.69 0.23 7.26 1.15 1.26 0.08 0.25 2.96

3540 3120 3097 3091 3049 3035 3025 3019 2990 2968 2963 2938 2919 2910 1635 1608 1556 1528 1483 1476 1467 1462 1456 1452 1452 1441 1437 1412 1397 1387 1380 1303 1298 1262 1251 1246 1211 1173 1169 1129 1140 1101 1088 1039 1036 1030 990 976 941 940 890 811 810 780 770 744 695 656 628 603 592 560 582 511 469 408 390 350 334 313 280 276 241

55.94 11.33 12.98 10.73 26.25 30.66 12.09 15.07 10.38 42.54 19.71 27.36 52.61 71.92 24.73 65.83 2.90 113.25 55.87 68.56 10.24 5.42 34.02 7.51 16.18 47.17 4.52 12.41 1.76 17.86 1.56 28.25 94.11 38.72 265.13 72.55 36.71 13.10 45.01 0.76 18.09 16.70 18.50 0.07 65.00 1.456 1.58 0.65 1.90 0.90 1.43 38.26 4.50 19.13 10.18 3.48 0.01 0.17 4.00 1.05 6.71 24.53 7.81 13.19 1.26 1.57 0.09 17.49 16.31 4.81 5.26 9.70 3.36

35.60 30.37 86.08 150.17 43.09 172.94 79.79 55.19 84.36 59.16 128.76 208.42 345.50 143.88 39.65 1038.85 8.88 907.77 17.18 11.12 35.57 32.30 170.11 29.30 453.28 37.44 17.67 320.54 17.07 9.18 110.86 17.36 16.84 172.03 20.96 11.53 2.06 14.86 95.18 5.314 44.46 3.94 37.20 0.80 5.46 0.79 9.97 8.98 59.52 7.57 2.46 1.80 21.60 3.71 5.22 31.20 3.57 0.54 4.76 1.02 1.09 1.55 7.38 0.43 2.69 0.19 4.95 2.48 2.16 0.09 3.42 1.30 1.20

3566 3119 3109 3098 3063 3058 3036 3032 3004 2996 2979 2933 2916 2914 1630 1600 1547 1523 1464 1460 1458 1455 1455 1450 1435 1428 1426 1405 1404 1387 1361 1308 1293 1256 1247 1221 1182 1171 1148 1129 1106 1098 1077 1046 1035 993 990 978 972 945 938 843 809 789 746 736 725 673 628 623 582 570 550 521 472 458 414 390 343 312 305 277 276

58.17 20.77 8.23 8.71 32.10 28.56 20.06 17.30 15.38 51.60 23.85 29.77 49.03 80.60 34.22 65.82 0.56 112.23 4.75 24.69 10.47 15.30 12.22 157.92 9.35 4.07 31.95 8.34 8.03 8.96 2.46 1.72 30.61 38.14 53.54 185.72 117.80 57.002 0.98 19.79 0.00 28.52 23.13 0.05 4.62 4.04 12.45 51.13 0.73 0.37 5.40 67.24 27.68 2.30 1.01 2.59 2.74 3.19 3.67 0.07 8.02 26.13 8.26 46.79 65.81 2.05 0.48 9.45 19.28 010 4.74 1.80 0.38

33.08 8.75 101.55 46.50 148.19 37.30 75.88 42.97 67.13 50.16 95.27 226.73 359.92 141.26 80.32 1300.52 55.76 1098.24 18.66 28.34 7.63 16.37 29.66 196.76 12.37 190.73 87.67 15.15 152.92 184.48 7.78 18.18 5.67 72.62 130.99 4.04 52.34 70.99 13.33 55.92 8.71 2.81 23.13 0.43 2.08 0.91 5.91 3.93 8.76 0.31 80.91 0.10 0.38 15.43 11.34 2.50 40.71 0.78 6.20 2.48 0.96 1.62 10.44 0.16 1.20 3.20 0.40 5.07 3.48 0.38 0.19 5.34 0.60

3567 3120 – – 3063 – – – 3009 – 2960 – 2922 – 1653 1612 1552 1505 1462 – – – – 1442 – – – – 1400 – 1340 1302 – 1255 – 1219 1184 – 1152 – 1116 1093 – – 1032 – – – 961 – 924 834 – 776 746 – – 680 641 – 594 575 – 524 486 450 418 – – – – – –

3558 3126 3112 3086 – 3056 3037 3029 3011 2998 2964 2925 – – 1647 1614 1556 1520 1464 – – – – 1446 – – – – 1404 1384 1358 1307 1290 1259 1248 1222 1186 1170 1149 1135 1115 1093 – 1045 1039 1010 988 – 958 950 926 839 808 787 740 – 726 665 645 625 599 577 550 520 473 454 413 391 332 311 – 286 264

tNH(99) tCHI(94) tCHI(89) tCHI(99) tasMeI(100) tCHI(99) tasMeII(85) tasMeII(98) tasMeII(100) tasMeI(100) tasMeII(100) tsyMeII(100) tsyMeII(98) tsyMeI(99) tC@C(58), tCC(20) tPhI(57), dCHI(12) tPhI(49) tPhI(46) tC@N(46), dMeI(11) dasMeI(76), dMeII(12) dasMeII(83) dasMeII(97) dasMeI(99) dasMeII(86) dasMeII(97) tC@N(16), dMeI(12) dsyMeI(65), dCHI(15) dsyMeII(91) dMeII(39), tCC(18) dsyMeII(67) tPhI(46), dCHI(12) tPhI(43), dCHI(36) dCHI(56), tPhI(30) dNH(38), tCC(19) tCN(44), tCC(11) tCO(45), tPhI(11), dCHI(15) tNO(56), tCN(26), dCHI(10) dCHI(52), tCN(9) dMeI(77) tCN(55), tCC(20), dMeII(11) dMeI(95) dCHI(45), tPhI(19) dMeII(21), tNO(8), tPhI(12) dMeII(76) dMeII(88) cCHI(86) dCHI(48), dPhI(22), tCO(10) tCO(63), dPhI(21) dMeII(59), tCN(17) cCHI(77), sPhI(15) tCN(39), dMeII(35), tC@C(10) cCHI(74) cCHI(79) tPhI(36), dPhI(13), tCC(18) tCC(38), dRingII(18), dPhI(19), tNO(10) tCC(61), sPhI(14), cCO(14) tCC(49), dNO(19) sRingII(44), cNO(25), cCC(17) dPhI(75) sRingII(58), cCC(32) dCC(41), dNO(17), dRingII(9) dPhI(29), dCO(27) dRingII(37), tCC(18), dNO(15) cCO(32), sPhI(31), cCC(21) cNH(72) dCO(60) sPhI(72) sPhI(30), cNO(14), cCO(12), cCC(22) dCC(40), dNO(22) sRingII(23), cNO(21), cCC(23) dCC(59), dNO(11) dCC(33), dPhI(16), dNO(11) cCC(54)


