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NLMO investigations of pantoprazole
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx
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Experimental, quantum chemical and NBO/NLMO investigations of pantoprazole P. Rajesh a,⇑, S. Gunasekaran b, T. Gnanasambandan c, S. Seshadri d a
Department of Physics, Pachaiyappa’s College, Chennai 600 030, India Research & Development, St. Peter’s University, Avadi, Chennai 600 054, India c Department of Physics, Pallavan College of Engineering, Kanchipuram 631502, India d Department of Physics, L.N. Govt. Arts College, Ponneri 601204, India b
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
FT-IR and FT-Raman spectra of PPZ in
A complete vibrational analysis of PPZ is performed by combining the experimental and theoretical information using Pulay’s density functional theory (DFT) based on scaled quantum chemical approach. The calculated HOMO and LUMO energies show that charge transfer occur within the molecule. Comparison of simulated spectra with the experimental spectra provides important information about the ability of the computational method to describe the vibrational modes. B3LYP/6-31G(d,p) 1.0 0.8 0.6 0.4 0.2 0.0
-0.2 -0.4 -0.6 -0.8 0 H4 36 2 H 3 8 H 2 H 4 AT C2C20 6 OM C1 12 C
S
a r t i c l e
i n f o
Article history: Received 25 May 2014 Received in revised form 11 August 2014 Accepted 11 September 2014 Available online xxxx Keywords: PPZ B3LYP NBO NLMO
Charges (eV )
solid phase were recorded and analyzed. The vibrational wavenumbers were computed using B3LYP with 6-31G (d, p) basis set. The vibrational assignment and spectroscopic analysis have been carried out. The HOMO, LUMO energy gap were theoretically predicted.
B
C8 4 C
a b s t r a c t The complete vibrational assignment and analysis of the fundamental modes of pantoprazole (PPZ) was carried out using the experimental FT-IR, FT-Raman and UV–Vis data and quantum chemical studies. The observed vibrational data were compared with the wavenumbers derived theoretically for the optimized geometry of the compound from the DFT–B3LYP gradient calculations employing 6-31G (d, p) basis set. Thermodynamic properties like entropy, heat capacity and enthalpy have been calculated for the molecule. HOMO–LUMO energy gap has been calculated. The intramolecular contacts have been interpreted using natural bond orbital (NBO) and natural localized molecular orbital (NLMO) analysis. Important non-linear properties such as electric dipole moment and first hyperpolarizability of PPZ have been computed using B3LYP quantum chemical calculation. Finally, the Mulliken population analysis on atomic charges of the title compound has been calculated. Ó 2014 Elsevier B.V. All rights reserved.
⇑ Corresponding author. Tel.: +91 8189823556. E-mail address: [email protected] (P. Rajesh). http://dx.doi.org/10.1016/j.saa.2014.09.029 1386-1425/Ó 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: P. Rajesh et al., Experimental, quantum chemical and NBO/NLMO investigations of pantoprazole, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2014), http://dx.doi.org/10.1016/j.saa.2014.09.029
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P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx
Introduction Pantoprazole(PPZ)5-(difluoromethoxy)-2-[[(3,4-dimethoxy2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleis an oral pharmaceutically active compound having promising anti-ulcer activity. PPZ is a medication used to treat gastroesophageal reflux disease (GERD), a condition that causes gastric juices to flow upward from the stomach and into the esophagus. PPZ can also be used to treat irritation and ulceration of the stomach caused by non-steroidal anti-inflammatory drugs (NSAIDs). It can also be used as one part of a treatment to get rid of Helicobacter pylori, a bacterium found in the stomach, which can cause ulcers. The PPZ and its derivatives were investigated by several authors. Spectrophotometric determination of omeprazole, lansoprazole and pantoprazole in pharmaceutical formulations were done by Wahbi et al. [1]. Structural identification and characterization of potential impurities of pantoprazole sodium was investigated by Reddy et al. [2]. Toxicology and Toxicokinetics of Oral pantoprazole in Neonatal and Juvenile Dogs were done by Mansell et al. [3]. Thermodynamic and Electrochemical Investigation of pantoprazole: {(RS)-6-(difluoromethoxy)-2-[(3,4-dimethoxypyridin-2 yl)methylsulfinyl]-1H-benzo[d]-imidazole} as Corrosion Inhibitor for Mild Steel in Hydrochloric Acid Solution was reported earlier by Sudheer and Quraishi [4]. The site of action of pantoprazole in the gastric H+/K+-ATPase was studied by Jai Moo Shin et al. [5]. Validation of the spectrophotometric determination of omeprazole and pantoprazole sodium via their metal chelates was reported earlier by Salama et al. [6]. A literature study reveals that so far there is no complete theoretical and experimental study on PPZ was carried out except in our work. Organic molecule containing extended p-conjugated electrons and characterized by large values of molecular first hyperpolarizabilities show enhanced NLO properties. PPZ molecule can show large first order hyperpolarizabilities (b) related to an electronic intramolecular charge-transfer excitation between the ground and excited states. The redistribution of electron density (ED) in various bonding, antibonding orbital’s and E(2) energies have been calculated by natural bond orbital (NBO) analysis and natural localized molecular orbital interactions to give clear evidence of stabilization originating from the hyperconjugation of various intramolecular interactions. The experimental and theoretical results supported each other and the calculations are valuable for providing a reliable insight into the vibrational spectra and molecular properties. Experimental details The compound under investigation PPZ was purchased from Aldrich chemicals, USA. The FT-IR spectrum of PPZ was recorded in the region 4000–400 cm1 on IFS 66 V spectrophotometer using KBr pellet technique. The FT-Raman spectrum of PPZ has been recorded using 1064 nm line of Nd: YAG laser as excitation wavelength in the region 3500–100 cm1 on a spectrophotometer equipped with FT-Raman module accessory. The UV–Vis absorption spectrum of PPZ was examined in the range 200–700 nm using water as solvent with the help of SHIMADZU UV-1650 PC. Computational details Density functional theoretical (DFT) computations of PPZ were performed by using Gaussian 03 program package [7] at the Becke–Lee–Yang–Parr hybrid exchange–correlation three-parameter functional (B3LYP) level with standard 6-31G(d, p) basis set to derive the complete geometry optimization. All the optimized
geometry corresponding to minimum on the potential energy surface has been obtained by solving self-consistent field equation iteratively. The calculated harmonic vibrational wavenumbers have been analytically calculated by taking second order derivative of energy using the similar level of theory. The calculated wavenumbers were scaled with scaling factor of 0.963 for B3LYP. The vibrational modes were assigned on the basis of PED analysis using VEDA 4 program [8]. The Raman activities (Si) calculated with Gaussian 03 program Converted to relative Raman intensities (Ii) using the following relationship derived from the intensity theory of Raman scattering.
Ii ¼
f ð#o #i Þ4 Si #i ½1 ðexphc#i =KT Þ
ð1Þ
where m0 is the exciting frequency in cm1, mi the vibrational wavenumber of the ith normal mode, h, c and k fundamental constants and is a suitably chosen common normalization factor for all peak intensities. Results and discussion Molecular geometry In order to find the most optimized geometry, the energies were carried out for PPZ using B3LYP/6-31G(d, p) method and basis set for various possible conformers. There are nine conformers. The computationally predicted various possible conformers obtained for the compound PPZ is shown in Fig. 1. The total energies obtained for these conformers were listed in Table 1. It is clear from Table 1, the structure optimizations have shown that the conformer C1 have produced the global minimum energy. Therefore C1 form is the most stable conformer than the other conformer. The optimized molecular structure of PPZ calculated by DFTB3LYP level with the 6-31G(d, p) basis set are listed in Table 2 in accordance with the atom numbering scheme given in Fig. 2. The optimized molecular structure of PPZ belongs to C1 point group symmetry. Table 2 compares the calculated bond lengths and bond angles of PPZ. As the crystal structure of the exact title compound is not available as yet, the optimized structure can only be compared with other similar systems. Vibrational assignments The molecular structure of PPZ belongs to C1 point group symmetry. The molecule PPZ consists of 41 atoms and expected to have 117 normal modes of vibrations of the same species under C1 symmetry. These modes are found to be IR and Raman active suggesting that the molecule possesses a non-centro symmetric structure, which recommends the title compound for nonlinear optical applications. The harmonic vibrational modes calculated for PPZ at B3LYP level using the 6-31G(d, p) basis set along with Potential energy distribution have been summarized in Table 3. The force fields thus determined used to calculate the vibrational potential energy distribution (PED) using the VEDA 4 program [8]. The observed and experimental FT-IR and FT-Raman spectra of PPZ are shown in Figs. 3 and 4 respectively. C–S vibration The C–S stretching bands [9–11] are observed in the range 800– 130 cm1, usually with a moderate intensity. Since the S atom is less electronegative than the O atom, the C–S group is not as polar as the C–O group and less prone to form bridges. In our present study the weak band observed in FT-IR and FT-Raman spectrum at 696 and 710 cm1 respectively are assigned to C–S stretching vibration. The computed wavenumber for this vibration is at
Please cite this article in press as: P. Rajesh et al., Experimental, quantum chemical and NBO/NLMO investigations of pantoprazole, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2014), http://dx.doi.org/10.1016/j.saa.2014.09.029
P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx
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Fig. 1. Different possible conformers of pantoprazole.
