Spectroscopic (FT-IR, FT-Raman, UV, NMR, NLO) investigation, molecular docking and molecular simulation dynamics on 1-Methyl-3-Phenylpiperazine

Journal of Molecular Structure 1143 (2017) 328e343

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Spectroscopic (FT-IR, FT-Raman, UV, NMR, NLO) investigation, molecular docking and molecular simulation dynamics on 1-Methyl3-Phenylpiperazine K. Subashini a, *, S. Periandy b a b

R & D, Bharathiar University, Coimbatore, Tamil Nadu, India Department of Physics, Kanchi Mamunivar, Centre for Post-Graduation Studies, Puducherry, India

a r t i c l e i n f o

a b s t r a c t

Article history: Received 2 March 2017 Received in revised form 5 April 2017 Accepted 5 April 2017 Available online 10 April 2017

The title compound was analyzed, by recording FT-IR (4000-400 cm
1) and FT-Raman (4000-100 cm
1) spectra in solid phase, 1H and 13C NMR in CDCl3 (deuterated chloroform) and UV spectrum (200 e400 nm) in solid phase and in ethanol solution. Conformational analysis was done using semi-empirical method PM6. The computed wavenumbers obtained from B3LYP and B3PW91 functionals along with 6 e311þþG (d, p) basis sets were scaled so as to agree with the experimental values and the scaling factors have been reported. All fundamental modes have been assigned based on the potential energy distribution (PED) values and the structure of the molecule was analyzed in terms of parameters like bond length, bond angle and dihedral angles through B3LYP and B3PW91 functionals along with 6 e311þþG(d,p) basis set. The observed HOMO-LUMO mappings reveal the different charge transfer possibilities within the molecule. The percentage contribution of a group to each molecular orbital was calculated using Gauss Sum program. Natural bond orbital analysis was computed and possible transition were correlated with the electronic transitions. Mulliken charges, electrostatic potential charges and natural charges are also predicted. The theoretical 1H and 13C NMR chemical shifts were computed using B3LYP functionals using 6-311þþG (2d, p) basis sets. The temperature dependence of the thermodynamic properties; heat capacity, entropy and enthalpy for the title compound were also determined by B3LYP functional with 6e311þþG (d, p) basis set. Molecular docking study shows that the title compound might exhibit inhibitory activity against Clostridium botulinum (2J3X). The interaction of the ligand (title molecule) with 2J3X for 2 ns duration and radial distribution function have been observed through molecular dynamics simulations. © 2017 Elsevier B.V. All rights reserved.

1. Introduction Piperazine is a six membered heterocycle, containing nitrogen atoms and exhibits pharmacological activities [1]. The other names of pure piperazine are hexahydropyrazine, piperazidine, diethylenediamine and 1, 4-Diazinane. It is a weak base with versatile binding properties. It is a centrosymmetric molecule with centroid on inversion center. The molecule has chair conformation with NeH bonds in the equatorial position [2]. In our title compound, 1Methyl-3-Phenylpiperazine (MPPZ), there are two substituents attached to piperazine ring i.e. methyl group and benzene ring in 1, 3 position. Also, MPPZ, has a structure similar to b-phenyl ethyl

* Corresponding author. E-mail address: [email protected] (K. Subashini). http://dx.doi.org/10.1016/j.molstruc.2017.04.016 0022-2860/© 2017 Elsevier B.V. All rights reserved.

amine (b-PEA) unit which acts as a potent anti-microbial against certain pathogenic strains of Escherichia coli [3]. Piperazine shows numerous physiological effect such as antituberculosis, antihelmenitics, antianginals, anticancer, analgesic, antidepressant, antipsychotic and antidiabetic activities [4]. Literature [5e21] indicate that the piperazine template forms the important backbone in today's drug discovery. A novel piperazine based b-amino alcohols of benzosuberone derivatives were evaluated for their in vitro anti-proliferative activity against cancer cells by Vanguru [5]. Benzothiazole-piperazine compounds were designed, synthesized and were observed to be acetylcholine esterase inhibitors [6]. The potent pharmocophoric activities of piperazine were studied by Ghorbani et al., [7]. The electrochemical investigations of piperazine were studied by Shah et al., [8]. The conformational analysis of 2-substituted piperazines were observed by Kallel et al., [9].

K. Subashini, S. Periandy / Journal of Molecular Structure 1143 (2017) 328e343

Synthesis and antitubercular activity of chiral 1, 2, 4trisubstituted piperazines derived from resin bound acylated dipeptides against Mycobacterium tuberculosis strain H37Rv was reported by Michaels et al., [10]. Biological activities of fluorine and piperazine containing 1, 2, 4 etriazole thione derivatives were observed by Zhang et al., [11]. Novel dicarbonlyalkyl piperazine derivatives as neuroprotective agents were studied by Wang et al., [12]. Antifungal activities and insecticidal activities were observed in piperazine-containing 1, 5-Diphenyl-2-penten-1-one analogues by Xu et al., [13]. A series of N-aryl piperazine based CXC4 antagonists act as anti-HIV entry agent [14]. Piperazine conjugated benzothiazole, synthesized by Ghorbani et al. [15], exhibits tumor suppression. Anti-nociceptive and anti-inflammatory effects of piperazine derivative were observed by Silva et al., [16]. Huang et al. [17], observed that piperazine derivatives may facilitate the development of a novel class of drugs for the treatment of schizophrenia. Fytas et al. [18], have synthesized piperazine derivatives and examined their antitumor properties against breast cancer, pancreatic cancer and lung cancer. Waszkielewicz et al. [19], observed that phenylpiperazine derivatives may be selectively active on the central nervous system as antidepressant-like agents. Mao et al. [20], synthesized hybrid compounds between benzofuran and N-aryl piperazine and they were proved to be potential anticancer agents. The significance of piperazine derivatives has been reviewed by Shaquiquzzaman et al., [21]. Through various articles, we observe that the title compound MPPZ, has not been investigated till date. Hence, in order to explore its properties related to pharmaceutics, theoretical and experimental investigations have been carried out. In this connection, FTIR, FT-Raman, UV, NMR, Frontier molecular Orbital analysis (FMO), Non-linear optics (NLO), Natural Bonding Orbital (NBO) have been analyzed. The theoretical calculations were performed using DFT methods in combination with triple zeta basis set [22]. The experimental results and theoretical results are close to each other. Also, radial distribution function (RDF) through molecular simulation dynamics has been calculated. Molecular docking and dynamics of MPPZ with receptor 2J3X has been performed to observe the ligand-receptor interactions as well as to observe root mean square deviation (RMSD) of the protein. 2. Experimental details The title compound, 1-Methyl-3-Phenylpiperazine, was purchased in powder form from Sigma-Aldrich Chemicals, Chennai with 98% purity. The FT-IR spectrum of the compound was recorded using a Thermo Nicolet 6700 spectrometer in the range of 4000e400 cm
1 with a spectral resolution of ±2 cm
1. The FTRaman was recorded using Bruker RFS 27, equipped with ND: YAG laser source operating at 1.064 mm line widths, in the scan range 4000e100 cm
1 with a spectral resolution of 2 cm
1. The high resolution 1H NMR and 13CNMR were recorded using 300 MHz and 75 MHz NMR spectrometer respectively. The UVeVis spectra was recorded in solid phase and ethanol solution in the range 200e800 nm, with scanning internal of 0.2 nm, using Schimadzu UV-250 spectrometer. 3. Computational details The computational calculation of the title compound MPPZ, were carried out with the Gaussian 09 W program [23] and visualized using Gauss view [24]. The potential energy surface scan was done using semiemprical method PM6. The structural parameters and vibrational modes were calculated for the minimum energy conformer using B3LYP [25] and B3PW91 functionals with 6e311þþG (d, p) basis set for comparison purpose. The