971

Table 2 (continued) HF/6-31G(6D, 7F) 1

B3LYP/6-31G(d)(6D, 7F) 1

B3LYP/SDD(6D, 10F) 1

IR

Raman 1

Assignmentsa

1

t(cm )

IRI

RA

t(cm )

IRI

RA

t(cm )

IRI

RA

t(cm )

t(cm )

241 214 202 168 146 107 101 92 85 49 15

1.27 1.86 0.93 0.43 14.18 0.44 6.45 0.04 3.17 1.11 9.00

1.18 0.37 3.16 0.16 0.22 0.17 0.47 0.60 0.67 0.43 1.51

235 234 212 165 143 104 102 90 73 47 8

0.13 49.36 0.20 0.69 3.70 0.68 3.64 0.52 0.00 0.42 9.44

0.38 1.11 5.75 0.05 0.07 0.10 0.67 0.82 0.84 0.19 1.12

238 223 205 166 144 101 101 95 74 52 35

2.06 1.00 0.63 0.06 9.94 5.17 0.14 1.88 0.01 0.03 8.04

2.05 0.71 5.56 0.34 0.22 0.81 0.14 0.66 0.80 0.28 0.40

– – – – – – – – – – –

244 223 206 188 150 103 – – – – –

dCC(58) sMeI(79) dCO(46), dCC(26) cCC(36), dPhI(19), sRingII(18) sPhI(30), sCO(23), sRingII(24) dCC(71) sMeII(19) sCO(62), sMeI(19) sMeII(81) sRingII(23), cCC(32) sRingII(62), cNH(11), PhI(11)

a t-stretching; d-in-plane bending; c-out-of-plane deformation; s-torsion; PhI-phenyl ring; RingII-imidazole ring; as-asymmetric; sy-symmetric; Me-Methyl; IRI-IR intensity; RA-Raman activity; potential energy distribution is given in brackets in the assignment column.

in Raman spectrum and 924 cm1 in IR spectrum. These modes are not pure but contain a significant contribution from other modes. For 5-nitro-2-(4-nitrobenzyl) benzoxazole C–N stretching vibrations are observed in the region 1228–1195 cm1 [54]. C–N stretching modes are reported at 1268, 1220, 1151 cm1 theoretically for benzimidazolium salts by Malek et al. [38]. The C@N stretching modes were reported at 1535–1666 cm1 [55], 1592 cm1 [56] as experimentally and at 1584 cm1 theoretically [56]. In the present case the SDD calculation give C@N stretching mode at 1464 cm1. Experimentally C@N stretching mode is observed at 1462 cm1 in the IR spectrum and at 1464 cm1 in the Raman spectrum. This is in agreement with the work of Almajan et al. [57]. The benzene ring possesses six ring stretching vibrations, of which the four with the highest wave numbers (occurring near 1600, 1580, 1490 and 1440 cm1) are good group vibrations. For the title compound, the bands observed at 1612, 1552, 1505, 1340,1302 cm1 in the IR spectrum, 1614, 1556, 1520, 1358, 1307 cm1 in the Raman spectrum and at 1600, 1547, 1523, 1361, 1308 cm1 theoretically (SDD) are assigned as phenyl ring stretching modes. These modes are expected in the region 1250– 1620 cm1 [32]. The sixth ring stretching vibration or ring breathing mode appears as a weak band near 1000 cm1 in mono, 1,3-di and 1,3,5-trisubstituted benzenes. In the otherwise substituted benzene, however, this vibration is substituent sensitive and difficult to distinguish from the ring in-plane deformation. The ring breathing modes for the para di-substituted benzenes with entirely different substituent [58] have been reported to be strongly IR active with typical bands in the interval 740–840 cm1. For the title compound the ring breathing mode is assigned at 789 cm1 (SDD) and observed at 776 cm1 (IR) and 787 cm1 (Raman). Ambujakshan et al. [59] reported a value 792 cm1 (IR) and 782 cm1 (HF) as ring breathing mode. For aromatic ring tC–H modes occur above 3000 cm1 [32]. For the title compound the stretching bands are observed at 3119, 3109, 3098, 3058 cm1 (SDD) and 3126, 3112, 3086, 3056 cm1 in Raman spectrum, 3120 cm1 in IR spectrum. For para substituted benzenes, the dC–H modes are seen in the range 990– 1315 cm1 [32]. Bands observed at 1093 cm1 in the IR spectrum and at 1290, 1170, 1093, 988 cm1 in the Raman spectrum are assigned as dC–H modes for the ring Ph. The corresponding theoretical values (SDD) are 1293, 1171, 1098 and 990 cm1. The C–H out-of-plane deformations are observed between 1000 and 700 cm1 [32]. Generally the C–H out-of-plane deformations with the highest wave numbers have a weaker intensity than those absorbing at lower wave numbers. A very strong C–H out-of-plane deformation band, occurring at 840 ± 50 cm1 is typical for 1,4-disubstituted benzenes [32]. For the title compound, a

very strong cC–H is observed at 834 cm1 in IR spectrum and 808, 839, 950, 1010 cm1 in Raman spectrum. The SDD calculations give cC–H vibration at 809, 843, 945, 993 cm1. Again according to literature [52,32] a lower cC–H absorbs in the neighborhood 820 ± 45 cm1, but is much weaker or infrared inactive and the corresponding theoretical mode is 809 cm1. In order to investigate the performance of vibrational wavenumbers of the title compound, the root mean square (RMS) value and correlation coefficients between the calculated and observed wavenumbers were calculated (Fig. 4). The RMS values of wavenumbers were calculated using the following expression [60].

vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi u n u 1 X exp 2 RMS ¼ t t tcal i n 1 i¼1 i The RMS errors of the observed IR and Raman bands are found to be 23.09 and 25.45 for HF/631-G(6D, 7F), 20.06 and 17.13 for B3LYP/6-31G(d)(6D, 7F) and 10.13 and 7.64 for B3LYP/SDD(6D, 10F) methods, respectively. The small differences between experimental and calculated vibrational modes are observed. This is due to the fact that experimental results belong to solid phase and theoretical calculations belong to gaseous phase. 4.2. Optimized geometry To the best of our knowledge, the XRD of the title compound is not yet reported. The optimized molecular structure of 2-(4-meth oxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide was determined by using Gaussian09 program. From Table 1, it is clearly seen that the dihedral angles C1–C6–C16–N17, C5–C6–C16–N18 are 180° and C1–C6–C16–N18, C5–C6–C16–N17 are 0°. This indicates that the benzene ring and the imidazole ring moieties of the title compound are planar. For the title compound the carbon–carbon bond lengths in the phenyl ring lies between 1.3959 and 1.4186 Å. The C–H bond lengths lies between 1.08 and 1.09 Å for the phenyl ring. Here for the title compound, benzene is a regular hexagon with bond lengths somewhere in between the normal values for a single (1.54 Å) and a double (1.33 Å) bond [61]. The bond length of C1–C6 is large (1.42 Å) due to the presence of imidazole ring [59]. The C–O bond lengths are, C3–O11 = 1.3956 Å and C12–O11 = 1.4569 Å for the title compound which are in close agreement with reported values C3–O11 = 1.3959 Å and C12–O11 = 1.4565 Å [62]. For the title compound, the bond angle of C2–C1–C6, C1–C2–C3 are 121.2°, 119.7°, and which is in agreement with the reported values 120.4° and 120.0° [59,63]. The bond angles of C3–C4–C5 (120.1°) and C1–C6–C5 (118.1°) which are agreement with literature [59].

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Fig. 4. Correlation graph.

For the imidazole ring the bond angles of N17–C16–N18 and N17– C21–C22 are 112.0° and 108.5°, where the reported values are 113.1° and 110.0° [64]. For the title compound, the bonds C16–N17 = 1.3679 Å shows typical double bond characteristics. However, C21–N17 = 1.4176 Å, C22–N18 = 1.4001 Å, C16–N18 = 1.391 Å bond lengths are shorter than the normal C–N single bond length of about 1.48 Å, where the reported values are 1.407, 1.395, 1.3874 Å [64,65]. The shortening of the C–N bonds reveal the effects of resonance in this part of the molecule [66] and this situation can be attributed to the difference in hybridization of the different carbon atoms. Purkayastha and Chattopadhyay [62] reported N17–C16, N17–C21 bond lengths as 1.3270, 1.400 Å for benzothiazole and 1.3503, 1.407 Å for benzimidazole compounds. Lifshitz et al. [67] reported the bond lengths for C22–C24, C21–C23 as 1.374 and 1.4 Å. In the present case the bond length of C22–C24 and C21–C23 are 1.4988 and 1.4923 Å, the bond length is very high due to the presence of methyl group. The bond length of C21–C22 is 1.383 Å which is agreement with the reported value [67]. Bigotto et al. [68] reported the bond length of C21–C22 as 1.3827 Å. 4.3. Frontier molecular orbitals

Fig. 5. HOMO and LUMO plots of 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide.

Frontier molecular orbital refer to the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). The HOMO is outermost higher energy orbital containing electrons so it acts as an electron donor. The LUMO is the lowest energy orbital that has the room to accept electrons so it acts as

Fig. 6. MEP plot of 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide.

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K.B. Benzon et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 151 (2015) 965–979 Table 3 Second-order perturbation theory analysis of Fock matrix in NBO basis corresponding to the intra molecular bonds of the title compound. Donor (i) C1–C2 – – – C1–C2 – C1–C6 – – – C2–C3 – – C3–C4 – C3–C4 – – C3–O11 – C4–C5 – – – C5–C6 – – – C5–C6 – – C6–C16 – – – – – – – O11–C12 C16–N17 – – – – – C16–N17 – – C16–N18 – – – – – – N17–O20 – – – N17–C21 – – – – – – N18–H19 – N18–C22 – – – –

Type

r – – –

p –

r – – –

r – –

r –

p – –

r –

r – – –

r – – –

p – –

r – – – – – – –

r r – – – – –

p – –

r – – – – – –

r – – –

r – – – – – –

r –

r – – – –

ED/e 1.97593 – – – 1.72938 – 1.97234 – – – 1.97188 – – 1.98089 – 1.65921 – – 1.98850 – 1.97368 – – – 1.96951 – – – 1.62358 – – 1.96938 – – – – – – – 1.99108 1.98003 – – – – – 1.85803 – – 1.97796 – – – – – – 1.98848 – – – 1.97651 – – – – – – 1.98747 – 1.97858 – – – –

Acceptor (j) C1–C6 C2–C3 C3–O11 C6–C16 C3–C4 C5–C6 C1–C2 C5–C6 C6–C16 C16–N17 C1–C2 C3–C4 O11–C12 C2–C3 C4–C5 C1–C2 C3–C4 C5–C6 C1–C2 C4–C5 C3–C4 C3–O11 C5–C6 C6–C16 C1–C6 C4–C5 C6–C16 C16–N18 C1–C2 C3–C4 C16–N17 C1–C2 C1–C6 C4–C5 C5–C6 C16–N17 C16–N18 N17–C21 N18–C22 C2–C3 C1–C6 C6–C16 N17–C21 N18–H19 C21–C23 C22–C24 C5–C6 C16–N17 C21–C22 C5–C6 C6–C16 N17–O20 N18–H19 N18–C22 C21–C23 C22–C24 C16–N17 C16–N18 N17–C21 C21–C22 C6–C16 C16–N17 C16–N18 N18–C22 C21–C22 C21–C23 C22–C24 C16–N17 C21–C22 C6–C16 C16–N17 C16–N18 N17–O20 N17–C21

Type ⁄

r r⁄ r⁄ r⁄ r⁄ p⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ p⁄ p⁄ p⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ p⁄ p⁄ p⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ p⁄ p⁄ p⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄

ED/e

E(2)a (kJ/mol)

E(j) E(i)b (a.u.)

F(i,j)c (a.u.)