Table 1 Total energies of different conformers of pantoprazole. Conformer
Hartrees
kJ/mol
Energy difference (kJ/mol)
C1 C2 C3 C4 C5 C6 C7 C8 C9
1673.92557928 1681.44208475 1681.59758586 1681.61280410 1681.62969468 1681.64931149 1681.67204038 1681.74330967 1681.75755245
4394891.94318475 4414626.52979954 4415034.79799495 4415074.75348711 4415119.09970828 4415170.60364686 4415230.27835210 4415417.39588724 4415454.79030899
00000.0000 19734.587 408.26820 39.955492 44.346221 51.503739 59.674705 186.61754 37.394422
699 cm1 by B3LYP/6-31G(d, p) methods are in good agreement with the literature [11].
N–H vibrations It has been observed that the presence of N–H in various molecules may be correlated with a constant occurrence of absorption bands whose positions are slightly altered from one compound to another; this is because of atomic group which vibrates independently from the other groups in the molecule and has its own
frequency. In all the hetero cyclic compounds the N–H stretching vibrations occur in the region 3500–3300 cm1 [12–14]. In the present investigation the N–H stretching vibrations have been found in both IR and Raman at 3626 cm1 with 100% of PED contribution. C–F vibrations The vibrations belonging to the bond between the ring and halogens are worth to discuss here since mixing of vibrations are possible due to the lowering of the molecular symmetry and the presence of heavy atoms on the periphery of the molecule [15]. The assignments of C–F stretching and deformation vibrations have been made by comparison with similar molecules like pbromophen [16] and the halogen-substituted benzene derivatives [17]. Mooney [18,19] assigned vibrations of C–X group (X = Cl, F, Br, I) in the frequency range of 1129–480 cm1. In the present investigation FT-IR and FT-Raman bands observed at 1082 cm1 and 1088 cm1 are assigned to C–F stretching vibration. C–O vibration Generally the C–O occurs in the region 1260–1000 cm1 [20,21]. In the present study, the bands observed at 1049 and 1226 cm1 in FTIR spectra and a weak band obtained at 1040
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P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx
Table 2 Optimized geometrical parameters of pantoprazole. Bond length
B3LYP
Bond angle
B3LYP
Bond angle
B3LYP
N1–C5 N1–H27 C2–N3 C2–S10 N3–C4 C4–C5 C4–C6 C5–C9 C6–C7 C6–H28 C7–C8 C7–H29 C8–C9 C8–O23 C9–H30 S10–O11 S10–C12 C12–C13 C12–H31 C12–H32 C13–C14 C13–N18 C14–C15 C14–O21 C15–C16 C15–O19 C16–C17 C16–H33 C19–N18 C17–H34 O19–C20 C20–H35 C20–H36 C20–H37 O21–C22 C22–H38 C22–H39
1.380 1.012 1.306 1.805 1.390 1.418 1.400 1.397 1.386 1.084 1.409 1.084 1.390 1.398 1.080 1.520 1.875 1.499 1.091 1.093 1.399 1.344 1.411 1.368 1.396 1.356 1.395 1.082 1.332 1.088 1.424 1.090 1.096 1.096 1.438 1.091 1.092
C22–H40 O23–C24 C24–F25 C24–F26 C24–H41 C15–C16–H33 C2–N1–C5 C5–N1–H27 N1–C2–N3 N1–C2–S10 N3–C2–S10 C2–N3–C4 N3–C4–C5 N3–C4–C6 C5–C4–C6 N1–C5–C4 N1–C5–C9 C4–C5–C9 C4–C6–C7 C4–C6–H28 C7–C6–H28 C6–C7–C8 C6–C7–H29 C8–C7–H29 C7–C8–C9 C7–C8–O27 C9–C8–O23 C5–C9–C8 C5–C9–H30 C8–C9–H30 C2–S10–O11 C2–S10–C12 O11–10S–2C S10–C12–C13 S10–C12–H31 S10–C12–H32 C1–C12–H31
1.095 1.363 1.368 1.358 1.092 121.599 106.173 130.765 114.914 117.401 127.514 103.741 110.465 130.121 119.409 104.696 132.027 123.272 118.198 120.516 121.283 121.006 121.135 117.857 122.618 113.659 123.699 115.486 122.432 122.081 103.500 98.391 105.512 115.967 105.126 102.127 110.162
C13–C12–H32 H31–C12–H32 C12–C13–C14 C12–C13–N18 C14–C13–N18 C13–C14–C15 C13–C14–O21 C15–C14–O21 C14–C15–C16 C14–C15–O19 C16–C15–O19 C15–C16–C17 C16–C17–N18 C16–C17–H34 N18–C17–H34 C13–N18–C17 C15–O19–C20 O19–C20–H35 O19–C20–H36 O19–C20–H37 H35–C20–H36 H35–C20–H37 H36–C20–H37 C14–O21–C22 O21–C22–H38 O21–C22–H39 O21–C22–H40 H38–C22–H39 H38–C22–H40 H39–C22–H40 C8–O23–C24 O23–C24–F25 O23–C24–F26 O23–C24–H41 F25–C24–F26 F25–C24–H41 F26–C24–H41
112.604 110.359 120.558 116.164 123.272 118.473 118.484 122.941 118.084 116.738 125.174 118.489 124.157 119.554 116.288 117.484 118.193 105.812 111.459 111.313 109.403 109.366 109.402 116.710 105.679 111.178 110.502 109.953 109.533 109.907 121.037 111.978 112.006 107.649 106.423 108.805 109.946
C–C vibrations The C–C stretching vibration gives rise to characteristic bands in both IR and Raman spectra covering the spectral region ranging from 1625 to 1400 cm1 [23]. The band observed at 1445 cm1 in both FT-IR and FT-Raman are assigned to C–C stretching vibrations. The calculated wavenumber at 1452 cm1 at B3LYP method shows a good agreement with the experimental data as given Table 3. C–H Vibrations The hetero aromatic structure shows the presence of C–H stretching vibrations in the region 3250–2950 cm1 which is the characteristic region for the ready identification of C–H stretching vibrations and particularly the regions 3250–3100 cm1 for asymmetric stretching and 3100–2950 cm1 for symmetric stretching modes of vibration [24]. Accordingly in PPZ bands observed at 3018, 3081 and 3107 cm1 in FT-IR and 3020, 3083 and 3108 cm1 in FT-Raman are assigned to C–H stretching vibration. The values of wave numbers observed in FT-IR and FT-Raman spectra are in excellent agreement with the theoretical values. The bands due to C–H in-plane bending vibrations are observed in the region 1000–1300 cm1 [25–29]. For this compound, the C–H in-plane bending vibrations are observed at 1217 cm1 in FT-IR and at 1212 cm1 in FT-Raman. The PED of vibration shows that they are not in pure modes. The theoretically scaled vibrations by B3LYP method also show good agreement with experimentally recorded data. The C–H out-of-plane bending vibrations appear in the region 900–675 cm1 [30]. The bands at 853 and 898 cm1 in FT-IR and at 851 and 885 cm1 in FT-Raman are assigned to C–H out-of-plane bending vibrations for PPZ. After scaling procedure, the theoretical C–H vibrations are in good agreement with the experimental values and literature. Methyl group vibrations The compounds under consideration PPZ possess a CH3 group in the side substitution chain. There are nine fundamentals one can expect to a CH3 group, namely the symmetrical stretching in CH3 (CH3 sym. stretch) and asymmetrical stretching (in plane hydrogen stretching mode); the symmetrical (CH3 sym. deform) and asymmetrical (CH3 asym. deform) deformation modes; inplane rocking, out-of-plane rocking, twisting and bending modes [31]. Each methyl group has three stretching vibrations, one being symmetric and other two asymmetric. The frequencies of asymmetric vibrations are higher than the symmetric one [32]. The theoretically computed values 3052 for CH3 symmetric stretching and 3131 cm1 for CH3 asymmetric stretching shows an excellent agreement with the range allotted by Dudley et al. [33]. NBO/NLMO analysis
Fig. 2. Optimized structure of pantoprazole.
and 1232 cm1 in FT-Raman spectrum is assigned as C–O stretching vibration. These vibrational assignments are in line with the B3LYP method. According to the literature, the C–O vibration is pushed to the lower region by the influence of other vibrations. In PPZ C–O in plane bending vibration is found at 505, 510 and 529 cm1 at B3LYP/6-31G(d, p) level, which is found mixed with the O–H deformation mode. A medium band is found at 233 and 257 cm1 for C–O out-of-plane bending vibration for a title molecule and it is also observed at 233 and 243 cm1 in FT-Raman spectrum. These assignments are in good agreement with the literature value [22].