329

corresponding potential energy distribution (PED) for each vibrational mode was analyzed using VEDA software [26]. The NMR chemical shifts, were computed using gauge independent atomic orbital (GIAO) theory in combination with B3LYP/6-311þþ G (2d, p) basis set. Computational UV-spectra was obtained using time dependent self-consistent field (TD-SCF) theory at B3LYP/6311þþG (d, p) level in gas and solvent phase [27]. Non-linear optical (NLO) property was examined by calculating dipole moment (m), polarizability (a), first hyper polarizability (b) and anisotropy (Da) using B3LYP/6-311þþG(d,p) method [28]. The b components of Gaussian output are reported in atomic units and therefore the calculated values were converted into e.s.u units (for a: 1 a.u. ¼ 0.1482  10
24 e.s.u, for b; 1 a.u. ¼ 8.6393  10
33 e.s.u). The thermodynamic properties such as heat capacity, entropy and enthalpy were calculated for different temperatures from the computed vibrational frequencies using B3LYP functional and 6311þþG (d, p) basis set. Molecular dynamics simulation calculation was performed using GROMACS (Groningen Machine for Chemical Simulation), version 5.1.1 [29]. The input files were prepared using Amber force field [30,31] and pictured using Visual Molecular Dynamics (VMD) [32] and PyMOL [33]. For radial distribution function (RDF), one molecule of MPPZ was placed in cubic box with 2550 water molecules. NPT ensemble was used, with temperature and pressure set to 298.15 K and 1 bar, respectively. Simulation time was set to 10 ns with cut-off radius of 2 nanometer (nm). The system was brought to equilibrium in the first 100 ps using NPT model. SPC/E model [34] was implemented for water molecules (solvent). 4. Results and discussion 4.1. Potential energy surface (PES) scan for conformational analysis The different orientations of the molecule and their corresponding energy is calculated using potential energy surface scan. It was performed using semiemprical method PM6, because, this method yields reliable results and is less time consuming when compared with DFT [35]. The calculations were performed for two different dihedral angles, namely, C6eC5eC12eN13 and C6eC5eC12eC15. In Fig. 1a, the minimum energy conformer is observed at 28.16 kcal/mol and in Fig. 1b at 28.14 kcal/mol. Piperazine ring adopts chair configuration. The methyl group (which is attached to N14) and the phenyl ring have equatorial orientation and the hydrogen atom attached to N13 occupies axial orientation in tune with literature [36]. The potential energy surface scan was also analyzed for 2-Phenyl Piperazine, using the above mentioned dihedrals (for comparative purpose). The diagrams are displayed in Supplementary data (S1 & S2). The minimum energy conformer is observed at 28.0 kcal/mol. Here, the hydrogen atom attached to N13 occupies equatorial position and the hydrogen atom attached to N14 occupies axial position. Thus, we infer that the equatorial and axial positions, in the piperazine moiety, have been exchanged due to the presence of methyl group. 4.2. Structural analysis The optimized geometrical parameters of MPPZ obtained through B3LYP and B3PW91 methods using 6-311þþG (d, p) are listed in Table S1 (Supplementary data). The molecular structure depicted in Fig. 2. The carbon atom, namely, C12 is asymmetric, since it is attached to four non-identical groups, namely, benzene, hydrogen, nitrogen and carbon of piperazine ring. Hence, it is chiral carbon. The carbon-carbon bond length of the benzene ring through experimental technique [37] as well as theoretical approach is

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Fig. 1. a. Potential energy surface scan along the dihedral angle C6eC5eC12eN13. b. Potential energy surface scan along the dihedral angle C6eC5eC12eC15.

Fig. 2. Molecular structure of 1-Methyl-3-Phenylpiperazine.

1.39 Å. This length is consistent with electron delocalization within the ring. r (CeH) differs between, benzene ring, piperazine ring and the methyl group. Their theoretical values are 1.08 Å, 1.10 Å and 1.09 Å respectively. The values are close to the experimental values displayed in Table S1 (Supplementary data). The theoretical values of r (CeC) and r (NeC) in the piperazine moiety are 1.54 Å and

1.47 Å respectively, which are close to literature [38,39]. We also observe that, there is a significance difference between r (CC) of benzene and piperazine ring. Angle CeCeH in the benzene ring is slightly less than 120 due to the presence of the piperazine ring. The experimental bond angle of HeCeH in pure piperazine is 109 [38]. Through theoretical

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331

Table 1 Vibrational frequencies of 1-METHYL-3-PHENYLPIPERAZINE. Sl.No Symmetry species FTIR

FT-RAMAN

B3LYP (UNSCALED) B3LYP (SCALED) B3PW91 (UNSCALED) B3PW91 (SCALED) PED% and vibration assignment

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73

3251 (vw) 3068 (m) 3043(w)

3523 3187 3177 3169 3160 3156 3091 3079 3074 3047 3032 3025 3010 2913 2891 2886 1644 1622 1526 1517 1510 1501 1498 1495 1486 1483 1456 1403 1392 1379 1364 1354 1347 1326 1300 1274 1259 1237 1219 1202 1181 1169 1149 1129 1126 1100 1071 1051 1037 1017 1006 997 992 985 940 928 895 864 830 794 781 746 718 685 633 632 553 541 425 415 372 365 298

A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A

3250 (s)

3020 (m) 3001 (vw) 2970(m) 2952 2940 2928 2841

(m) (m) (m) (w)

2810 (vs) 2793 (s)

1603(m) 1584(vw) 1500 (m) 1467(vw) 1450 (s) 1340 (m)

1330 (s) 1310 (s) 1300 (m) 1295 (s)

1291 (vw) 1252 (vw)

1230 (vs) 1220 (m) 1210 (vw) 1173 (vw) 1140 (vw) 1130 1120 1100 1090

(vs) (vs) (s) 1099 (vw) (m)

1050 (m) 1020 (s) 980 (m) 960 (vw) 950 (vw)

1023 (vw) 1001 (vs) 981 (vw)

928 (vw) 925 875 850 825 810

(m) (s) (m) (s) (m)

813 (vw)

755 (s) 700 (vs) 645 (m) 639 (vw) 621 (vw) 599 (s) 508 (vw) 447 (vw)

295 (vw)

3249 3060 3049 3043 3034 3029 2967 2956 2951 2925 2910 2904 2890 2796 2775 2770 1578 1557 1465 1457 1450 1441 1438 1435 1427 1424 1398 1347 1337 1323 1309 1300 1293 1273 1248 1223 1209 1187 1171 1154 1134 1122 1103 1084 1081 1056 1028 1009 995 977 966 957 952 946 902 891 859 830 797 763 750 716 689 658 608 606 531 519 408 398 357 350 286

3542 3198 3187 3178 3169 3165 3106 3092 3084 3059 3042 3036 3019 2925 2903 2898 1658 1636 1527 1510 1504 1498 1490 1486 1483 1478 1448 1400 1390 1375 1359 1357 1349 1332 1301 1276 1266 1237 1222 1198 1178 1177 1156 1147 1128 1102 1079 1055 1043 1016 1007 1004 992 986 945 934 900 865 837 799 783 750 718 689 631 628 552 540 425 412 368 361 298