0.02346 0.02355 0.03692 0.02716 0.03033 0.39430 0.01118 0.02236 0.02716 0.04954 0.01118 0.03033 0.01164 0.02355 0.01365 0.31363 0.39338 0.39430 0.01118 0.01365 0.03033 0.03692 0.02236 0.02716 0.02346 0.01365 0.02716 0.02212 0.31363 0.39338 0.61705 0.01118 0.02346 0.01365 0.02236 0.04954 0.02212 0.05978 0.02913 0.02355 0.02346 0.02716 0.05978 0.01696 0.01310 0.01463 0.39430 0.61705 0.31227 0.02236 0.02716 0.01675 0.01696 0.02913 0.01310 0.01463 0.04954 0.02212 0.05978 0.02675 0.02716 0.04954 0.02212 0.02913 0.02675 0.01310 0.01463 0.04954 0.02675 0.02716 0.04954 0.02212 0.01675 0.05978

2.13 1.65 3.90 4.34 20.73 16.88 1.95 2.70 1.97 4.30 1.65 2.57 4.08 2.76 1.84 18.50 0.56 23.08 2.20 1.99 2.15 5.42 1.82 4.51 2.88 1.55 2.21 4.31 22.22 19.37 32.40 2.91 1.76 2.99 2.03 1.74 1.02 3.19 2.77 3.10 2.24 2.05 1.23 3.38 3.14 0.68 7.11 1.36 15.91 2.52 1.44 4.75 0.65 1.09 0.84 3.87 0.80 1.68 0.73 1.48 4.83 1.36 0.78 0.95 0.64 0.56 5.35 2.23 2.25 4.28 0.64 1.10 0.61 0.90

1.21 1.22 0.99 1.17 0.28 0.29 1.24 1.21 1.16 1.10 1.25 1.22 0.91 1.23 1.26 0.29 0.28 0.29 1.43 1.43 1.21 0.98 1.21 1.16 1.19 1.23 1.15 1.06 0.27 0.27 0.19 1.24 1.20 1.25 1.21 1.10 1.07 1.06 1.07 1.31 1.35 1.31 1.20 1.26 1.24 1.21 0.39 0.30 0.38 1.34 1.29 1.09 1.24 1.20 1.22 1.19 1.26 1.23 1.21 1.40 1.26 1.20 1.17 1.16 1.34 1.18 1.16 1.13 1.27 1.28 1.22 1.19 1.08 1.17

0.045 0.040 0.056 0.064 0.070 0.065 0.044 0.051 0.043 0.062 0.041 0.050 0.055 0.052 0.043 0.066 0.011 0.075 0.050 0.048 0.045 0.065 0.042 0.065 0.052 0.039 0.045 0.061 0.070 0.064 0.075 0.054 0.041 0.055 0.044 0.039 0.030 0.052 0.049 0.057 0.049 0.046 0.035 0.058 0.056 0.026 0.050 0.021 0.072 0.052 0.039 0.064 0.025 0.032 0.029 0.061 0.029 0.041 0.027 0.041 0.070 0.036 0.027 0.030 0.026 0.023 0.070 0.045 0.048 0.066 0.025 0.032 0.023 0.029 (continued on next page)

974


Table 3 (continued) Donor (i) – – – C21–C22 – – – – – C21–C22 C21–C23 – – C 22–C24 – – LPO11 LPO11 LPN18 – LPO20 – LPO20 – – LPO20 a b c

Type – – –

r – – – – –

p r – –

r – –

r p r –

r –

p – – n

ED/e – – – 1.96794 – – – – – 1.81825 1.98097 – – 1.98152 – – 1.96767 1.85312 1.63091 – 1.97462 – 1.92769 – – 1.74852

Acceptor (j) N18–H19 C21–C22 C21–C23 C6–C16 N17–O20 N18–H19 N18–C22 C21–C23 C22–C24 C16–N17 C16–N17 N18–C22 C21–C22 C16–N18 N17–C21 C21–C22 C3–C4 C3–C4 C16–N17 C21–C22 C16–N17 N17–C21 C16–N17 C16–N18 N17–C21 C16–N17

Type ⁄

r r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ p⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ r⁄ p⁄ p⁄ p⁄ r⁄ r⁄ r⁄ r⁄ r⁄ p⁄

ED/e

E(2)a (kJ/mol)

E(j) E(i)b (a.u.)

F(i,j)c (a.u.)

0.01696 0.02675 0.01310 0.02716 0.01675 0.01696 0.02913 0.01310 0.01463 0.61705 0.04954 0.02913 0.02675 0.02212 0.05978 0.31227 0.03033 0.39338 0.61705 0.31227 0.04954 0.05978 0.04954 0.02212 0.05978 0.61705

0.69 0.73 5.39 0.82 4.65 4.94 0.60 2.42 2.24 13.09 3.72 2.14 2.76 3.41 2.32 2.69 7.29 27.28 50.66 32.60 6.58 4.12 7.50 0.59 10.08 42.80

1.23 1.36 1.21 1.20 1.00 1.15 1.11 1.13 1.10 0.23 1.06 1.03 1.20 1.05 1.03 1.22 1.07 0.33 0.24 0.31 1.18 1.13 0.64 0.61 0.59 0.16

0.026 0.028 0.072 0.028 0.061 0.067 0.023 0.047 0.044 0.055 0.057 0.042 0.052 0.053 0.044 0.051 0.079 0.091 0.105 0.092 0.079 0.061 0.062 0.017 0.069 0.081

E(2) means energy of hyper-conjugative interactions (stabilization energy). Energy difference between donor and acceptor i and j NBO orbitals. F(i,j) is the Fock matrix element between i and j NBO orbitals.

an electron acceptor. The frontier molecular orbitals can offer a reasonable qualitative prediction of the excitation properties and the ability of electron transport [69,70]. The HOMO and LUMO are also very popular quantum chemical parameters which determine the molecular reactivity. The energies of the HOMO and LUMO orbitals of the title compound are calculated using DFT/B3LYP method and shown in Fig. 5. The energies of HOMO and LUMO are negative, which indicates that the studied compound is stable [71]. For understanding various aspects of pharmacological science including drug design and the possible eco-toxicological characteristics of the drug molecules, several new chemical reactivity descriptors have been proposed. Conceptual DFT based descriptors have helped in many ways to understand the structure of the molecules and their reactivity by calculating the chemical potential, global hardness and electrophilicity. Using HOMO and LUMO orbital energies, the ionization energy and electron affinity can be expressed as: I = EHOMO, A = ELUMO, g = (EHOMO + ELUMO)/2 and l = (EHOMO + ELUMO)/2 [72]. Parr et al. [73] proposed the global electrophilicity power of a ligand as x = l2/2g. This index measures the stabilization in energy when the system acquired an additional electronic charge from the environment. Electrophilicity encompasses both the ability of an electrophile to acquire additional electronic charge and the resistance of the system to exchange electronic charge with the environment. It contains information about both electron transfer (chemical potential) and stability (hardness) and is a better descriptor of global chemical reactivity. The hardness g and chemical potential l are given by the following relations: g = (I A)/2 and l = (I + A)/2, where I and A are the first ionization potential and electron affinity of the chemical species [74]. For the title compound, EHOMO = 7.97 eV, ELUMO = 5.11 eV, Energy gap = HOMO–LUMO = 2.86 eV, Ionization potential I = 7.97 eV, Electron affinity A = 5.11 eV, global hardness g = 1.43 eV, chemical potential l = -6.54 eV and global electrophilicity = l2/2g = 14.95 eV. It is seen that the chemical potential of the title compound is negative and it means that the compound is stable.