NBO (Natural Bond Orbital) analysis provides an efficient method for studying intra-and intermolecular bonding and interaction among the bonds. It also provides a convenient basis for the investigation of charge transfer or conjugative interactions in the molecular system [34]. Another useful aspect of the NBO method is that it gives information about the interactions in both filled and virtual orbital spaces that could enhance the analysis of intra- and intermolecular interactions. The second order Fock matrix was carried out to evaluate the donor–acceptor interactions in the NBO analysis [35]. For each donor NBO (i) and acceptor NBO (j), the stabilization energy associated with i ? j delocalization can be estimated as, 2
Eð2Þ ¼ DEij ¼ qi
Fði; jÞ ej ei
ð2Þ
Please cite this article in press as: P. Rajesh et al., Experimental, quantum chemical and NBO/NLMO investigations of pantoprazole, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2014), http://dx.doi.org/10.1016/j.saa.2014.09.029
P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx Table 3 Vibrational assignments of pantoprazole.
Table 3 (continued) Experimental
Experimental FTIR cm1
FTRaman cm1
– – – – – – – – – – – – – – – – – – – – – – – – – – – 478 503 513 531 545 – 570 587 595 616 629 654 680 696 735 750 766 781 793 805 833 – 853 875 898 916 936 – 967 980 1020 1049 1082 1095 1111 – – 1139 1159 1163 – 1198 1208 1217 1226
– 18 27 35 45 47 70 83 – 108 110 – – 165 188 209 – 233 243 267 282 297 324 384 405 409 448 495 509 512 519 – – 554 582 598 615 626 639 687 710 719 748 764 771 795 – 835 – 851 874 885 938 959 – – 979 1021 1040 1088 – 1114 1125 1131 1148 – – 1177 1188 1210 1212 1232
5
B3LYP/631G(d, p) Scaled cm1
Vibrational assignments + PED (%)
7 15 23 36 52 58 76 89 98 104 117 150 158 168 205 207 221 233 257 270 277 298 335 381 407 416 438 486 505 510 529 542 549 553 580 602 610 625 637 691 699 728 758 761 790 795 828 832 842 847 849 901 953 959 960 969 982 1027 1044 1077 1109 1113 1117 1130 1142 1156 1164 1176 1180 1208 1212 1222
sCCSC(10) dFCF(15) dCSC(26) dCSC(27) tSC (22) + dCOC(11) dSCN(26) tNC(30) tNC(11) sCOCC(31) dCOC(20) dOSC(19) cNC(10) dCOC(19) sHCOC(29) sHCOC(19) sHCOC(10) tCH(11) sCOCC(12) cOCCS(11) sCCCN(10) tOC(11) sCNCC(27) tSCS(16) cOCCS(16) cOCCS(10) dOSC(12) dCCC(22) tOC(27) tOC(25) + tFC(16) tOC(21) + tFC(18) dFCF(20) + dFCO(10) + sCOCC(10) sCOCC(12) dOCC(11) cOCCS(10) tNH(16) tNH(20) tOC(25) + dCNCC(14) dCNC(11) dOCC(15) tNC(11) tCS(13) sNCCS(11) dCNC(11) dCNC(11) tFC(16) tCC(31) + dOCC(17) dHCC(34) dHCC(10) tCH(42) tCH(10) dHCC(11) tCH(15) tCH(10) dHCN(17) tCH(11) tOC(31) tCH(23) + sCSCN(21) tOC(65) tOC(19) + tSO(14) + dOSC(9) tCF(27) sHCCN(19) cFOFC(25) tOC(18) tOC(22) + dHNC(10) sCCCC(24) + dHCC(16) sCC(12) dHNC(14) + dHCC(8) dHCH(31) + sHCOC(11) dHCH(23) + sHCOC(11) dHCH(16) dHCH(10) tOC(26) + dHCC(15) + sCOCC(8)
FTIR cm1
FTRaman cm1
1249 – 1275 1283 1305 1317 1342 1358 1370 1385 1421 1422 1445 1467 1471 1477 – – 1505 1514 – – – 1557 1620 1634 1634 1676 3018 3062 3081 3107 3131 3141 3155 – 3171 3183 3195 3218 – 3257 3626
– 1251 1276 – 1306 – – 1361 1379 – – 1427 1445 1464 – – 1491 – – 1514 1518 1525 1537 1568 1622 1632 1649 1678 3020 3054 3083 3108 3121 3146 – 3162 3181 3184 3211 3225 3234 3242 3626
B3LYP/631G(d, p) Scaled cm1
Vibrational assignments + PED (%)
1247 1253 1268 1298 1306 1321 1329 1344 1384 1390 1409 1427 1452 1464 1481 1484 1493 1497 1505 1516 1526 1528 1532 1545 1620 1630 1634 1680 3020 3045 3088 3096 3130 3139 3158 3160 3166 3171 3210 3224 3229 3257 3625
dHCH(44) tNC(19) + dHCC(9) cNCC(10) dHCC(40) + tNC(12) tCC(17) sHCCN(13) tCC(20) + cOC(10) cOCCC(26) tOC(41) + dHCF(13) + cCFOH(9) dHCF(21) + cCFOH(11) dHCF(46) + cCFOH(14) dHNC(37) + dHCF(11) tCH(39) + sHCCC(25) dHCH(20) dHCCH(24) tCH(27) + dHCH(12) sHCOC(30) tCH(11) tCH(59) sHCOC(13) dHCH(14) dHCH(37) + sHCOC(23) cOCCC(10) cSNNC(12) dCCN(15) tNC(59) + dCCC(16) + dCCN(9) sCCCC(18) tCC(27) + cCC(21) dHCH(50) + tCH(34) cCH3(48) tCH(63) tCH(71) tCH3(25) + dHCH(11) tCH(72) tCH(53) tCH(47) + sHCNC(32) tCH(71) sHCCC(40) sHCCC(9) + tCH(72) sHCCC(8) + tCH(62) tCH(91) tCH(70) tNH(100)
t-Stretching; d-in plane bending; c-out of plane bending; s-torsion.
where qi is the donor orbital occupancy, ei and ej are diagonal elements (orbital energies) and F(i, j) is the off-diagonal NBO Fock matrix element. In Table 4, the perturbation energies of significant donor–acceptor interactions are presented. The larger the E(2) value, the more intensive is the interaction between electron donors and electron acceptors. In PPZ, the interactions between the first lone pair of C4 and the antibonding of N1–C5 have the highest E(2) value around 243.91 kJ/mol. The other significant interactions giving stronger stabilization energy value of 224.67 kJ/mol to the structure are the interactions between p*C17–N18 and the p*C13–C14. Table 5 gives the occupancy of electrons and p-character [36] in significant NBO natural atomic hybrid orbitals. In C–H bonds, the hydrogen atoms have almost 0% of p character. The 100% p-character was observed in the first lone pairs of C4 and in the second lone pair of O19. The natural localized molecular orbital (NLMO) analysis has been carried out since they show how bonding in a molecule is composed from orbitals localized on different atoms. The derivation of NLMOs from NBOs gives direct insight into the nature of the localized molecular orbital’s ‘‘delocalization tails’’ [37,38]. Table 6
Please cite this article in press as: P. Rajesh et al., Experimental, quantum chemical and NBO/NLMO investigations of pantoprazole, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2014), http://dx.doi.org/10.1016/j.saa.2014.09.029
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P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx
Fig. 3. FT-IR spectra of pantoprazole. Fig. 4. FT-Raman spectrum of pantoprazole.
shows significant NLMO’s occupancy, percentage from parent NBO and atomic hybrid contributions of PPZ calculated at the B3LYP level using 6-31G(d, p) basis set. The NLMO of first lone pair of carbon atom C4 is the most delocalized NLMO and has only 46% contribution from the localized LP(1) C4 parent NBO and the delocalization tail (41%) consists of the hybrids of N1, C2, C5 and C6.
Table 4 Second order perturbation theory analysis of Fock matrix in NBO basis. Donor (i) *
p N1–C5 p*C2–N3 p*C6–C7 p*C8–C9 p*C15–C16 p*C17–C18
UV–Vis spectral analysis All the structures allow strong p–p* or r–r* transition in the UV–Vis region with high extinction coefficients. The UV–Vis absorption spectrum of PPZ is shown in Fig. 5. On the basis of fully optimized ground-state structure, TD-DFT/B3LYP/6-31G(d, p) calculations have been used to determine the low-lying excited states of PPZ. The calculated results involving the vertical excitation energies and wavelength are carried out and compared with measured experimental wavelength. Typically, according to Frank–Condon principle, the maximum absorption peak (kmax) corresponds in an UV–Vis spectrum to vertical excitation. TD-DFT/B3LYP/6-31G(d, p) predicts one intense electronic transition at (280.22 nm) shows good agreement with measured experimental data (kexp = 290 nm) as shown in Table 7. Both the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) are the main orbitals that take part in chemical stability [23]. The HOMO represents the ability to donate an electron, LUMO as an electron acceptor represents the ability to obtain an electron. The HOMO and LUMO energy calculated by B3LYP/6-31G(d, p) method is shown in Table 9. This electronic absorption corresponds to the transition from the ground to the first excited state and is mainly described by one electron excitation from the highest occupied molecular orbital
LP(1) C4 LP(1) C4 LP(1) C4 LP(2) O19 p*N1–C5 p*N1–C5 p*C8–C9 p*C13–C14 p*C17–N18 a b c
Acceptor (j) *
p C2–N3 LP(1) C4 LP(1) C4 p*N1–C5 p*C17–N18 p*C13–C14 p*N1–C5 p*C2–N3 p*C6–C7 p*C15–C16 p*C2–N3 p*C8–C9 p*C6–C7 p*S10–C12 p*C13–C14
E(2)a kJ/mol)
E(j)–E(i)b (a.u.)