3266 3070 3059 3051 3042 3039 2982 2969 2961 2937 2920 2914 2898 2808 2787 2782 1592 1571 1466 1450 1444 1438 1430 1427 1424 1419 1390 1344 1335 1320 1305 1302 1295 1279 1249 1225 1215 1188 1174 1150 1131 1130 1110 1101 1082 1058 1035 1013 1001 976 967 964 952 946 907 896 864 830 804 767 752 720 690 661 605 603 530 518 408 396 354 347 286

n NH (100) n CH (92) n CH (85) n CH (98) n CH (96) n CH (84) n CH3 (93) n CH3 (95) n CH3 (93) n CH2 (95) n CH2 (98) n CH2 (98) n CH2 (97) n CH2 (93) n CH2 (94) n CH (87) n CC (40) þ n CCH (12) n CC (40) þ n CCH (12) n CC (40) þ n CCH (12) b NH (30) þ n CCN (12) n CC (40) þ n CCH (12) n CC (40) þ n CCH (12) b CH3(35) þ n CC (20) b CH3 (38) þ n CN (14) b CH3 (35) þ n CN (12) b CH2 (40) þ n CN (11) b CH2 (40) þ n CN (12) b CH2 (40) þ b NCC (15) b CH2 (40) þ b CCC (12) b CH2 (40) þ b CNC(11) b CH2 (40)þ n CC (19) b CH (40) þ n CN (11) d CH2 (35) þ d CH3 (19) b CH (40) þ n CC (12) d CH2 (35)þ d CH3 (20) d CH2 (35) þ b CH (12) d CH2 (35) þ d CH3 (21) b CH(40) þ b CH2(12) n CC(39) þ b NH(12) n CC(40) þ d CH2 (12) n CN(65) þ b CH2(11) n CN (65) þ b CH2 (11) n CN (50) þ b CH2 (11) n CN (45) þ b CH2 (11) b CH(40) þ b HCN (11) n CN (40) þ n CC (11) b CH (40) þ t HCNC (11) b CCC (60) þ n CC (20) d CH (30) þ b CH2 (11) d CH(30) þ t HCNC (11) b CCN (30)þ b CCC (11) b NCC(30))þ b CCC (11) t HCNC (30) þ b CH (11) t CCCC (30) þ t HCNC (11) t HCCC (50) þ d CCC (11) t HNCC (40) þ n CC (11) d CH(50) þ d CC(11) d CH (50) þ t HCCC (11) t HCCC (30)þ d CH (11) t HCNC (40) þ b CH2 (12) d CCC (60) þ d CH (11) t HCNC (30) þ d CH2 (10) b CN (30) þ b CH2 (10) b CCC (30) þ b CH2 (11) b CN (30) þ b CH2 (11) d NH (50) þ d CC (11) b CCC (34) þ n CN (12) b CC (35) þ b CCN (19) d CCC (30) þ b CH2 (12) d CCC (30) þ b CH2 (12) b CC (40) þ d CH2 (11) b CC (40) þ d CH2 (11) d CC (40) þ d CH2 (11) (continued on next page)

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Table 1 (continued ) Sl.No Symmetry species FTIR

FT-RAMAN B3LYP (UNSCALED) B3LYP (SCALED) B3PW91 (UNSCALED) B3PW91 (SCALED) PED% and vibration assignment

74 75 76 77 78 79 80 81

258 (vw)

A A A A A A A A

88 (vs) 74 (vs)

291 252 247 206 133 88 53 34

280 242 237 198 127 85 51 32

290 253 245 204 137 88 55 36

279 243 236 196 131 84 53 35

d CC (40) þ d CH2 (11) d CNCC (30) þ d CC (11) d CNCC (29)þ b CNC (12) d CH (21) þ t NCCC (14) t NCCC (19)þ t CCCC (11) t CCNC (65) þ t CCCC (11) t CCCN (67) t CCCC (30) þ t CNCC (13)

n e Stretching vibrations; b in-plane bending vibrations; d out-of plane bending vibrations; vs e very strong; s e strong; m e medium; w e weak; vw - very weak.

approach, it is observed at 106.4 by B3LYP/6-311þþG (d, p) technique in MPPZ. In literature [39], the value of angle HeCeH was observed at 108 . Thus, we infer that, piperazine moiety is affected by substituents in general and by the presence of methyl group and benzene ring in particular i.e. in our title compound MPPZ. Also, the CeCeN bond angle in pure piperazine is 110 [38], whereas in our title compound it is 109 through computational method. Bond angles of C4eC5eC12, C6eC5eC12 measures 120 through theoretical approach. Their experimental angle is 122 according to literature [40e42] for a similar molecule. Thus, we observe that, the methyl group attached to N14 influences the configuration of the molecule appreciably.

4.3. Vibrational analysis The vibrational frequencies and their corresponding potential energy distribution is displayed in Table 1. The calculations were performed using B3LYP and B3PW91 functionals along with 6e311þþG (d, p) basis set. Since, the title compound contains asymmetric carbon atom, which acts as a chiral center, it is assigned C1 symmetry. Thus, all vibrations are represented by “A” according to [43]. The title compound has 29 atoms and 81 modes of vibrations. The experimental and computational IR and Raman of the title compound are displayed in Figs. 3 and 4 respectively. The unscaled wavenumber 3523 cm
1 in B3LYP and 3522 cm
1 in B3PW91 was scaled using 0.9221 scaling factor. The wavenumbers 3187 cm
1 to 34 cm
1 in B3LYP and 3198 cm
1 to 36 cm
1 in B3PW91 were scaled using 0.96. The calculated frequencies are close to the

experimental values. 4.3.1. NeH vibrations N13eH24 accounts for NeH stretching, in-plane bending and out-of plane bending vibrations in MPPZ. The stretching frequency, is observed at 3250 cm
1, as a strong intensity in IR region and weak in Raman region. It is in tune with literature [40,44,45]. The corresponding theoretical value obtained by B3LYP/6-311þþG (d, p) is 3249 cm
1. The PED indicates that it is a pure mode. The NeH in plane bending vibrations are expected at 14901580 cm
1 [46,47]. In our title compound MPPZ, it is observed at 1467 cm
1 as a weak intensity in Raman. It is a mixed mode with 12% contribution from n CCN. Prabavathi et al. [44], had reported the theoretical in-plane bending vibration of 1-(m-(trifluoromethyl) phenyl) piperazine (TFMPP) at 1478 cm
1. The NeH out of plane bending vibration is observed at 599 cm
1 and it is IR active. This value is close to literature [47]. It is a mixed mode, with 11% contribution from d CC. The theoretical value is observed at 606 cm
1 through B3LYP/6-311þþG (d, p) method. Overall, we infer that, since eNH bond lies at the periphery of the molecule, its vibrations are close to the expected values. 4.3.2. CeH vibrations MPPZ, contains 15 eCH bonds. Five bonds are associated with benzene ring, seven bonds are associated with the piperazine ring and three bonds in the methyl group attached to N14 of the piperazine ring. Since MPPZ is a mono substituted benzene, the vibrations were

Fig. 3. Experimental (A) and theoretical B3LYP/6-311þþG (d, p) (B) FT-IR spectra of 1-Methyl-3-PhenylPiperazine.

K. Subashini, S. Periandy / Journal of Molecular Structure 1143 (2017) 328e343

333

Fig. 4. Experimental (A) and theoretical B3LYP/6-311þþG (d, p) (B) FT-Raman spectra of 1-Methyl-3-PhenylPiperazine.