They do not decompose spontaneously into the elements they are made up of. The hardness signifies the resistance toward the deformation of electron cloud of chemical systems under small perturbation encountered during the chemical process. The principle of hardness works in chemistry and physics but it is not physically observable. Soft systems are large and highly polarisable, while hard systems are relatively small and much less polarisable. Mandal et al. [75] reported the cyclometalated rhodium and iridium complexes with imidazole containing Schiff bases and the HOMO, LUMO values are 48.73 and 16.21 eV for iridium complexes and 49.02 and 16.78 eV, rhodium complexes with imidazoles. Abood et al. [76] reported the energy gap for imidazole is 6.938 eV, benzimidazole is 6.639 eV, 2-methylbenzimidazole is 0.898 eV, 2-ethylbenzimidazle is 6.585 eV. 4.4. Molecular electrostatic potential (MEP) MEP is related to the ED and is a very useful descriptor in understanding sites for electrophonic and nucleophilic reactions as well as hydrogen bonding interactions [77,78]. The electrostatic potential V(r) is also well suited for analyzing processes based on the ‘‘recognition’’ of one molecule by another, as in drug–receptor, and enzyme–substrate interactions, because it is through their potentials that the two species first ‘‘see’’ each other [79,80]. To predict reactive sites of electrophilic and nucleophilic attacks for the investigated molecule, MEP at the B3LYP/6-31G(d)(6D, 7F) optimized geometry was calculated. The different values of the electrostatic potential at the MEP surface are represented by different colours: red, blue and green represent the regions of most negative, most positive and zero electrostatic potential respectively. The negative electrostatic potential corresponds to an attraction of the proton by the aggregate electron density in the molecule (shades of red), while the positive electrostatic potential corresponds to the repulsion of the proton by the atomic nuclei (shade of blue). The negative (red and yellow) regions of MEP were related to electrophilic reactivity and the positive (blue) regions to

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K.B. Benzon et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 151 (2015) 965–979 Table 4 NBO results showing the formation of Lewis and non-Lewis orbitals.

Table 5 The charge distribution calculated by the Mulliken and natural bond orbital methods.

Bond (A–B)

ED/ energya

EDA%

EDB%

NBO

s%

p%

Atoms

Atomic charges (Mulliken)

Natural charges

rC1–C2

1.9759 0.69347 1.72938 0.25415 1.97234 0.67901 1.97188 0.68840 1.98089 0.70009 1.65921 0.25509 1.98850 0.86672 1.97368 0.68017 1.96951 0.67070 1.62358 0.23755 1.96938 0.68235 1.99108

50.28 – 49.74 – 49.15 – 49.82 – 49.93 – 47.23 – 31.70 – 50.67 – 48.32 – 44.99 – 49.76 – 68.53

49.72 – 50.26 – 50.85 – 50.18 – 50.07 – 52.77 – 68.30 – 49.33 – 51.68 – 55.01 – 50.24 – 31.47

0.7091(sp1.77)C+ 0.7051(sp1.76)C 0.7053(sp1.00)C+ 0.7090(sp1.00)C 0.7011(sp1.80)C+ 0.7131(sp1.97)C 0.7058(sp1.89)C+ 0.7084(sp1.73)C 0.7066(sp1.61)C+ 0.7076(sp1.90)C 0.6873(sp1.00)C+ 0.7264(sp1.00)C 0.5631(sp3.01)C+ 0.8264(sp2.17)O 0.7118(sp1.74)C+ 0.7024(sp1.82)C 0.6952(sp1.95)C+ 0.7189(sp1.88)C 0.6707(sp1.00)C+ 0.7417(sp1.00)C 0.7054(sp2.16)C+ 0.7088(sp1.42)C 0.8279(sp2.86)O+

36.10 36.21 0.00 0.00 35.69 33.64 34.57 36.60 38.34 34.48 0.00 0.00 24.94 31.55 36.54 35.40 34.20 34.73 0.00 0.00 31.62 41.32 25.92

63.90 63.79 100.00 100.00 64.31 66.36 65.43 36.60 61.66 65.52 100.00 100.00 75.06 68.45 63.46 64.60 65.80 65.27 100.00 100.00 68.38 58.68 74.08

0.78312 1.98003

– 37.63

– 62.37

0.5609(sp3.86)C 0.6135(sp2.33)C+

20.56 30.03

79.44 69.97

0.83144 1.85803

– 34.93

– 65.07

0.7897(sp1.79)N 0.5910(sp1.00)C+

35.80 0.00

64.20 100.00

C1 C2 C3 C4 C5 C6 H7 H8 H9 H10 O11 C12 H13 H14 H15 C16 N17 N18 H19 O20 C21 C22 C23 C24 H25 H26 H27 H28 H29 H30

0.337036 0.359929 0.334677 0.351214 0.392701 0.349569 0.181209 0.242241 0.233008 0.314680 0.309431 0.472751 0.231073 0.207774 0.207773 0.222320 0.072804 0.439401 0.319194 0.441407 0.201919 0.214161 0.710113 0.735072 0.243422 0.190965 0.243331 0.225751 0.233121 0.225671

0.19974 0.24119 0.33180 0.29719 0.16668 0.12831 0.19796 0.23293 0.22328 0.26520 0.56678 0.26165 0.21803 0.19278 0.19278 0.39736 0.02680 0.59538 0.43079 0.60140 0.14885 0.17463 0.66688 0.66743 0.24641 0.21950 0.24633 0.23093 0.23894 0.23091

0.34614 1.97796

– 37.00

– 63.00

0.8066(sp1.00)N 0.6083(sp2.49)C+

0.00 28.66

100.00 71.34

0.80882 1.98848

– 52.94

– 47.06

0.7937(sp1.89)N 0.7276(sp2.37)N+

34.58 29.69

65.42 29.69

0.83895 1.97651

– 63.45

– 36.55

0.6860(sp5.29)O 0.7965(sp1.92)N+

15.90 34.21

84.10 65.79

0.77673 1.98747

– 72.06

– 27.94

0.6046(sp2.95)C 0.8489(sp2.38)N+

25.34 29.55

74.66 70.45

0.70536 1.97858

– 63.49

– 36.51

0.5286(sp)H 0.7968(sp1.79)N+

100.00 35.80

0.00 64.20

0.80038 1.96794

– 49.71

– 50.29

0.6043(sp2.89)C 0.7051(sp1.68)C+

25.73 37.35

74.27 62.65

0.71883 1.81825

– 50.19

– 49.81

0.7091(sp1.66)C 0.7085(sp1.00)C+

37.53 0.00

62.47 100.00

0.27327 1.98097

– 50.73

– 49.27

0.7058(sp1.00)C 0.7122(sp1.68)C+

0.00 37.25

100.00 62.75

rC22–

0.63902 1.98152

– 50.31

– 49.69

0.7019(sp2.43)C 0.7093(sp1.73)C+

29.15 36.67

70.85 63.33

C24 – n1O11 – n2O11 – n1N18 – n1O20 – n2O20 – n3O20 –

0.65794 1.96767 0.54075 1.85312 0.30496 1.63091 0.28165 1.97462 0.75356 1.92769 0.21448 1.74852 0.20334