F(i, j)c (a.u.)
30.13 29.40 44.44 32.33 25.70 23.83 243.91 58.32 64.53 29.92 58.50 96.83 182.76 73.19 224.67
0.32 0.21 0.14 0.22 0.27 0.31 0.07 0.10 0.15 0.32 0.03 0.07 0.01 0.01 0.01
0.093 0.096 0.089 0.087 0.076 0.079 0.119 0.079 0.105 0.094 0.049 0.094 0.079 0.055 0.078
E(2) means energy of hyper conjugative interaction (stabilization energy). Energy difference between donor and acceptor i and j NBO orbitals. F(i, j) is the fork matrix element between i and j NBO orbitals.
(HOMO) to the lowest unoccupied molecular orbital (LUMO). The HOMO is located over the O–H and N–H group, the HOMO ? LUMO transition implies an electron density transfer to ring from O–H and N–H bond. Moreover, these orbitals significantly overlap in their position for PPZ. The atomic orbital compositions of the frontier molecular orbital are shown in Fig. 8.
HOMO energy ðB3LYPÞ ¼ 5:95308 a:u: LUMO energy ðB3LYPÞ ¼ 0:92737 a:u: HOMO LUMO energy gap ðB3LYPÞ ¼ 5:02571 a:u:
Please cite this article in press as: P. Rajesh et al., Experimental, quantum chemical and NBO/NLMO investigations of pantoprazole, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2014), http://dx.doi.org/10.1016/j.saa.2014.09.029
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P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx Table 5 Occupancy, percentage of p-character of significant natural atomic hybrid of the NBO of pantoprazole. Bond
ED(e)
Hybrid
Atom
p.%
p*C2–N3
1.88924
0.6569 (sp1.00) C + 0.7540 (sp1.00) N
p*C6–C7
1.72443
0.6935 (sp1.00) C + 0.7205 (sp1.00) C
p*C8–C9
1.73247
0.7042 (sp1.00) C + 0.7100 (sp1.00) C
p*C13–C14
1.64283
0.7050 (sp1.00) C + 0.7092 (sp1.00) C
p*C17–C18
1.74056
0.6512 (sp1.00) C + 0.2589 (sp1.00) N
LP(1) C4 LP(2) O19
1.95946 1.91003
P1.00 p1.00
C2 N3 C6 C7 C8 C9 C13 C14 C17 C18 C4 O19
99.98 99.94 99.96 99.98 99.99 99.99 99.98 99.99 99.98 99.94 99.96 99.98
Table 6 Significant NLMO’s occupancy, % from parent NBO and atomic hybrid contributions of pantoprazole. Bond
LP(1) C4
Occupancy
2.0000
% From parent NBO
45.814
Hybrid contributions Atom
%
N1 C2 C5 C6
6.825 6.287 20.891 7.053
LP(3) O11
2.0000
93.054
C2 S10 C12
1.281 3.077 1.663
LP(2) O19
2.0000
92.075
C15 C16
3.218 1.559
Table 8 Natural population analysis of pantoprazole. Atoms
Charge (eV)
Atom
Charge (eV)
N1 C2 N3 C4 C5 C6 C7 C8 C9 S10 O11 C12 C13 C14 C15 C16 C17 N18 O19 C20 O21
0.7158 0.0916 0.4200 0.0591 0.3071 0.1018 0.1385 0.2253 0.0372 0.8944 0.6746 0.5101 0.1515 0.3213 0.3252 0.1319 0.0021 0.3852 0.5580 0.1741 0.5716
C22 O23 C24 F25 F26 H27 H28 H29 H30 H31 H32 H33 H34 H35 H36 H37 H38 H39 H40 H41
0.1931 0.5482 0.6058 0.3059 0.3023 0.3710 0.1471 0.1484 0.1855 0.2275 0.2144 0.1422 0.1476 0.1778 0.1588 0.1605 0.1594 0.1732 0.1858 0.1852
Table 9 Molecular properties of pantoprazole. Molecular properties
B3LYP/631G(d, p)
EHOMO (eV)
5.95308
ELUMO (eV) EHomo–Lumo gap (eV)
0.92737 5.02571
Ionization potential (I) eV Electron affinity (A) eV
5.95308 0.92737
Molecular properties Chemical hardness (g) Softness (S) Chemical potential (l) Electronegativity (v) Electrophilicity index (x)
B3LYP/631G(d, p) 2.51285 0.39795 3.44022 3.44022 5.91757
bonding orbital with maximum electron density. The NBOs are one of a sequence of natural localized orbital sets that include ‘‘natural atomic orbitals’’ (NAO), ‘‘natural hybrid orbitals’’ (NHO), ‘‘natural bonding orbitals’’ (NBO) and ‘‘natural (semi-)localized molecular orbitals’’ (NLMO). These natural localized sets are intermediate between basis atomic orbitals (AO) and molecular orbitals (MO):
Atomic orbital ! NAO ! NHO ! NBO ! NLMO ! Molecular orbital
Fig. 5. UV–Vis spectrum of pantoprazole.
Natural population analysis Atomic charges of PPZ, calculated by natural population analysis at the B3LYP/6-31G(d, p) level of theory, are given in Table 8. In quantum chemistry, a natural bond orbital or NBO is a calculated
Natural (localized) orbitals are used in computational chemistry to calculate the distribution of electron density in atoms and in bonds between atoms is shown in Fig. 6. They have the ‘‘maximum-occupancy character’’ in localized 1-center and 2-center regions of the molecule. Natural bond orbitals (NBOs) include the highest possible percentage of the electron density. It can be seen from Table 8, the magnitudes of the carbon atomic charges were
Table 7 The UV–Vis excitation energy of pantoprazole. States
TD-B3LYP/6-31G(d, p) Gas phase
S1 S2 S3
Expt. kobs
Major contributions
290 263 240
HOMO ? LUMO (68%) H 1 ? LUMO (70%) H 1 ? L + 1 (21%), H ? L (24%)
Water
kcal
E (eV)
kcal
E (eV)
280.22 260.26 257.18
4.4245 4.7639 4.8210
282.98 269.25 240.38
4.3217 4.7071 4.9785
Please cite this article in press as: P. Rajesh et al., Experimental, quantum chemical and NBO/NLMO investigations of pantoprazole, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2014), http://dx.doi.org/10.1016/j.saa.2014.09.029
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P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx
B3LYP/6-31G(d,p)
1.0
0.4 0.2
0.0 -0. 2 -0. 4 -0. 6 -0. 8
0 H4 36 2 H 3 8 H 2 4 H 2 0 C 2 C 16 AT C 12 OM C C8
S
Charges (eV)
0.8 0.6
Fig. 8. Frontier molecular orbitals of pantoprazole.
in which ZA is the charge of nucleus A, located at RA and q(r0 ) is the electronic density function for the molecule and r0 is the dummy integration variable [39,40]. At any given point r (x, y, z) in the vicinity of a molecule, the MEP, V(r) is defined in terms of the interaction energy between the electrical charge generated from the molecule, electrons and nuclei and a positive test charge (a proton) located at r [41]. The MEP is related to electron density and a very useful descriptor for determining sites for electrophilic attack and nucleophilic reactions as well as hydrogen-bonding interactions [42,43]. The different values of the electrostatic potential at the surface are represented by different colours is shown in Fig. 7. Potential increases in the order red < orange < yellow < green < blue. The colour code of these maps is in the range between 0.105 a.u. (deepest red) to 0.0676 a.u. (Deepest blue) in compound, where blue indicates the strongest attraction and red indicates the strongest repulsion. The negative (red, orange and yellow) regions of the MEP are related to electrophilic reactivity. The maximum positive region is localized on the HFF bonds, indicating a possible site for nucleophilic attack. The MEP map shows that the negative potential sites are on electronegative oxygen atoms (O11) and the positive potential sites are around the hydrogen atoms. These sites give information about the region from where the compound can have intermolecular interactions. This predicted the most reactive site for both electrophilic and nucleophilic attack.
B
C4
Fig. 6. Natural population analysis chart of pantoprazole.