assigned according to Varsanyi [48]. There are five eCH stretching frequencies expected between 3010 and 3120 cm
1 in monosubstitution. Vibrations are expected at modes 2, 7a, 7b, 20a, 20b [48]. The corresponding regions are 3030e3070 cm
1, 30003060 cm
1, 3030-3080 cm
1, 3070-3110 cm
1, 3020-3080 cm
1. In our title compound, the experimental bands, observed at 3068 cm
1, 3043 cm
1, 3001 cm
1 are Raman active. The IR active vibration is observed at 3020 cm
1 as a medium intensity. The theoretical vibrations are observed at 3060 cm
1, 3049 cm
1, 3043 cm
1, 3034 cm
1 and 3028 cm
1. They are observed to be pure modes through PED. The in plane bending vibrations correspond to modes 3, 9a, 15, 18a and 18b of benzene [48]. The regions are 1270e1331 cm
1, 1170-1181 cm
1, 1150-1160 cm
1, 1018-1030 cm
1 and 10651082 cm
1 respectively. In MPPZ, the experimental vibrations are observed at 1300 cm
1, 1252 cm
1 and 1020 cm
1. The theoretical vibrations through B3LYP/6-311þþG (d, p) are observed at 1300 cm
1, 1273 cm
1, 1187 cm
1, 1081 cm
1, 1028 cm
1. The PED calculations point out that, they are mixed modes with contributions from n (CN), n (CC), b (CH2), b (CCH), t (HCNC). Prabavathi et al. [44], had reported the theoretical values of in plane CeH bending vibrations at 1335 cm
1, 1193 cm
1, 1180 cm
1 and 1077 cm
1 in TFMPP. In Ref. [44], the nitrogen of the piperazine ring is directly attached to benzene. But, in our title compound MPPZ, the carbon atom of piperazine, is attached to the benzene ring. Hence, we observe the changes in frequencies. The out-of-plane bending vibration, correspond to modes 5, 10a, 10b, 11, 17a [48]. The regions are 970e1000 cm
1, 810-850 cm
1, 880-910 cm
1, 720-760 cm
1 and 940-980 cm
1. In our title compound, the experimental vibrations are observed at 980 cm
1, 960 cm
1, 825 cm
1, 810 cm
1. The theoretical vibrations are observed at 995 cm
1, 977 cm
1, 859 cm
1, 830 cm
1. Literature [44] have also reported CeH out-of-plane vibrations in the region 1000e700, which is close to the obtained values for our compound. The piperazine ring contains one CeH and three CH2 groups. In Ref. [45], the values of n (CH2) have been reported at 2944 cm
1 and 2824 cm
1. In 2-methyl piperazine [47], the symmetric stretching vibrations appear at 2806 cm
1, 2790 cm
1, 2539 cm
1 and 2444 cm
1. The infra-red and Raman spectra of piperazine have been reported by Hendra and Powell [49]. The experimental values are observed at 2940 cm
1, 2928 cm
1, 2841 cm
1, 2810 cm
1 and 2793 cm
1. They are distributed in IR and Raman regions. The scaled frequencies are observed at 2925 cm
1, 2910 cm
1, 2904 cm
1, 2890 cm
1, 2796 cm
1, 2775 cm
1, 2770 cm
1. We infer that, they are pure modes and they agree with the literature. Literature [49] have observed the in plane bending vibration of

CH2 in the region 1458e1431 cm
1 (in pure piperazine). Prabavathi et al. [44], have reported the values of b (CH2) at 1506 cm
1, 1498, 1491 and 1487 cm
1 in TFMPP. O. Alver et al. [45], have observed the values in the region 1498-1452 cm
1 in 1-phenyl piperazine. In Refs. [44,45], there are no substituents attached to piperazine, except benzene. In our title compound, the b (CH2) values are observed at 1424 cm
1, 1398 cm
1, 1347 cm
1, 1337 cm
1, 1323 cm
1, 1309 cm
1 through theoretical approach. The experimental vibrations are observed at 1330 and 1310 cm
1. Through PED, we infer that they are mixed modes with contributions from n (CN), b (NCC), b (CCC), b (CNC), n (CC). This is less than the expected range, due to the interference of methyl group attached to N14. However, the obtained values of MPPZ, is closer with literature [47]. Krishnakumar and Seshadri [47], have also reported values in the range 1450 cm
1 e 1305 cm
1. The out of plane bending vibrations, of MPPZ, are observed at 1293 cm
1, 1248 cm
1, 1223 cm
1, 1209 cm
1 through B3LYP/6311þþG(d,p) method. Experimentally, these values are observed at 1295 cm
1, 1230 cm
1, 1220 cm
1, 1210 cm
1. They are distributed in IR and Raman regions. Through PED distribution, they are observed to be mixed modes. The out-of plane bending vibrations in pure piperazine are reported at 1382-1320 cm
1 [49]. Thus, in MPPZ, the vibrations are out of the expected range, due to the interference of benzene ring and methyl group. The stretching frequencies of methyl group are observed at 2970 cm
1 and 2952 cm
1. They are Raman active. Krishnakumar and Seshadri [47] have reported the methyl stretching at 2978 and 2827 cm
1. The theoretical values are observed at 2967 cm
1, 2956 cm
1, 2951 cm
1 through B3LYP/6-311þþG(d,p). Ref. [47] reports in plane bending of CH3 at 1245 cm
1, 1262 cm
1 and out of plane bending vibration at 1231 and 1224 cm
1. In the above reference, the methyl group is attached to carbon of the piperazine ring. But, in MPPZ, the methyl group is connected to nitrogen atom. Hence, the in plane bending vibrations are observed at 1438 cm
1, 1435 cm
1, 1427 cm
1 through theoretical approach. The out of plane bending vibrations are observed as coupled vibrations along with d CH2. 4.3.3. CeC vibrations There are five normal vibrations of benzene having character of CeC stretching mode: 8a, 8b, 19a, 19b and 14 according to Wilson's numbering convention [48]. The respective bands are 1575e1614 cm
1, 1562-1597 cm
1, 1470-1515 cm
1, 14401470 cm
1, 1300 - 1350 cm
1. In our title compound, it is observed at 1603 cm
1, 1584 cm
1, 1500 cm
1, 1450 cm
1 and 1340 cm
1. The theoretical vibration through B3LYP/6-311þþG (d, p) are observed

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at 1578 cm
1, 1557 cm
1, 1465 cm
1, 1450 cm
1, 1441 cm
1. The computed and experimental vibrations are observed well within the expected range. Normal modes 6a, 6b and 12 denotes b (CCC) for mono-substituted benzene. They regions are 300e530 cm
1, 605e630 cm
1 and 990 - 1010 cm
1 respectively. In MPPZ, they are observed at 1001 cm
1, 639 cm
1, 508 cm
1. They are Raman active. The theoretical vibrations are observed at 1009 cm
1, 658 cm
1, 531 cm
1. Normal mode 4 (ring puckering vibration), 16a and 16b represents out-of-pane bending [48]. They are expected at 680 700 cm
1, 400 cm
1 and 430-560 cm
1. Experimentally, they are observed at 700 cm
1 and 447 cm
1. They are distributed in IR and Raman regions. Theoretically, they are observed at 750 cm
1, 408 cm
1, 398 cm
1. Overall, the CeC vibrations lie within the specified range. C5 of benzene ring is connected to C12 of piperazine ring. Normal mode 12 couples with CeC stretching of benzene's carbon atom and its substituent's carbon atom [48]. The in plane bending of CeC ranges from 200 to 410 cm
1. In MPPZ, it is observed at 357 cm
1 and 350 cm
1 theoretically. The out of plane bending vibration is less than 400 cm
1 [48]. They are observed at 295 cm
1 and 258 cm
1 and they are Raman active. The theoretical values are present at 286 and 280 cm
1 respectively. The n (CC) is observed at 1055 cm
1 in ethylamines [50]. C12eC15 and C16eC17 is responsible for CeC stretching in the piperazine ring. In our title compound, n (CC) is observed at 1173 cm
1 and 1140 cm
1. The theoretical vibrations are observed at 1171 cm
1 and 1154 cm
1 through B3LYP/6-311þþG(d,p). The b (CC) is coupled with CCN bending vibration in ethylamines [50] and is observed at 403 cm
1. In MPPZ, it is observed at 519 cm
1 theoretically. Ref. [50] discusses aliphatic amine, whereas the present compound contains cyclic amine. Hence, we observe the differences in vibrational frequencies. 4.3.4. CeN vibrations The bonds C12eN13, C17eN13, C16eN14 and C15eN14 are responsible for eCN vibrations in the piperazine ring. n (CN) vibrations for MPPZ are observed at 1130 cm
1, 1120 cm
1, 1100 cm
1 and 1090 cm
1. They are IR active. The theoretical vibrations are observed at 1134 cm
1, 1122 cm
1, 1103 cm
1 and 1084 cm
1. According to literature [51], the expected region for n (CN) is 1175e1126 cm
1. The obtained vibrations are out of the above said range due to the interference of methyl group. Also, n (C18eN14) causes CN stretching vibrations. C18 of methyl group is attached to N14 of the piperazine ring. The observed value in MPPZ is at