– – – – – – – – – – – – –

– – – – – – – – – – – – –

0.7049(sp2.39)C sp1.35 – sp1.00 – sp1.00 – sp0.19 – sp99.99 – sp1.00 –

29.50 42.54 – 0.00 – 0.00 – 83.84 – 0.33 – 0.00 –

70.50 57.46 – 100.00 – 100.00 – 16.16 – 99.67 – 100.00 –

–

pC1–C2 –

rC1–C6 –

rC2–C3 –

rC3–C4 –

pC3–C4 –

rC3–O11 –

rC4–C5 –

rC5–C6 –

pC5–C6 –

rC6–C16 –

rO11– C12 –

rC16– N17 –

pC16– N17 –

rC16– N18 –

rN17– O20 –

rN17–

nucleophilic reactivity (Fig. 6). From the MEP it is evident that the negative charge covers the nitro group and the positive region is over the NH part of the imidazole ring. The more electro negativity in the nitro group makes it the most reactive part in the molecule.

C21 –

rN18– H19 –

rN18– C22 –

rC21– C22 –

pC21– C22 –

rC21– C23 –

a

ED/energy is a.u.

4.5. Natural bond orbital analysis The natural bond orbital (NBO) calculations were performed using NBO 3.1 program [81] as implemented in the Gaussian09 package at the DFT/B3LYP level in order to understand various second-order interactions between the filled orbital of one subsystem and vacant orbital of another subsystem, which is a measure of the intra-molecular delocalization or hyper conjugation. NBO analysis provides the most accurate possible ‘natural Lewis structure’ picture of ‘j’ because all orbital details are mathematically chosen to include the highest possible percentage of the electron density. A useful aspect of the NBO method is that it gives information about interactions of both filled and virtual orbital spaces that could enhance the analysis of intra and inter molecular interactions. The second-order Fock-matrix was carried out to evaluate the donor–acceptor interactions in the NBO basis. The interactions result in a loss of occupancy from the localized NBO of the idealized Lewis structure into an empty non-Lewis orbital. For each donor (i) and acceptor (j) the stabilization energy (E2) associated with the delocalization i ? j is determined as

Eð2Þ ¼ DEij ¼ qi

ðF i;j Þ2 ðEj Ei Þ

where, qi ? donor orbital occupancy, Ei, Ej ? diagonal elements and Fij ? the off diagonal NBO Fock matrix element. In NBO analysis large E(2) value shows the intensive interaction between

976


Table 6 Calculated Mulliken charges of 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3oxide. Atom

HF/6-31G(6D, 7F)

B3LYP/6-31G(d)(6D, 7F)

B3LYP/SDD(6D, 10F)

C1 C2 C3 C4 C5 C6 H7 H8 H9 H10 O11 C12 H13 H14 H15 C16 N17 N18 H19 O20 C21 C22 C23 C24 H25 H26 H27 H28 H29 H30

0.158548 0.231114 0.418596 0.247592 0.141779 0.058898 0.193573 0.226736 0.217967 0.322264 0.779993 0.126999 0.193848 0.164538 0.163603 0.860594 0.619395 1.039620 0.400926 0.571839 0.282130 0.282961 0.409683 0.448756 0.202125 0.146903 0.202649 0.181245 0.193164 0.180394

0.194063 0.179781 0.380638 0.203805 0.197292 0.146480 0.102050 0.136257 0.136002 0.199798 0.508689 0.215745 0.168781 0.147472 0.161828 0.492165 0.136535 0.724064 0.341057 0.572160 0.257850 0.288968 0.512045 0.537676 0.188066 0.144654 0.173848 0.161472 0.179671 0.174798

0.336689 0.359992 0.334708 0.350909 0.393066 0.349662 0.181115 0.242231 0.232965 0.314824 0.309406 0.472846 0.231110 0.215025 0.200508 0.221904 0.072919 0.439435 0.319196 0.440929 0.202369 0.213815 0.710515 0.735216 0.236431 0.190963 0.250560 0.232910 0.233115 0.218511

electron-donors and electron-acceptors, and greater the extent of conjugation of the whole system, the possible intensive interaction are given in Table 3. The second-order perturbation theory analysis of Fock-matrix in NBO basis shows strong intra-molecular hyper conjugative interactions are formed by orbital overlap between n(O), n(N) and p*(C–C), p*(C–N), bond orbital which result in ICT causing stabilization of the system. These interactions are observed as an increase in electron density (ED) in C–C and C–N anti bonding orbital that weakens the respective bonds. There occurs a strong intra-molecular hyper conjugative interaction of C3–C4 from O11 of n2(O11) ? p*(C3–C4) which increases ED (0.39338 e) that weakens the respective bonds C3–C4 leading to stabilization of 27.28 kJ/mol. There occurs a strong inter molecular hyper conjugative interaction of C16–N17 from N18 of n1(N18) ? p*(C16–N17) which increases ED (0.61705 e) that weakens the respective bonds C16–N17 leading to stabilization of 50.66 kJ/mol and also the hyper conjugative interaction of C16–N17 from O20 of n3(O20) ? p*(C16–N17) which increases ED (0.61705 e) that weakens the respective bonds C16–N17 leading to stabilization of 42.80 kJ/mol. The increased electron density at the oxygen atoms leads to the elongation of respective bond length and a lowering of the corresponding stretching wave number. The electron density (ED) is transferred from the n(O) and n(N) to the anti-bonding p* orbital of the C–C and C–N bonds, explaining both the elongation and the red shift [82]. The hyper conjugative interaction energy was deduced from the second-order perturbation approach. Delocalization of electron density between occupied Lewis-type (bond or lone pair) NBO orbitals and formally unoccupied (anti bond or Rydberg) non-Lewis NBO orbitals corresponds to a stabilizing donor–acceptor interaction. Hence the structure 2-(4-methoxyphenyl)-4,5-dimethyl-1H-i midazole 3-oxide is stabilized by these orbital interactions. The NBO analysis also describes the bonding in terms of the natural hybrid orbital n2(O11), which occupy a higher energy orbital (0.30496 a.u.) with considerable p-character (100%) and low occupation number (1.85312) and the other n1(O11) occupy a lower