Local reactivity descriptors Fig. 7. Molecular electrostatic potential of pantoprazole.
noted to change from 0.1931 to 0.6058. The magnitudes of the carbon atom attached to the oxygen atoms (O19, O21, O23) have corresponding negative value, whereas the carbon atoms attached to the hydrogen atoms (H27 to H41) were calculated to be generally positive. In fact, S10 connected to oxygen atoms (O11) have the maximum charge magnitude 0.8944 at B3LYP/6-31G(d, p) calculation level. Molecular electrostatic potential (MEP) MEP and electrostatic potential are useful quantities to illustrate the charge distributions of molecules and used to visualize variably charged regions of a molecule. Therefore, the charge distributions can give information about how the molecules interact with another molecule. MEP is widely used as a reactivity map displaying most probable regions for the electrophilic attack of charged point-like reagents on organic molecules [39]. The molecular electrostatic potential V(r) that is created in the space around a molecule by its nuclei and electrons is well established as a guide to molecular reactive behaviour. It is defined by:
VðrÞ ¼
X A
ZA ðRA rÞ
Z
qðr0 Þ ðr 0 rÞ
dr
0
ð3Þ
The energy gap between HOMO and LUMO is a critical parameter to determine molecular electrical transport properties. By using HOMO and LUMO energy values for a molecule, the global chemical reactivity descriptors of molecules such as hardness, chemical potential, softness, electronegativity and electrophilicity index as well as local reactivity are being defined [44–48]. Pauling introduced the concept of electronegativity as the power of an atom in a molecule to attract electrons to it. Hardness (g), chemical potential (l) and electronegativity (v) and softness are defined follows.
1 @2E 1 @l VðrÞ ¼ VðrÞ 2 @N 2 2 @N @E l¼ VðrÞ @N @E VðrÞ v ¼ l ¼ @N
g¼
ð4Þ ð5Þ ð6Þ
where E and V(r) are electronic energy and external potential of an N-electron system respectively. Softness is a property of molecule that measures the extent of chemical reactivity. It is the reciprocal of hardness.
S¼
1
g
ð7Þ
Please cite this article in press as: P. Rajesh et al., Experimental, quantum chemical and NBO/NLMO investigations of pantoprazole, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2014), http://dx.doi.org/10.1016/j.saa.2014.09.029
P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx
Using Koopman’s theorem for closed-shell molecules, g, l and v can be defined as
g¼
1A ðI þ AÞ IþA l¼ v¼ 2 2 2
ð8Þ
where A and I are the ionization potential and electron affinity of the molecules respectively. The ionization energy and electron affinity can be expressed through HOMO and LUMO orbital energies as I = EHOMO and A = ELUMO. Electron affinity refers to the capability of a ligand to accept precisely one electron from a donor. The ionization potential calculated by B3LYP/6-31 G(d, p) method for PPZ is 5.9530 eV respectively. Considering the chemical hardness, large HOMO–LUMO gap means a hard molecule and small HOMO–LUMO gap means a soft molecule. One can also relate the stability of the molecule to hardness, which means that the molecule with least HOMO–LUMO gap means it is more reactive. Recently Parr et al. [44] have defined a new descriptor to quantify the global electrophilic power of the molecule as electrophilicity index (x), which defines a quantitative classification of the global electrophilic nature of a molecule Parr et al. [47] have proposed electrophilicity index (x) as a measure of energy lowering due to maximal electron flow between donor and acceptor. They defined electrophilicity index (x) as follows:
x¼
l2 2
ð9Þ
Using the above equations, the chemical potential, hardness and electrophilicity index are being calculated for PPZ and their values are shown in Table 9. The usefulness of this new reactivity quantity has been recently demonstrated in understanding the toxicity of various pollutants in terms of their reactivity and site selectivity [49–51]. Conclusion In this paper we have reported on complete structural, vibrational and electronic properties of PPZ by using experimental techniques FT-IR and FT-Raman. The vibrational frequencies of the fundamental modes of the compound have been precisely assigned and analyzed and theoretical results were compared with the experimental vibrations. Close agreement between the experimental frequencies were achieved. The energies of important MOs and the kmax of the compound are also evaluated from TD-DFT method. Moreover, HOMO and LUMO orbitals have been visualized. The intermolecular contacts have been interpreted by NBO/NLMO analysis. The MEP map shows that the negative potential sites are on electronegative atoms as well as the positive potential sites are around the hydrogen atoms. References [1] M.A. Wahbi, O.A. Razak, A. Azza, J. Pharm. Biomed. Anal. 30 (2002) 1133–1142. [2] G.M. Reddy, B.V. Bhaskar, P. Pratap, J. Pharm. Biomed. Anal. 45 (2007) 201–210. [3] P. Mansell, K. Robinson, D. Minck, E. Hurtt, Original Art. Birth Defects Res. (Part B) 92 (2011) 345–352. [4] M. Sudheer, A. Quraishi, Arab. J. Sci. Eng. 38 (2013) 99–109. [5] Jai Moo Shin, Marie Besancon, Alexander Simon, George Sachs, Biochimica et Biophysica Acta 1148 (1993) 223–233. [6] F. Salama, N. El-Abasawy, S.A. Abdel Razeq, M.M.F. Ismail, M.M. Fouad, J. Pharm. Biomed. Anal. 33 (2003) 411–421. [7] Gaussian 03, Revision C.02, M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E.Scuseria, M.A. Robb, J.R. Cheeseman, J.A. Montgomery Jr., T. Vreven, K.N. Kudin, J.C.
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Experimental, quantum chemical and NBO/NLMO investigations of pantoprazole P. Rajesh a,⇑, S. Gunasekaran b, T. Gnanasambandan c, S. Seshadri d a
Department of Physics, Pachaiyappa’s College, Chennai 600 030, India Research & Development, St. Peter’s University, Avadi, Chennai 600 054, India c Department of Physics, Pallavan College of Engineering, Kanchipuram 631502, India d Department of Physics, L.N. Govt. Arts College, Ponneri 601204, India b
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
FT-IR and FT-Raman spectra of PPZ in
A complete vibrational analysis of PPZ is performed by combining the experimental and theoretical information using Pulay’s density functional theory (DFT) based on scaled quantum chemical approach. The calculated HOMO and LUMO energies show that charge transfer occur within the molecule. Comparison of simulated spectra with the experimental spectra provides important information about the ability of the computational method to describe the vibrational modes. B3LYP/6-31G(d,p) 1.0 0.8 0.6 0.4 0.2 0.0
-0.2 -0.4 -0.6 -0.8 0 H4 36 2 H 3 8 H 2 H 4 AT C2C20 6 OM C1 12 C
S
a r t i c l e
i n f o
Article history: Received 25 May 2014 Received in revised form 11 August 2014 Accepted 11 September 2014 Available online xxxx Keywords: PPZ B3LYP NBO NLMO
Charges (eV )
solid phase were recorded and analyzed. The vibrational wavenumbers were computed using B3LYP with 6-31G (d, p) basis set. The vibrational assignment and spectroscopic analysis have been carried out. The HOMO, LUMO energy gap were theoretically predicted.
B
C8 4 C
a b s t r a c t The complete vibrational assignment and analysis of the fundamental modes of pantoprazole (PPZ) was carried out using the experimental FT-IR, FT-Raman and UV–Vis data and quantum chemical studies. The observed vibrational data were compared with the wavenumbers derived theoretically for the optimized geometry of the compound from the DFT–B3LYP gradient calculations employing 6-31G (d, p) basis set. Thermodynamic properties like entropy, heat capacity and enthalpy have been calculated for the molecule. HOMO–LUMO energy gap has been calculated. The intramolecular contacts have been interpreted using natural bond orbital (NBO) and natural localized molecular orbital (NLMO) analysis. Important non-linear properties such as electric dipole moment and first hyperpolarizability of PPZ have been computed using B3LYP quantum chemical calculation. Finally, the Mulliken population analysis on atomic charges of the title compound has been calculated. Ó 2014 Elsevier B.V. All rights reserved.