1050 cm
1 and the expected value is at 1086 cm
1 [51]. b (CN) and d (CN) are expected in the range 561e499 cm
1 and 328-318 cm
1 [52]. In MPPZ, the experimental b (CN) vibrations are observed at 645 cm
1 and 621 cm
1. Theoretical d (CN) vibrations are observed at 242 cm
1 and 237 cm
1. They are out of the expected range due to the interference of benzene ring vibrations. 4.4. Charge distribution and molecular electrostatic potential map (MEP) The charge distribution of the title compound were computed by Mulliken Population (MP), Natural atomic charge (NAC), and Electrostatic Potential Analysis (ESP) using B3LYP functional and 6311þþG(d,p) basis set and the values are presented in Table S2 (Supplementary data). Carbon atoms of the benzene ring are electronegative except C4 and C5 which exhibits electro positivity through ESP and MP respectively. All the hydrogen atoms are electropositive through all the methods. Hence, we understand that C4 atom can interact with negative part of the receptor. C16, C15 and C18 are electronegative by all the three methods. C12 and C17 are less electronegative compared to N13. N13 is more electronegative than N14, in all the three methods. This is because, in N13eH24, nitrogen attracts the electrons of hydrogen to itself. This makes H24 electron deficient and exhibits high electro positivity than rest of the other hydrogen atoms. Therefore, the NeH bond is polarized. Also, due to the presence of tertiary amine and secondary amine, the title compound is a base. The charge distribution is also elucidated through molecular electrostatic potential map, in Fig. 5. MEP characterizes the electronic structure of the molecule, and gives an insight on the reactivity of molecules and their electron density [53]. The potential varies with color. The most negative potential is colored RED. The most positive potential is colored BLUE [54]. Intermediate potentials are assigned colors in the order red < orange < yellow < green < blue. The red region is observed near nitrogen atom of N13. Green region is observed indicating that the isolated molecule is neutral. Yellow color is observed on carbon atoms of the benzene ring, indicating electronegativity, which agrees with atomic charge analysis. We notice variation in electron distribution in different regions of the molecule. 4.5. NMR spectral analysis Table 2 presents the experimental and theoretical NMR spectra

Fig. 5. The electron density from Total SCF density (Iso value ¼ 0.00046 a.u; [mapped with ESP]) of MPPZ.

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335

Table 2 Calculated H1 and C13 NMR chemical shifts (ppm) of 1-METHYL-3-PHENYLPIPERAZINE. gas/TMS/B3LYP/6-311þþG(2d,p) GIAO Carbon atoms C1 132.07 C2 131.39 C3 133.58 C4 129.25 C5 155.33 C6 133.29 C12 64.64 C15 59.78 C16 56.62 C17 44.38 C18 45.79 Hydrogen atoms H7 7.41 H8 7.45 H9 7.59 H10 8.33 H11 7.45 H19 1.95 H20 2.43 H21 2.50 H22 2.37 H23 2.60 H24 0.57 H25 3.74 H26 2.68 H27 3.01 H28 1.97 H29 2.97

DMSO/TMS/B3LYP/6-311þþG(2d,p)GIAO

Experimental values

Residual

Squared Residual

RMSD

132.26 131.58 133.90 129.91 155.80 132.96 63.96 59.31 55.95 43.87 45.39

128.45 127.53 127.02

3.62 3.86 6.56

13.10 14.89 43.03

7.22

142.58

12.75

162.56

77.48 63.38 55.30 46.39


12.84
3.6 1.32
2.01

164.86 12.96 1.74 4.04

7.38 7.37 7.30

0.03 0.08 0.29

0.0009 0.0064 0.0841

7.24 1.97 2.29 2.15 2.12 2.11

0.21
0.02 0.14 0.35 0.25 0.49

0.0441 0.0004 0.0196 0.1225 0.0625 0.2401

3.86


0.12

0.0144

3.07 1.94


0.06 0.03

0.0036 0.0009

7.56 7.59 7.75 8.43 7.56 1.99 2.47 2.55 2.50 2.61 0.76 3.83 2.76 3.07 2.05 3.06

0.22

Residual ¼ Theoretical values obtained in gas phase minus the experimental values. RMSD ¼ Root mean square deviation.

of the title compound. The computational NMR spectra was obtained using GIAO technique with B3LYP functional and 6-311þþG (2d, p) basis set in gas and DMSO phase. Experimental H1 NMR is displayed in Fig. S3 (Supplementary data). The signals are observed at 7.38, 7.37, 7.30, 7.24, 1.97, 2.29, 2.15, 2.12, 2.11, 3.86, 3.07, 1.94 ppm. Hydrogen atoms attached to benzene ring (H7, H8, H9, H10 and H11) exhibit down field shift at 7.38, 7.37, 7.30 and 7.24 ppm. They are deshielded by the diamagnetic anisotropy of the ring [46]. We observed that H24 exhibits greater electro positivity in atomic charge analysis. In the proton NMR spectra, we note that, H24, which is attached to N13, shows upfield shift due to the shielding effect of lone pair of electrons in nitrogen. This is termed as “local diamagnetic shielding” [46]. Thus, NMR analysis agrees with charge distribution. Theoretically, the value is observed at 0.57 ppm in gas phase. The piperazine hydrogen atoms are H22, H23, H25, H26, H27, H28 and H29. Their experimental values are observed at 2.12, 2.11, 3.86, 3.07, 1.94 ppm. The obtained values were compared with literature [52] which describes 1-(2-Methoxyphenyl) Piperazine (MPP) and 1-(2-Chlrophenyl) Piperazine (CPP). The values of hydrogen atoms in piperazine ring were observed at 3.01 ppm, due to the fact that, the symmetry of piperazine moiety in MPP and CPP [52]. However, in our title compound, since C12 (carbon of piperazine) is attached to benzene ring, the symmetry does not exists. Hence, we observe difference in values. The methyl hydrogen atoms are H19, H20 and H21 and exhibit shift at 1.97, 2.29, 2.15 ppm respectively. The experimental values are close to theoretical values. Thus, NMR spectrum differentiates the hydrogen atoms of benzene, piperazine and methyl groups. In proton NMR, the RMSD is observed to be 0.22 ppm. C13 spectra is used to determine the types of carbon atoms that may be present in the compound. Thus, it provides direct information about the carbon skeleton of a molecule [46]. In benzene ring of MPPZ, ipso carbon is located at C5. Hence, a larger shift is observed at 142.58 ppm corresponding to C5. It shows electro

positivity through Mulliken charge analysis. The other carbon atoms of benzene exhibit shift at 128.45 ppm, 127.53 ppm, 127.02 ppm. In piperazine ring, C12 carbon atom exhibits higher shift at 77.48 ppm. Carbon atom C17 exhibit lower shift at 46.39 ppm. This is due to the fact that, the electron cloud of nitrogen shields C17 carbon atom. This atom exhibits electro positivity through ESP method. C15 and C16 exhibit shift at 63.38 ppm and 55.30 ppm. In literature [52], piperazine ring carbons produce average chemical shift of about 49.6 ppm (MPP), 46.2 ppm (CPP) and 54.3 ppm (MPP) and 52.6 ppm (CPP). The values in MPPZ differ, because, our title compound contains a chiral carbon and hence, there is lack of symmetry. In C13 NMR spectra, the RMSD is observed to be ±7.22 ppm. 4.6. Natural Bond orbital (NBO) analysis The NBO calculation was done using B3PW91 functional and 6311þþG (d, p) basis set. Natural Bond orbital is a calculated Bond orbital with maximum electron density. The pop ¼ nbo option of Gaussian program requests default NBO analysis. The output is produced in the log file. Each NBO is labeled as being of core (CR), bond (BD), valence lone pair (LP), or extra-valence Rydberg type, with affixed asterisk (*) for non-Lewis orbitals. For example, the label “LP (1) N 13” identifies a valence lone pair on N 13. The output file contains, second order perturbation theory analysis section which tabulates donor-acceptor pairs and the values of the donoracceptor stabilization energy as estimated by the following equation