Fig. 7. Mulliken plot of2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide.

energy orbital (0.54075 a.u.) with p-character (57.46%) and high occupation number (1.96767). The NBO analysis also describes the bonding in terms of the natural hybrid orbital n3(O20), which occupy a higher energy orbital (0.20334 a.u.) with considerable p-character (100%) and low occupation number (1.74852) and the other n1(O20) occupy a lower energy orbital(0.75356 a.u.) with p-character (16.16%) and high occupation number (1.97462). Thus, a very close to pure p-type lone pair orbital participates in the electron donation to the p⁄(C3–C4) orbital for n2(O11) ? p⁄(C3–C4), p⁄(C16–N17) orbital for n1(N18) ? p⁄(C16– N17) and p⁄(C16–N17) orbital for n3(O20) ? p⁄(C16–N17) interaction in the compound. The results are tabulated in Table 4. 4.6. Hyperpolarizability Nonlinear optics deals with the interaction of applied electromagnetic fields in various materials to generate new electromagnetic fields, altered in wavenumber, phase, or other physical properties [83]. Organic molecules able to manipulate photonic signals efficiently are of importance in technologies such as optical communication, optical computing and dynamic image processing [84,85]. In this context, the dynamic first hyperpolarizability of the title compound is also calculated in the present study. The first hyperpolarizability (b0) of this novel molecular system is calculated using SDD method, based on the finite field approach. In the presence of an applied electric field, the energy of a system is a function of the electric field. First hyperpolarizability is a third rank tensor that can be described by a 3 3 3 matrix. The 27 components of the 3D matrix can be reduced to 10 components due to the Kleinman symmetry [86]. The components of b are defined as the coefficients in the Taylor series expansion of the energy in the external electric field. When the electric field is weak and homogeneous, this expansion becomes

E ¼ E0

X

li F i

i

1X 1X 1 X aij F i F j b FiF jFk c FiF jFkFl 2 ij 6 ijk ijk 24 ijkl ijkl

þ ::: where E0 is the energy of the unperturbed molecule, Fi is the field at the origin, lij, aij, bijk and cijkl are the components of dipole moment, polarizability, the first hyperpolarizability, and second hyperpolarizability, respectively [87]. The calculated first hyperpolarizability of the title compound is 2.95 1030 esu, which is 22.69 times that of standard NLO material urea (0.13 1030 esu) [88]. The reported values of hyperpolarizability of similar derivatives are 2.7 1030 esu and 2.24 1030 esu [64,89]. Karnan et al. [90] reported the first hyperpolarizability of an imidazole derivative as


977

Table 7 Experimental and calculated 1H NMR parameters (with respect to TMS). Protons

rTMS

B3LYP/6-31G(d)(6D, 7F)

dcalc = rTMS rcalc

Exp. dppm

H7 H8 H9 H10 H13 H14 H15 H19 H25 H26 H27 H28 H29 H30

32.7711

25.7092 24.8813 24.9408 25.7595 28.7590 28.7699 28.8697 28.6668 30.7174 30.6430 30.6685 30.8907 30.7873 30.8174

7.0619 7.8898 7.8303 7.0116 4.0121 4.0012 3.9014 4.1043 2.0537 2.1281 2.1026 1.8804 1.9838 1.9537

6.96 8.35 8.35 6.96 3.77 3.77 3.77 3.77 2.03 2.03 2.03 1.79 1.79 1.79

2.18 1030 esu. The average second hyperpolarizability is = (cxxxx + cyyyy + czzzz + 2cxxyy + 2cxxzz + 2cyyzz)/5. The theoretical second order hyperpolarizability was calculated using the Gaussian09 software and is equal to 0.137513 1035 esu [91–93]. We conclude that the title compound is an attractive object for future studies of nonlinear optical properties. Benzon et al. [94] reported the first and second hyperpolarizability of an imidazole derivative as 2.55 1030 esu and 8.502 1037 esu. 4.7. Mulliken charges The calculation of atomic charges plays an important role in the application of quantum mechanical calculations to molecular systems. Mulliken charges are calculated by determining the electron population of each atom as defined in the basis functions. The charge distributions calculated by the Mulliken [95] and NBO methods for the equilibrium geometry of 2-(4-methoxypheny l)-4,5-dimethyl-1H-imidazole 3-oxide are given in Table 5. The charge distribution on the molecule has an important influence on the vibrational spectra. In 2-(4-methoxyphenyl)-4,5-dimethy l-1H-imidazole 3-oxide, the Mulliken atomic charge of the carbon atoms in the neighborhood of C3, C6, C16 and C22 become more positive, shows the direction of delocalization and shows that the natural atomic charges are more sensitive to the changes in the molecular structure than Mulliken’s net charges. Also we done a comparison of Mulliken charges obtained by different basis sets and tabulated it in Table 6 in order to assess the sensitivity of the calculated charges to changes in (i) the choice of the basis set, (ii) the choice of the quantum mechanical method. The results can, however, better be represented in graphical form as shown in Fig. 7. We have observed a change in the charge distribution by changing different basis sets. 4.8. 1H NMR spectrum With TMS as internal standard, experimental spectrum data of 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide in DMSO is obtained at 500 MHz and is shown in Table 7. B3LYP/ GIAO was used to calculate the absolute isotropic chemical shielding of 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide [96]. Numerical values of chemical shift dpred = rcalc (TMS) rcalc together with calculated values of rcalc (TMS), are reported in Table 7. It is seen that chemical shift was in agreement with the experimental 1H NMR data. Thus, the results has shown that the predicted proton chemical shifts were in good agreement with the experimental data for 2-(4-methoxyphenyl)-4,5-dimethyl1H-imidazole 3-oxide.

Fig. 8. Schematic representation of interaction regions in Protein (PDB-ID-2BDM) with 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide.