⇑ Corresponding author. Tel.: +91 8189823556. E-mail address: [email protected] (P. Rajesh). http://dx.doi.org/10.1016/j.saa.2014.09.029 1386-1425/Ó 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: P. Rajesh et al., Experimental, quantum chemical and NBO/NLMO investigations of pantoprazole, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2014), http://dx.doi.org/10.1016/j.saa.2014.09.029
2
P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx
Introduction Pantoprazole(PPZ)5-(difluoromethoxy)-2-[[(3,4-dimethoxy2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleis an oral pharmaceutically active compound having promising anti-ulcer activity. PPZ is a medication used to treat gastroesophageal reflux disease (GERD), a condition that causes gastric juices to flow upward from the stomach and into the esophagus. PPZ can also be used to treat irritation and ulceration of the stomach caused by non-steroidal anti-inflammatory drugs (NSAIDs). It can also be used as one part of a treatment to get rid of Helicobacter pylori, a bacterium found in the stomach, which can cause ulcers. The PPZ and its derivatives were investigated by several authors. Spectrophotometric determination of omeprazole, lansoprazole and pantoprazole in pharmaceutical formulations were done by Wahbi et al. [1]. Structural identification and characterization of potential impurities of pantoprazole sodium was investigated by Reddy et al. [2]. Toxicology and Toxicokinetics of Oral pantoprazole in Neonatal and Juvenile Dogs were done by Mansell et al. [3]. Thermodynamic and Electrochemical Investigation of pantoprazole: {(RS)-6-(difluoromethoxy)-2-[(3,4-dimethoxypyridin-2 yl)methylsulfinyl]-1H-benzo[d]-imidazole} as Corrosion Inhibitor for Mild Steel in Hydrochloric Acid Solution was reported earlier by Sudheer and Quraishi [4]. The site of action of pantoprazole in the gastric H+/K+-ATPase was studied by Jai Moo Shin et al. [5]. Validation of the spectrophotometric determination of omeprazole and pantoprazole sodium via their metal chelates was reported earlier by Salama et al. [6]. A literature study reveals that so far there is no complete theoretical and experimental study on PPZ was carried out except in our work. Organic molecule containing extended p-conjugated electrons and characterized by large values of molecular first hyperpolarizabilities show enhanced NLO properties. PPZ molecule can show large first order hyperpolarizabilities (b) related to an electronic intramolecular charge-transfer excitation between the ground and excited states. The redistribution of electron density (ED) in various bonding, antibonding orbital’s and E(2) energies have been calculated by natural bond orbital (NBO) analysis and natural localized molecular orbital interactions to give clear evidence of stabilization originating from the hyperconjugation of various intramolecular interactions. The experimental and theoretical results supported each other and the calculations are valuable for providing a reliable insight into the vibrational spectra and molecular properties. Experimental details The compound under investigation PPZ was purchased from Aldrich chemicals, USA. The FT-IR spectrum of PPZ was recorded in the region 4000–400 cm1 on IFS 66 V spectrophotometer using KBr pellet technique. The FT-Raman spectrum of PPZ has been recorded using 1064 nm line of Nd: YAG laser as excitation wavelength in the region 3500–100 cm1 on a spectrophotometer equipped with FT-Raman module accessory. The UV–Vis absorption spectrum of PPZ was examined in the range 200–700 nm using water as solvent with the help of SHIMADZU UV-1650 PC. Computational details Density functional theoretical (DFT) computations of PPZ were performed by using Gaussian 03 program package [7] at the Becke–Lee–Yang–Parr hybrid exchange–correlation three-parameter functional (B3LYP) level with standard 6-31G(d, p) basis set to derive the complete geometry optimization. All the optimized
geometry corresponding to minimum on the potential energy surface has been obtained by solving self-consistent field equation iteratively. The calculated harmonic vibrational wavenumbers have been analytically calculated by taking second order derivative of energy using the similar level of theory. The calculated wavenumbers were scaled with scaling factor of 0.963 for B3LYP. The vibrational modes were assigned on the basis of PED analysis using VEDA 4 program [8]. The Raman activities (Si) calculated with Gaussian 03 program Converted to relative Raman intensities (Ii) using the following relationship derived from the intensity theory of Raman scattering.
Ii ¼
f ð#o #i Þ4 Si #i ½1 ðexphc#i =KT Þ
ð1Þ
where m0 is the exciting frequency in cm1, mi the vibrational wavenumber of the ith normal mode, h, c and k fundamental constants and is a suitably chosen common normalization factor for all peak intensities. Results and discussion Molecular geometry In order to find the most optimized geometry, the energies were carried out for PPZ using B3LYP/6-31G(d, p) method and basis set for various possible conformers. There are nine conformers. The computationally predicted various possible conformers obtained for the compound PPZ is shown in Fig. 1. The total energies obtained for these conformers were listed in Table 1. It is clear from Table 1, the structure optimizations have shown that the conformer C1 have produced the global minimum energy. Therefore C1 form is the most stable conformer than the other conformer. The optimized molecular structure of PPZ calculated by DFTB3LYP level with the 6-31G(d, p) basis set are listed in Table 2 in accordance with the atom numbering scheme given in Fig. 2. The optimized molecular structure of PPZ belongs to C1 point group symmetry. Table 2 compares the calculated bond lengths and bond angles of PPZ. As the crystal structure of the exact title compound is not available as yet, the optimized structure can only be compared with other similar systems. Vibrational assignments The molecular structure of PPZ belongs to C1 point group symmetry. The molecule PPZ consists of 41 atoms and expected to have 117 normal modes of vibrations of the same species under C1 symmetry. These modes are found to be IR and Raman active suggesting that the molecule possesses a non-centro symmetric structure, which recommends the title compound for nonlinear optical applications. The harmonic vibrational modes calculated for PPZ at B3LYP level using the 6-31G(d, p) basis set along with Potential energy distribution have been summarized in Table 3. The force fields thus determined used to calculate the vibrational potential energy distribution (PED) using the VEDA 4 program [8]. The observed and experimental FT-IR and FT-Raman spectra of PPZ are shown in Figs. 3 and 4 respectively. C–S vibration The C–S stretching bands [9–11] are observed in the range 800– 130 cm1, usually with a moderate intensity. Since the S atom is less electronegative than the O atom, the C–S group is not as polar as the C–O group and less prone to form bridges. In our present study the weak band observed in FT-IR and FT-Raman spectrum at 696 and 710 cm1 respectively are assigned to C–S stretching vibration. The computed wavenumber for this vibration is at
Please cite this article in press as: P. Rajesh et al., Experimental, quantum chemical and NBO/NLMO investigations of pantoprazole, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2014), http://dx.doi.org/10.1016/j.saa.2014.09.029
P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx
3
Fig. 1. Different possible conformers of pantoprazole.
Table 1 Total energies of different conformers of pantoprazole. Conformer
Hartrees
kJ/mol
Energy difference (kJ/mol)
C1 C2 C3 C4 C5 C6 C7 C8 C9
1673.92557928 1681.44208475 1681.59758586 1681.61280410 1681.62969468 1681.64931149 1681.67204038 1681.74330967 1681.75755245
4394891.94318475 4414626.52979954 4415034.79799495 4415074.75348711 4415119.09970828 4415170.60364686 4415230.27835210 4415417.39588724 4415454.79030899
00000.0000 19734.587 408.26820 39.955492 44.346221 51.503739 59.674705 186.61754 37.394422
699 cm1 by B3LYP/6-31G(d, p) methods are in good agreement with the literature [11].