Eð2Þ ¼ DEij ¼ qi

Fði; jÞ2 εi
εj

This section is examined for significant delocalization effects [55,56]. Natural Hybrid Orbital (NHO) directionality and “bond

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bending” analysis section displays the angular deviations between the bonding hybrids and the direct line-of-sight between nuclei, showing where significant bond bending is present [57]. We observe that, there is 90 deviation in p (C1eC2), 89.6 in p (C3eC4) and 89.9 in p (C5eC6) of the benzene ring. They agree with literature [58]. The deviation of N13 in N13eC17 is 2.3 and C17 is 3.5 . The deviations of atoms in other bonds are depicted in Table 3. The direct measure of bond polarity and electronegativity difference is provided by the “natural ionicity parameter” [59]. It is displayed in Table S3 (Supplementary data). In the CeH competition for bonding electrons, positive (CH) > 0 indicates that, C12 is more electronegative than H25. But, in C12eN13, N13 is more electronegative than C12. Similarly, N13 is more electronegative than C17 and H24. p / p* transition in benzene ring show greater stabilization energy. It is observed in p (C1eC2) / p* (C3eC4), p (C1eC2) / p* (C5eC6), p (C3eC4) / p* (C1eC2), p (C3eC4) / p* (C5eC6), p (C5eC6) / p* (C1eC2), p (C5eC6) / p* (C3eC4) which exhibit 20.49, 19.68, 20.23, 21.2, 21.21, 20.13 kcal/mol respectively. Highest stabilization energy in n / s* transition is observed in N14 / C18eH19, which is 8.53 kcal/mol. N14 / C15eH22, N14 / C16eH28, N13 / C16eC17 transitions exhibit stabilization energies of 8.51 kcal/mol, 8.24 kcal/mol and 8.26 kcal/mol respectively. They are displayed in Table S4 (Supplementary data).

4.7. Frontier molecular orbitals (FMO) and ultravioletevisible spectral analysis Frontier molecular orbital is used to describe chemical reactivity [60e62]. It explains highest occupied and lowest unoccupied molecular orbital (HUMO and LUMO). According to this theory, HOMO is electron rich and they are free to participate in the reaction. Likewise, a site where the lowest unoccupied orbital is localized, is a good electrophilic site. Table 4 displays HOMO-LUMO analysis of MPPZ and the corresponding figure is 6a. Partial density of states (PDOS) plotted through Gauss Sum

Table 3 NHO Directionality and “Bond Bending” (deviations from line of nuclear centers). NBO

s p s p p s s s s s s s s s s s s s s s s s s LP (1) LP (1)

C1eC2 C1eC2 C1eC6 C3eC4 C5eC6 C5eC12 C12eN13 C 12 - C 15 N 13 - C 17 N 13 - H 24 N 14 - C 15 N 14 - C 16 N 14 - C 18 C 15 - H 22 C 15 - H 23 C 16 - C 17 C 16 - H 28 C 16 - H 29 C 17 - H 26 C 17 - H 27 C 18 - H 19 C 18 - H 20 C 18 - H 21 N 13 N 14

Line of centers

Hybrid 1

Hybrid 2

Theta

Phi

Theta

Phi

Dev

Theta

Phi

Dev

123.8 123.8 79 78.8 69.1 79.1 146.2 67.2 87.2 141.7 43.5 111.5 74.1 44.6 63.9 96.2 53.4 151.6 39.4 144.9 41.5 73.2 141 e e

82 82 201 201 330.3 201.3 227 131.5 183.5 64.4 323.9 226.1 118.3 215.8 53.3 296.8 187.1 134.6 249 233.6 191.4 44.9 143.1 e e

123.9 34.4 79.5 145.7 146 79.5 146.4 70.1 88.4 143 e 112.3 e 47.6 65.5 95.5 50.7 152.3 37.8 146.2 41.4 72.9 142.5 99.1 138.3

83.3 94.3 199.9 274.3 274.2 200.1 220.7 132.1 185.4 62.9 e 226.9 e 214.4 53.5 298.1 185.7 132.5 249.4 232.2 197 43.2 144.6 294.8 19.8

1.1 90.1 1.2 90.1 90.3 1.2 3.5 3 2.3 1.6 e 1.2 e 3.1 1.7 1.5 2.9 1.2 1.6 1.5 3.7 1.7 1.7 e e

e 34.5 e 34.2 34.1 101.4 33.3 114.6 92 e 135.4 66.6 104.3 e e 82.7 e e e e e e e e e

e 94.4 e 93.4 94.7 23 43.1 310.6 6.9 e 146.6 46.4 297 e e 113.4 e e e e e e e e e

e 90 e 89.6 89.9 1.7 2.2 1.9 3.5 e 2.1 1.9 2 e e 3.6 e e e e e e e e e

Table 4 HOMO, LUMO, Kubo gap, global electronegativity, global hardness and softness, global electrophilicity index of 1-METHYL-3-PHENYLPIPERAZINE. Parameters

Benzene

1-METHYL-3PHENYLPIPERAZINE Gas

Ethanol

EHOMO (eV) ELUMO (eV) DEHOMO - ELUMO gap (eV) Chemical hardness(h) (eV) Global softness(s) (eV) Electronegativity(c) (eV) Electrophilicity index(u) (eV) Dipole moment (m) (Debye)


7.1131
0.4910 6.6221 3.3110 0.1510 3.80205 2.1829 0.0008


6.0261
0.3247 5.7014 2.8507 0.1753 3.1754 1.7685 1.3751


6.0013
0.5109 5.4904 2.7452 0.1821 3.2561 1.931 1.9518

Program [63] is displayed in 6b. From the output file (orbital_data.txt), we note that benzene contributes 7%, piperazine contributes 89% and methyl group contributes 4% to HOMO. Also, 71% contribution to LUMO is from the benzene ring, 18% from the piperazine group and 11% from the methyl group. In MPPZ, HOMO in gas phase is observed at
6.0261 eV and LUMO at
0.3247 eV. The energy difference is 5.7014 eV. In ethanol solution, the difference is reduced to 5.4904 eV. Thus, we observe that the energy levels are closer to each other, compared to benzene which is 6.6221 eV. Chemical hardness signifies the resistance towards the deformation or polarization of the electron cloud of the atoms, ions or molecules under small perturbation of chemical reaction. The softness is the reciprocal of hardness [64]. If the electron cloud is strongly held by the nucleus, the chemical species is “hard” but if it is loosely held by the nucleus the system is “soft” [65]. The chemical hardness of MPPZ is observed at 2.8507 eV in gas phase and 2.7452 eV in ethanol solution. Electrophiles are attracted to an electron rich center. The electrophilicity index (u) encompasses both the propensity of the electrophile to acquire an additional electronic charge driven by c2 (the square of electronegativity) and the resistance of the system to exchange electronic charge with the environment described by ƞ. A good electrophile is in this sense characterized by a high value of c and a low value of ƞ [66]. The value of u in MPPZ is 1.7685 eV in gas phase and 1.931 eV in ethanol solution. The dipole moment of pure benzene is zero, whereas, in MPPZ, it is 1.3751 Debye. The three descriptors, namely, electronegativity, hardness and electrophilicity index of atoms and molecules are operationally the same. All three represent the attraction of screened nuclei towards the electron pair/bond [67]. Hence, we conclude that the title compound is more reactive when compared to benzene. Time-dependent self-consistent field (TD-SCF) is used to calculate excitation energies, oscillator strength (f), absorption wavelength (l) of significant transition in the molecule in gas phase and ethanol solution. The experimental and theoretical values are displayed in Table 5. The computed values in gas phase are 252.51 nm, 249.80 nm, 245.15 nm, 243.33 nm, 241.65 nm and 238.07 nm with major contributions from H / Lþ1, H/L, H/Lþ2, H-1/Lþ1, H-1/L, H-1/Lþ2 respectively with p/p* assignment. The experimental value is observed at 263 nm. The UV spectrum of pure benzene displays absorption band at 180 nm [68]. Thus, we infer that, due to the presence of auxochromes, which carry unshared electrons, namely nitrogen in N13eH24 and N14, it produces bathochromic or red shift. Thus, it significantly affects the position and intensity of absorption bands. In ethanol solution, the calculated absorption bands are observed at 262.62 nm, 260.12 nm, 248.95 nm, 245.56 nm, 241.96 nm, 233.02 nm with major contributions H/L, H/Lþ1, H1/Lþ1, H-1/L, H/Lþ2, H-2/L respectively. The experimental bands are observed at 252 nm and 222 nm. They are assigned

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337

Fig. 6. a. Frontier molecular orbitals of MPPZ b. Partial density of states of MPPZ using Gauss Sum Program.