4.9. Molecular docking The cytochrome P450 protein ubiquitous super family (P450) consists of many b-type hemoproteins, comprises structural as well as functional similarity. Cytochrome P450 from the 2B subfamily (CYP2B4) was first isolated from rabbit liver microsomes and is mainly inducible by barbiturates [97]. Moreover, fifty-seven cytochrome P450 which accounts for 90% of drug metabolism are encoded by human genome and mainly occurred as five isoforms [98]. Cytochrome P540s generally found on the endoplasmic reticulum as component of electron transport system in eukaryotic cells, but few are localized in mitochondria. Freshly, CYP2B4 enzyme has been considered as entity for numerous biochemical investigations. It is also reported that they are involved into metabolism of various physiological compounds that is xenobiotics, fat soluble vitamins as well as in activation of several carcinogens [99]. Recently, inhibitory activity of imidazole with CYP2B4 enzyme was studied and explored by molecular docking and dynamics. Based on the molecular docking and molecular dynamics approach they observed that imidazoles compounds have better binding affinities with the active site pocket (comprising of Thr-302) of the CYP2B4 enzyme [100]. Protein target, Cytochrome P450 from the 2B subfamily CYP2B4 (PDB ID: 2BDM) was retrieved from database Protein Data Bank (PDB) [101]. 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide structure was created by Chem Sketch and 3D structures of ligand was obtained by using ‘‘Chemdraw’’. Prior to molecular docking, all water molecules were removed and on final stage hydrogen atoms were added to receptor molecule. The molecular Docking was performed using Autodock 4 [102]. The polar hydrogen’s were added to 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imid azole 3-oxide using the hydrogen’s module in auto dock tool. Docking of CYP2B4 to 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imi dazole 3-oxide was carried out using LGA with standard docking protocol. The required grid maps were calculated using auto grid and grid size was set to 60 Å 60 Å 60 Å points with grid spac0

ing of 0.375 Å A. Total ten conformations were obtained as output of docking in autodock. The conformation have lowest binding energy was selected for the binding analysis and visualized by using Molegro molecular viewer [103]. The present study helps us to understand the interaction between the imidazole and receptor CYP2B4 protein and also explore their binding mode. The top 10 docking confirmations for imidazole were obtained and having lowest binding energy

978


generated by Autodock 4 was selected for binding analysis. The result revealed that the binding energy was 8.26 kJ/mol. The ligands formed three hydrogen bonds with residues, Thr-306, Ile-363 and Gln-357 (Fig. 8). On comparing binding pattern of the receptor with other imidazoles, found that binding with active site in terms of hydrogen bonds with the various residues. Our docking results indicated that the said compound bound in the pocket include the residues construct the active pocket of CYP2B4. 5. Conclusion The vibrational spectroscopic studies of 2-(4-methoxyphenyl)4,5-dimethyl-1H-imidazole 3-oxide in the ground state were reported experimentally and theoretically. Potential energy distribution of normal modes of vibrations was done using GAR2PED program. The observed wavenumbers are found to be in agreement with calculated (SDD) values. The ring stretching modes in IR and Raman spectra are evidence for charge transfer interaction between the donor and the acceptor group through the p system. This along with the lowering of HOMO–LUMO band gap supports for the bioactivity of the molecule. From the MEP plot, it is evident that the negative charge covers the nitro group and the positive region is over the NH part of the imidazole ring. The calculated first hyperpolarizability of the title compound is 22.69 times that of standard NLO material urea and comparable with the reported values of similar derivatives and is an attractive object for future studies in nonlinear optics. The calculated 1H NMR results are in good agreement with experimental data. From the molecular docking study, the title compound formed three hydrogen bonds with residues, Thr-306, Ile-363 and Gln-357 and the results indicated that the said compound bound in the pocket include the residues construct the active pocket of CYP2B4. Acknowledgements The authors are thankful to University of Antwerp for access to the university’s CalcUA Supercomputer Cluster. KBB thanks University of Kerala for a research fellowship. References [1] H. Kucukbay, R. Durmaz, E. Orhan, S. Gunal, II Farmaco 58 (2003) 431–437. [2] N.M.A. Atabay, B. Dulger, F. Gucin, Eur. J. Med. Chem. 38 (2003) 875–881. [3] E.G. Brown, Ring Nitrogen and Key Biomolecules, Kluwer Academic Press, 1998. [4] J.W. Leahy, C.A. Buhr, H.W.B. Johnson, B. Gyu Kim, T.G. Baik, J. Cannoy, T.P. Forsyth, J.W. Jeong, M.S. Lee, S. Ma, K. Noson, L. Wang, M. Williams, J.M. Nuss, E. Brooks, P. Foster, L. Goon, N. Heald, C. Holst, C. Jaeger, S. Lam, J. Lougheed, L. Nguyen, A. Plonowski, J. Song, T. Stout, X. Wu, M.F. Yakes, P. Yu, W. Zhang, P. Lamb, O. Raeber, J. Med. Chem. 55 (2012) 5467–5482. [5] J. Cheng, J. Xie, X. Luo, Bioorg. Med. Chem. Lett. 15 (2005) 267–269. [6] Y. He, J. Yang, B. Wu, L. Risen, E.E. Swayze, Bioorg. Med. Chem. Lett. 14 (2004) 1217–1220. [7] M.A. Ismail, R. Brun, T. Wenzler, F.A. Tanious, D. Wilson, D.W. Boykin, Bioorg. Med. Chem. 12 (2004) 5405–5413. [8] R. Marquis, J. Sheng, T. Nguyen, J. Baldeck, J. Olsson, Arch. Oral Biol. 51 (2006) 1015–1023. [9] A.T. Mavrova, K. Anichina, D. Vuchev, J. Tsenov, P. Denkova, M. Kondeva, M. Micheva, Eur. J. Med. Chem. 41 (2006) 1412–1420. [10] M. Boiani, M. Gonzalez, Mini Rev. Med. Chem. 5 (2005) 409–424. [11] S.O.P. Kuzmonovic, L.M. Leovac, N.U. Perisicjanjic, J. Rogan, J. Balaz, J. Serb. Chem. Soc. 64 (5–6) (1999) 381–388. [12] A. Pesquet, A. Daiech, K.L. Van, J. Org. Chem. 71 (2006) 5303–5311. [13] C. Congiu, M.T. Cocco, V. Onnis, Bioorg. Med. Chem. Lett. 18 (2008) 989–993. [14] A.M. Venkatesan, A. Agarwal, T. Abe, H.O. Ushirogochi, D. Santos, Z. Li, G. Francisco, Y.I. Lin, P.J. Peterson, Y. Yang, W.J. Weiss, D.M. Shales, T.S. Mansour, Bioorg. Med. Chem. Lett. 16 (2008) 1890–1902. [15] T. Nakamura, H. Kakinuma, H. Umemiya, H. Amada, N. Miyata, K. Taniguchi, K. Bandoand, M. Sato, Bioorg. Med. Chem. Lett. 14 (2004) 333–336. [16] M. Hamada, V. Roy, T.R. McBrayer, T. Whitaker, C.U. Blanco, S.P. Nolan, J. Balzarini, R. Snoeck, G. Andrei, R.F. Schinazi, L.A. Agrofoglio, Eur. J. Med. Chem. 67 (2013) 398–408.

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