N–H vibrations It has been observed that the presence of N–H in various molecules may be correlated with a constant occurrence of absorption bands whose positions are slightly altered from one compound to another; this is because of atomic group which vibrates independently from the other groups in the molecule and has its own
frequency. In all the hetero cyclic compounds the N–H stretching vibrations occur in the region 3500–3300 cm1 [12–14]. In the present investigation the N–H stretching vibrations have been found in both IR and Raman at 3626 cm1 with 100% of PED contribution. C–F vibrations The vibrations belonging to the bond between the ring and halogens are worth to discuss here since mixing of vibrations are possible due to the lowering of the molecular symmetry and the presence of heavy atoms on the periphery of the molecule [15]. The assignments of C–F stretching and deformation vibrations have been made by comparison with similar molecules like pbromophen [16] and the halogen-substituted benzene derivatives [17]. Mooney [18,19] assigned vibrations of C–X group (X = Cl, F, Br, I) in the frequency range of 1129–480 cm1. In the present investigation FT-IR and FT-Raman bands observed at 1082 cm1 and 1088 cm1 are assigned to C–F stretching vibration. C–O vibration Generally the C–O occurs in the region 1260–1000 cm1 [20,21]. In the present study, the bands observed at 1049 and 1226 cm1 in FTIR spectra and a weak band obtained at 1040
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P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx
Table 2 Optimized geometrical parameters of pantoprazole. Bond length
B3LYP
Bond angle
B3LYP
Bond angle
B3LYP
N1–C5 N1–H27 C2–N3 C2–S10 N3–C4 C4–C5 C4–C6 C5–C9 C6–C7 C6–H28 C7–C8 C7–H29 C8–C9 C8–O23 C9–H30 S10–O11 S10–C12 C12–C13 C12–H31 C12–H32 C13–C14 C13–N18 C14–C15 C14–O21 C15–C16 C15–O19 C16–C17 C16–H33 C19–N18 C17–H34 O19–C20 C20–H35 C20–H36 C20–H37 O21–C22 C22–H38 C22–H39
1.380 1.012 1.306 1.805 1.390 1.418 1.400 1.397 1.386 1.084 1.409 1.084 1.390 1.398 1.080 1.520 1.875 1.499 1.091 1.093 1.399 1.344 1.411 1.368 1.396 1.356 1.395 1.082 1.332 1.088 1.424 1.090 1.096 1.096 1.438 1.091 1.092
C22–H40 O23–C24 C24–F25 C24–F26 C24–H41 C15–C16–H33 C2–N1–C5 C5–N1–H27 N1–C2–N3 N1–C2–S10 N3–C2–S10 C2–N3–C4 N3–C4–C5 N3–C4–C6 C5–C4–C6 N1–C5–C4 N1–C5–C9 C4–C5–C9 C4–C6–C7 C4–C6–H28 C7–C6–H28 C6–C7–C8 C6–C7–H29 C8–C7–H29 C7–C8–C9 C7–C8–O27 C9–C8–O23 C5–C9–C8 C5–C9–H30 C8–C9–H30 C2–S10–O11 C2–S10–C12 O11–10S–2C S10–C12–C13 S10–C12–H31 S10–C12–H32 C1–C12–H31
1.095 1.363 1.368 1.358 1.092 121.599 106.173 130.765 114.914 117.401 127.514 103.741 110.465 130.121 119.409 104.696 132.027 123.272 118.198 120.516 121.283 121.006 121.135 117.857 122.618 113.659 123.699 115.486 122.432 122.081 103.500 98.391 105.512 115.967 105.126 102.127 110.162
C13–C12–H32 H31–C12–H32 C12–C13–C14 C12–C13–N18 C14–C13–N18 C13–C14–C15 C13–C14–O21 C15–C14–O21 C14–C15–C16 C14–C15–O19 C16–C15–O19 C15–C16–C17 C16–C17–N18 C16–C17–H34 N18–C17–H34 C13–N18–C17 C15–O19–C20 O19–C20–H35 O19–C20–H36 O19–C20–H37 H35–C20–H36 H35–C20–H37 H36–C20–H37 C14–O21–C22 O21–C22–H38 O21–C22–H39 O21–C22–H40 H38–C22–H39 H38–C22–H40 H39–C22–H40 C8–O23–C24 O23–C24–F25 O23–C24–F26 O23–C24–H41 F25–C24–F26 F25–C24–H41 F26–C24–H41
112.604 110.359 120.558 116.164 123.272 118.473 118.484 122.941 118.084 116.738 125.174 118.489 124.157 119.554 116.288 117.484 118.193 105.812 111.459 111.313 109.403 109.366 109.402 116.710 105.679 111.178 110.502 109.953 109.533 109.907 121.037 111.978 112.006 107.649 106.423 108.805 109.946
C–C vibrations The C–C stretching vibration gives rise to characteristic bands in both IR and Raman spectra covering the spectral region ranging from 1625 to 1400 cm1 [23]. The band observed at 1445 cm1 in both FT-IR and FT-Raman are assigned to C–C stretching vibrations. The calculated wavenumber at 1452 cm1 at B3LYP method shows a good agreement with the experimental data as given Table 3. C–H Vibrations The hetero aromatic structure shows the presence of C–H stretching vibrations in the region 3250–2950 cm1 which is the characteristic region for the ready identification of C–H stretching vibrations and particularly the regions 3250–3100 cm1 for asymmetric stretching and 3100–2950 cm1 for symmetric stretching modes of vibration [24]. Accordingly in PPZ bands observed at 3018, 3081 and 3107 cm1 in FT-IR and 3020, 3083 and 3108 cm1 in FT-Raman are assigned to C–H stretching vibration. The values of wave numbers observed in FT-IR and FT-Raman spectra are in excellent agreement with the theoretical values. The bands due to C–H in-plane bending vibrations are observed in the region 1000–1300 cm1 [25–29]. For this compound, the C–H in-plane bending vibrations are observed at 1217 cm1 in FT-IR and at 1212 cm1 in FT-Raman. The PED of vibration shows that they are not in pure modes. The theoretically scaled vibrations by B3LYP method also show good agreement with experimentally recorded data. The C–H out-of-plane bending vibrations appear in the region 900–675 cm1 [30]. The bands at 853 and 898 cm1 in FT-IR and at 851 and 885 cm1 in FT-Raman are assigned to C–H out-of-plane bending vibrations for PPZ. After scaling procedure, the theoretical C–H vibrations are in good agreement with the experimental values and literature. Methyl group vibrations The compounds under consideration PPZ possess a CH3 group in the side substitution chain. There are nine fundamentals one can expect to a CH3 group, namely the symmetrical stretching in CH3 (CH3 sym. stretch) and asymmetrical stretching (in plane hydrogen stretching mode); the symmetrical (CH3 sym. deform) and asymmetrical (CH3 asym. deform) deformation modes; inplane rocking, out-of-plane rocking, twisting and bending modes [31]. Each methyl group has three stretching vibrations, one being symmetric and other two asymmetric. The frequencies of asymmetric vibrations are higher than the symmetric one [32]. The theoretically computed values 3052 for CH3 symmetric stretching and 3131 cm1 for CH3 asymmetric stretching shows an excellent agreement with the range allotted by Dudley et al. [33]. NBO/NLMO analysis
Fig. 2. Optimized structure of pantoprazole.
and 1232 cm1 in FT-Raman spectrum is assigned as C–O stretching vibration. These vibrational assignments are in line with the B3LYP method. According to the literature, the C–O vibration is pushed to the lower region by the influence of other vibrations. In PPZ C–O in plane bending vibration is found at 505, 510 and 529 cm1 at B3LYP/6-31G(d, p) level, which is found mixed with the O–H deformation mode. A medium band is found at 233 and 257 cm1 for C–O out-of-plane bending vibration for a title molecule and it is also observed at 233 and 243 cm1 in FT-Raman spectrum. These assignments are in good agreement with the literature value [22].
NBO (Natural Bond Orbital) analysis provides an efficient method for studying intra-and intermolecular bonding and interaction among the bonds. It also provides a convenient basis for the investigation of charge transfer or conjugative interactions in the molecular system [34]. Another useful aspect of the NBO method is that it gives information about the interactions in both filled and virtual orbital spaces that could enhance the analysis of intra- and intermolecular interactions. The second order Fock matrix was carried out to evaluate the donor–acceptor interactions in the NBO analysis [35]. For each donor NBO (i) and acceptor NBO (j), the stabilization energy associated with i ? j delocalization can be estimated as, 2
Eð2Þ ¼ DEij ¼ qi
Fði; jÞ ej ei
ð2Þ
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P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx Table 3 Vibrational assignments of pantoprazole.
Table 3 (continued) Experimental
Experimental FTIR cm1
FTRaman cm1
– – – – – – – – – – – – – – – – – – – – – – – – – – – 478 503 513 531 545 – 570 587 595 616 629 654 680 696 735 750 766 781 793 805 833 – 853 875 898 916 936 – 967 980 1020 1049 1082 1095 1111 – – 1139 1159 1163 – 1198 1208 1217 1226
– 18 27 35 45 47 70 83 – 108 110 – – 165 188 209 – 233 243 267 282 297 324 384 405 409 448 495 509 512 519 – – 554 582 598 615 626 639 687 710 719 748 764 771 795 – 835 – 851 874 885 938 959 – – 979 1021 1040 1088 – 1114 1125 1131 1148 – – 1177 1188 1210 1212 1232
5
B3LYP/631G(d, p) Scaled cm1
Vibrational assignments + PED (%)
7 15 23 36 52 58 76 89 98 104 117 150 158 168 205 207 221 233 257 270 277 298 335 381 407 416 438 486 505 510 529 542 549 553 580 602 610 625 637 691 699 728 758 761 790 795 828 832 842 847 849 901 953 959 960 969 982 1027 1044 1077 1109 1113 1117 1130 1142 1156 1164 1176 1180 1208 1212 1222
sCCSC(10) dFCF(15) dCSC(26) dCSC(27) tSC (22) + dCOC(11) dSCN(26) tNC(30) tNC(11) sCOCC(31) dCOC(20) dOSC(19) cNC(10) dCOC(19) sHCOC(29) sHCOC(19) sHCOC(10) tCH(11) sCOCC(12) cOCCS(11) sCCCN(10) tOC(11) sCNCC(27) tSCS(16) cOCCS(16) cOCCS(10) dOSC(12) dCCC(22) tOC(27) tOC(25) + tFC(16) tOC(21) + tFC(18) dFCF(20) + dFCO(10) + sCOCC(10) sCOCC(12) dOCC(11) cOCCS(10) tNH(16) tNH(20) tOC(25) + dCNCC(14) dCNC(11) dOCC(15) tNC(11) tCS(13) sNCCS(11) dCNC(11) dCNC(11) tFC(16) tCC(31) + dOCC(17) dHCC(34) dHCC(10) tCH(42) tCH(10) dHCC(11) tCH(15) tCH(10) dHCN(17) tCH(11) tOC(31) tCH(23) + sCSCN(21) tOC(65) tOC(19) + tSO(14) + dOSC(9) tCF(27) sHCCN(19) cFOFC(25) tOC(18) tOC(22) + dHNC(10) sCCCC(24) + dHCC(16) sCC(12) dHNC(14) + dHCC(8) dHCH(31) + sHCOC(11) dHCH(23) + sHCOC(11) dHCH(16) dHCH(10) tOC(26) + dHCC(15) + sCOCC(8)
FTIR cm1
FTRaman cm1
1249 – 1275 1283 1305 1317 1342 1358 1370 1385 1421 1422 1445 1467 1471 1477 – – 1505 1514 – – – 1557 1620 1634 1634 1676 3018 3062 3081 3107 3131 3141 3155 – 3171 3183 3195 3218 – 3257 3626
– 1251 1276 – 1306 – – 1361 1379 – – 1427 1445 1464 – – 1491 – – 1514 1518 1525 1537 1568 1622 1632 1649 1678 3020 3054 3083 3108 3121 3146 – 3162 3181 3184 3211 3225 3234 3242 3626
B3LYP/631G(d, p) Scaled cm1
Vibrational assignments + PED (%)
1247 1253 1268 1298 1306 1321 1329 1344 1384 1390 1409 1427 1452 1464 1481 1484 1493 1497 1505 1516 1526 1528 1532 1545 1620 1630 1634 1680 3020 3045 3088 3096 3130 3139 3158 3160 3166 3171 3210 3224 3229 3257 3625
dHCH(44) tNC(19) + dHCC(9) cNCC(10) dHCC(40) + tNC(12) tCC(17) sHCCN(13) tCC(20) + cOC(10) cOCCC(26) tOC(41) + dHCF(13) + cCFOH(9) dHCF(21) + cCFOH(11) dHCF(46) + cCFOH(14) dHNC(37) + dHCF(11) tCH(39) + sHCCC(25) dHCH(20) dHCCH(24) tCH(27) + dHCH(12) sHCOC(30) tCH(11) tCH(59) sHCOC(13) dHCH(14) dHCH(37) + sHCOC(23) cOCCC(10) cSNNC(12) dCCN(15) tNC(59) + dCCC(16) + dCCN(9) sCCCC(18) tCC(27) + cCC(21) dHCH(50) + tCH(34) cCH3(48) tCH(63) tCH(71) tCH3(25) + dHCH(11) tCH(72) tCH(53) tCH(47) + sHCNC(32) tCH(71) sHCCC(40) sHCCC(9) + tCH(72) sHCCC(8) + tCH(62) tCH(91) tCH(70) tNH(100)
t-Stretching; d-in plane bending; c-out of plane bending; s-torsion.