Table 5 Experimental and theoretical electronic absorption spectra of 1-METHYL-3-PHENYLPIPERAZINE using TD-SCF/B3LYP/6-311þþG (d, p) method. Experimental value

Theoretical value

SOLID PHASE

Major contribution

Assignment

GAS PHASE

l (nm)

E (eV)

263

4.71

ETHANOL SOLUTION 252 4.92 222 5.58

(f)

l (nm)

E (eV)

(f)

252.51 249.80 245.15 243.33 241.65 238.07

4.91 4.96 5.05 5.09 5.13 5.20

0.0120 0.0472 0.0286 0.0004 0.0013 0.0028

HOMO/Lþ1(76%) HOMO/LUMO (70%) HOMO/Lþ2 (66%) H-1/Lþ1 (79%) H-1/LUMO (92%) H-1/Lþ2 (83%)

p/p* p/p* p/p* p/p* p/p* p/p*

262.62 260.12 248.95 245.56 241.96 233.02

4.72 4.76 4.98 5.04 5.12 5.32

0.0016 0.0424 0.0020 0.0107 0.0266 0.0037

HOMO/LUMO (68%) HOMO/Lþ1 (66%) H-1/Lþ1 (77%) H-1/LUMO (79%) HOMO/Lþ2 (89%) H-2/LUMO (49%)

p/p* p/p* p/p* p/p* p/p* p/p*

p/p* transition according to [69]. On comparing UV in solid phase and in ethanol solution, we observe that, the solvent influences the position of the absorption peak as well as the intensity of absorption. The wavelength of absorption is less when compared to solid phase. The corresponding figures are displayed in Supplementary data (Figs. S5 and S6). 4.8. Molecular docking and molecular dynamics simulation of protein-ligand complex The aim of molecular docking is the identification of a ligand that binds to a specific receptor binding site and the identification of its preferred, energetically most favorable, binding pose [70]. The

term “binding pose” indicates the orientation of a ligand relative to its receptor as well as the ligand's conformation. Auto Dock 4.2 [71] and Auto Dock Vina [72] were used to perform molecular docking. The results were observed using Discovery Studio Visualizer Software 4.0 [73]. At first, the protein is loaded in auto dock tools (ADT). This is done to identify non-protein species and delete them. They include water (or other solvents), sugar and so on. ADT converts PDB files to PDBQT files and uses them as input files. Similarly, ligand pdb file is added to select bonds about which segments of the ligand will be rotated. Charges are added, using Gasteiger method. The active site is selected through Grid options widget, namely Grid / Grid Box. The size of the three e dimensional box was set to 30 Å, 30 Å, 30 Å.

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Table 6 Binding affinity of different poses of the title compound as predicted by Auto dock Vina. Mode

1 2 3 4 5 6 7 8

Affinity (kcal/mol)


6.7
6.5
6.5
6.3
6.0
6.0
6.0
5.8

Distance from best mode rmsd l.b.

rmsd u.b.

0.0000 1.916 2.091 2.705 3.218 2.546 3.246 2.847

0.0000 3.284 4.921 3.245 6.064 4.313 5.874 5.594

There are several websites, such as BAITOC [74] and PASS [75] which predict the target (receptor) for a given ligand. Bioactivity information to organic chemist (BAITOC), predicts Clostridium botulinum (2J3X) inhibitor activity of MPPZ. Clostridium botulinum [76e80] is a Gram-positive, rod shaped, anaerobic, spore-forming, motile bacterium with the ability to produce the neurotoxin botulinum. The toxin causes severe paralytic disease in humans and other animals [76] and is the most potent toxin known to mankind. C. botulinum has four distinct groups I-IV [77]. Foodborne botulism is a severe neuroparalytic disease caused by consumption of botulinum neurotoxin formed by strains of proteolytic C.botulinum and non-proteolytic C.botulinum during their growth in food [78]. The protein structure of C.botulinum was obtained from Protein Data Bank (PDB ID: 2J3X). The root mean square deviation (RMSD) predicted by Auto dock Vina [72] is displayed in Table 6. When a molecule (MPPZ) is subjected to docking at receptor's cavity, according to the nature of the selected cavity, conformations of the ligand, having high binding affinity are generated. Values up to 2 Å are considered reliable for docking protocol [81]. Figs. 7 and 8 display the ligand (MPPZ) within the active site of the protein. We observe that the residues GLU 389, GLU 387, PRO 355, SER 350 and THR 349 act as anchors for the piperazine moiety and benzene ring. Conventional hydrogen bond is observed between N13eH24 of piperazine and GLU 387, confirming the polarized nature of NeH bond as discussed in charge analysis section. Carbon hydrogen bond is observed with piperazine ring and GLU 389, SER 350, THR 349 of the protein. PiAnion interaction is observed between the benzene ring and GLU 387. These results indicate that, the title compound might exhibit inhibitory activity against C.botulinum and biological tests are need

to be done to validate the computational prediction. Protein-ligand simulations were done using Gromacs 5.1.1 [29]. The docked complex was used to generate separate receptor.pdb and ligand.mol2 file through UCSF Chimera [82]. The protonation state for the receptor was assigned using Hþþ server [83]. Using amber tools 15 [84] and Antechamber python parser interface [31] the gromacs topology file was created. The complex was solvated with 7994 water molecules using TIP4PEW water model [85]. The solvated electroneutral system was relaxed through a process called energy minimization (EM). The generated em.edr file contains all the energy terms that GROMACS collects during EM. It was analyzed using GROMACS energy module. The graph obtained is displayed in Fig. S7. (Supplementary data). During the first step of equilibration, restraint was put in the protein C-alpha and ligand heavy atoms using “make_ndx” command. This was equilibrated for 100 ps. Secondly, a non-restraint equilibration was done using ensemble with temperature at 298 K and pressure at 1.0 bar for 100 ps. Upon completion of the two equilibration phases, the system was well-equilibrated at the desired temperature and pressure. Finally, NVT production was performed for 2 ns. During the course of 2 ns, as visualized using PyMOL [33], we note that, the ligand remains in the active site of the protein without slipping. Small changes of the backbone RMSD during 2 ns show that the MD simulation was under stable condition. This is indicated in Fig. 9a. (Violet) The simulations were again carried out for protein in water (without ligand) using the above mentioned methods. In Fig. 9a, we also observe the RMSD of protein (2J3X) in water (green color) for comparative purposes. We observe that the figures are different, indicating the effect of ligand on the protein molecule. The minimum distance of the ligand (MPPZ) w.r.t the residue GLU of the protein (2J3X) fluctuates between 0.09 nm and 0.10 nm, signifying its proximity to the residue and it agrees with the result obtained from molecular docking. This is displayed in Fig. 10. The donors and acceptors during the course of simulation between protein and ligand are observed through “hbond” tool in gromacs. They are displayed in Table 7. Through VMD [32], we observe that, the hydrogen bond through N13-H24 has higher propensity to persist. Also, we observe conformational change in the active site of the protein during the course of simulation. They are displayed in Fig. 9b. 4.9. Radial distribution function (RDF) RDF, also known as pair distribution function, denoted as g(r),

Fig. 7. Ligand embedded in the active site of the protein.

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339

Fig. 8. The interaction between ligand and the protein is described. It takes place through hydrogen bond pi-anion, pi e alkyl and pi-sigma interaction. The distances in angstrom are also mentioned.

gives the probability of finding a particle at a distance “r” form another particle [86]. They are usually zero at small distances because of interatomic repulsion. The highest peak of C18 atom is observed at r ~0.36 nm with g(r) at 1.05. This means that, it is 1.05 times more likely that two molecules (in this case, C18 and water) would be found at this separation. The radial distribution function then falls and passes through a minimum value around ~0.49 nm, which implies that chances of finding two molecules with this separation are less. At long distances, g(r) approaches 1. We observe that, the RDF of C5 and C18 are different, which is due to the fact that, C18 is directly attached to nitrogen and C5 is attached to carbon atom of the piperazine ring. In nitrogen atom N13, the highest peak is observed at r ~0.17 nm and g(r) is at 0.75. Then it falls to a minimum value of r ~0.24 nm with g(r) at 0.03. In N14 atom, the first peak is higher than N13, and a second largest peak is observed at r ~0.47 nm with g(r) at 1.25. The plots of N13 and N14 are distinct, due to the fact that N13 is a secondary atom and N14 is a tertiary atom. They have appreciable interactions with water molecules. The diagram is displayed in Fig. 11. 4.10. Non-linear optical (NLO) property Generally, organic materials exhibit nonlinear optical properties due to delocalized electrons at p / p* orbitals [87,88]. In our title compound, the NLO properties have been computed using B3LYP functional and 6-311þþG (d, p) basis set. The values are displayed in Table S5 (Supplementary data). Dipole moment of MPPZ is observed to be 1.4112 Debye. The highest values is observed for my and is equal to 0.9306 Debye. The computed values of average polarizability and anisotropy are observed to be
11.6456  10
24 e.s.u. and 1.4516  10
24 e.s.u. respectively. The hyper polarizability is observed at 110.7307  10
33 e.s.u. The values of dipole moment and hyper polarizability for urea are 1.37 D and 373  10
33 e.s.u

[89]. It is used for comparison purpose. We infer that dipole moment of MPPZ is greater than urea, but, hyper polarizability is less than urea. 4.11. Thermodynamic functions Molecules have vibrational, rotational and translational degrees of freedom. They consist of atoms which move in different ways. This makes molecules distinct from the noble gases such as helium and argon, which are monoatomic. Heat energy is stored in molecules' internal motion which gives them an internal temperature. The thermochemical analysis in Gaussian is based on the harmonic vibrational frequencies and predicts thermochemical values for the desired temperature (100 K, 200 K, 300 K, 400 K, 500 K) and 1.0 atm. The zero point vibrational energy (ZPVE) results from the vibrational motion of molecular systems at 0 K and is observed at 158.5 kcal/mol. The key thermochemical properties are: Standard 0 ), standard entropies (S0 ) and standard heat capacities ( Cm m 0 ) and the values are presented in Table 8. enthalpy change (DHm They increase linearly with temperature (depicted in Fig. S8.). The output file lists 81 vibrational temperatures due to 81 vibrational modes. Thus we infer that, contribution from vibrational energy is greater than rotational and translational energies as the degrees of freedom meant for vibrations are more and the molecule tends to store the kinetic energy or total energy mostly in the form of vibrational motions. 5. Conclusion The methyl group attached to N14, not only influences the equatorial and axial positions of the piperazine ring, but also the geometrical structure of MPPZ. The vibrations were assigned according to PED. The stretching modes of NH, CH are pure modes,

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Fig. 9. a. Root mean square deviation (RMSD) of protein backbone during 2 ns MD simulation of protein ligand complex in water (purple) and protein in water (green). b. Conformational change in the active site of the protein as observed during the course of simulations. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Table 7 Summary of donors and acceptors between 2J3X and MPPZ as obtained through GROMACS hbond tool.

Fig. 10. Minimum distance during the first 200 ps duration between the ligand (MPPZ) and residue GLU of the protein. It fluctuates from 0.09 nm to 0.10 nm. Residue GLU was selected because of its interaction with MPPZ during molecular docking.

Donor

Hydrogen

Acceptor

SER347OG GLH386OE2 GLH388OE2 GLH388OE2 N13 of MPPZ N13 of MPPZ

SER347HG GLH386HE2 GLH388HE2 GLH388HE2 H24 of MPPZ H24 of MPPZ

N13 of MPPZ N14 of MPPZ N13 of MPPZ N14 of MPPZ LEU252O TYR256OH

whereas, CC and CN are mixed modes. The in plane and out of plane bending vibrations are mixed modes. Charge distribution and NMR

K. Subashini, S. Periandy / Journal of Molecular Structure 1143 (2017) 328e343

341

Fig. 11. a. RDF of C5 atom. b. RDF of C18 atom c. RDF of N13 atom d. RDF of N14 atom in MPPZ.

analysis support each other. Through NMR analysis, we can distinguish the hydrogen atoms and carbon atoms of benzene, piperazine and methyl groups. Atoms shielded by lone pair of electrons of nitrogen show upfield shift. They exhibit electropositvity through charge analysis. Molecular electrostatic potential map agrees with charge distribution. Red region is observed on top of nitrogen indicating that, it is electron rich. Natural ionicity parameter obtained from NBO analysis helps us to observe the bond polarity of N13eH24, C12eH25, N13eC17, N14eC15, N14eC16 and N14eC18. p / p* transition in benzene ring show greater stabilization energy, indicating significant delocalization effects within the ring. Through partial density of states, we understand that piperazine contributes 89% to HOMO and benzene contributes 71% to LUMO. The electronic energy levels have moved closer in the present compound compared to benzene and hence it is more reactive than benzene. The auxochromes N13 and N14 which possess unshared electrons, causes bathochromic shift. MPPZ forms a stable complex with C. botulinum with binding affinity
6.5 kcal/mol through molecular docking. The RMSD graph obtained from dynamics simulation indicate that the ligand influences the receptor (protein). Radial distribution function is one

of the many ways to quantify the structure of the molecule. G(r) is high for N14. Though title compound exhibits significant dipole moment, it has low hyper polarizability when compared to urea. Thus, it does not exhibit significant NLO property. From thermochemical analysis, we note that MPPZ, stores most of its energy in the form of vibrational motions, which is reflected through 81 vibrational temperatures corresponding to 81 vibrational modes. Acknowledgements We thank the Administration of St. Joseph's college of Arts and Science (Autonomous), Cuddalore for having provided us the Quantum Computational Research Lab for the computational works. We convey our special thanks to Govindarajan R, Surendran R and Mukund K from Pondicherry University, Pondicherry, India, for helping us with the experimental analysis and for their informative discussions and suggestions throughout this work. We extend our thanks to Sophisticated Analytical Instrument Facility (SAIF), IIT Madras, Chennai, India, for recording FT-Raman spectrum of the title compound. Appendix A. Supplementary data

Table 8 Thermodynamic properties at different temperatures at the B3LYP/6-311þþG (d, p) level of 1-METHYL-3-PHENYLPIPERAZINE. T (K)

0 (calmol
1K
1) Cm

S0m (calmol
1K
1)

0 (Kcalmol
1) DHm

100 200 300 400 500

15.528 29.408 45.652 62.456 77.367

69.470 85.784 101.510 117.541 133.568

159.547 161.781 165.515 170.929 177.941

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