where qi is the donor orbital occupancy, ei and ej are diagonal elements (orbital energies) and F(i, j) is the off-diagonal NBO Fock matrix element. In Table 4, the perturbation energies of significant donor–acceptor interactions are presented. The larger the E(2) value, the more intensive is the interaction between electron donors and electron acceptors. In PPZ, the interactions between the first lone pair of C4 and the antibonding of N1–C5 have the highest E(2) value around 243.91 kJ/mol. The other significant interactions giving stronger stabilization energy value of 224.67 kJ/mol to the structure are the interactions between p*C17–N18 and the p*C13–C14. Table 5 gives the occupancy of electrons and p-character [36] in significant NBO natural atomic hybrid orbitals. In C–H bonds, the hydrogen atoms have almost 0% of p character. The 100% p-character was observed in the first lone pairs of C4 and in the second lone pair of O19. The natural localized molecular orbital (NLMO) analysis has been carried out since they show how bonding in a molecule is composed from orbitals localized on different atoms. The derivation of NLMOs from NBOs gives direct insight into the nature of the localized molecular orbital’s ‘‘delocalization tails’’ [37,38]. Table 6
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P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx
Fig. 3. FT-IR spectra of pantoprazole. Fig. 4. FT-Raman spectrum of pantoprazole.
shows significant NLMO’s occupancy, percentage from parent NBO and atomic hybrid contributions of PPZ calculated at the B3LYP level using 6-31G(d, p) basis set. The NLMO of first lone pair of carbon atom C4 is the most delocalized NLMO and has only 46% contribution from the localized LP(1) C4 parent NBO and the delocalization tail (41%) consists of the hybrids of N1, C2, C5 and C6.
Table 4 Second order perturbation theory analysis of Fock matrix in NBO basis. Donor (i) *
p N1–C5 p*C2–N3 p*C6–C7 p*C8–C9 p*C15–C16 p*C17–C18
UV–Vis spectral analysis All the structures allow strong p–p* or r–r* transition in the UV–Vis region with high extinction coefficients. The UV–Vis absorption spectrum of PPZ is shown in Fig. 5. On the basis of fully optimized ground-state structure, TD-DFT/B3LYP/6-31G(d, p) calculations have been used to determine the low-lying excited states of PPZ. The calculated results involving the vertical excitation energies and wavelength are carried out and compared with measured experimental wavelength. Typically, according to Frank–Condon principle, the maximum absorption peak (kmax) corresponds in an UV–Vis spectrum to vertical excitation. TD-DFT/B3LYP/6-31G(d, p) predicts one intense electronic transition at (280.22 nm) shows good agreement with measured experimental data (kexp = 290 nm) as shown in Table 7. Both the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) are the main orbitals that take part in chemical stability [23]. The HOMO represents the ability to donate an electron, LUMO as an electron acceptor represents the ability to obtain an electron. The HOMO and LUMO energy calculated by B3LYP/6-31G(d, p) method is shown in Table 9. This electronic absorption corresponds to the transition from the ground to the first excited state and is mainly described by one electron excitation from the highest occupied molecular orbital
LP(1) C4 LP(1) C4 LP(1) C4 LP(2) O19 p*N1–C5 p*N1–C5 p*C8–C9 p*C13–C14 p*C17–N18 a b c
Acceptor (j) *
p C2–N3 LP(1) C4 LP(1) C4 p*N1–C5 p*C17–N18 p*C13–C14 p*N1–C5 p*C2–N3 p*C6–C7 p*C15–C16 p*C2–N3 p*C8–C9 p*C6–C7 p*S10–C12 p*C13–C14
E(2)a kJ/mol)
E(j)–E(i)b (a.u.)
F(i, j)c (a.u.)
30.13 29.40 44.44 32.33 25.70 23.83 243.91 58.32 64.53 29.92 58.50 96.83 182.76 73.19 224.67
0.32 0.21 0.14 0.22 0.27 0.31 0.07 0.10 0.15 0.32 0.03 0.07 0.01 0.01 0.01
0.093 0.096 0.089 0.087 0.076 0.079 0.119 0.079 0.105 0.094 0.049 0.094 0.079 0.055 0.078
E(2) means energy of hyper conjugative interaction (stabilization energy). Energy difference between donor and acceptor i and j NBO orbitals. F(i, j) is the fork matrix element between i and j NBO orbitals.
(HOMO) to the lowest unoccupied molecular orbital (LUMO). The HOMO is located over the O–H and N–H group, the HOMO ? LUMO transition implies an electron density transfer to ring from O–H and N–H bond. Moreover, these orbitals significantly overlap in their position for PPZ. The atomic orbital compositions of the frontier molecular orbital are shown in Fig. 8.
HOMO energy ðB3LYPÞ ¼ 5:95308 a:u: LUMO energy ðB3LYPÞ ¼ 0:92737 a:u: HOMO LUMO energy gap ðB3LYPÞ ¼ 5:02571 a:u:
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P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx Table 5 Occupancy, percentage of p-character of significant natural atomic hybrid of the NBO of pantoprazole. Bond
ED(e)
Hybrid
Atom
p.%
p*C2–N3
1.88924
0.6569 (sp1.00) C + 0.7540 (sp1.00) N
p*C6–C7
1.72443
0.6935 (sp1.00) C + 0.7205 (sp1.00) C
p*C8–C9
1.73247
0.7042 (sp1.00) C + 0.7100 (sp1.00) C
p*C13–C14
1.64283
0.7050 (sp1.00) C + 0.7092 (sp1.00) C
p*C17–C18
1.74056
0.6512 (sp1.00) C + 0.2589 (sp1.00) N
LP(1) C4 LP(2) O19
1.95946 1.91003
P1.00 p1.00
C2 N3 C6 C7 C8 C9 C13 C14 C17 C18 C4 O19
99.98 99.94 99.96 99.98 99.99 99.99 99.98 99.99 99.98 99.94 99.96 99.98
Table 6 Significant NLMO’s occupancy, % from parent NBO and atomic hybrid contributions of pantoprazole. Bond
LP(1) C4
Occupancy
2.0000
% From parent NBO
45.814
Hybrid contributions Atom
%
N1 C2 C5 C6
6.825 6.287 20.891 7.053
LP(3) O11
2.0000
93.054
C2 S10 C12
1.281 3.077 1.663
LP(2) O19
2.0000
92.075
C15 C16
3.218 1.559
Table 8 Natural population analysis of pantoprazole. Atoms
Charge (eV)
Atom
Charge (eV)
N1 C2 N3 C4 C5 C6 C7 C8 C9 S10 O11 C12 C13 C14 C15 C16 C17 N18 O19 C20 O21
0.7158 0.0916 0.4200 0.0591 0.3071 0.1018 0.1385 0.2253 0.0372 0.8944 0.6746 0.5101 0.1515 0.3213 0.3252 0.1319 0.0021 0.3852 0.5580 0.1741 0.5716
C22 O23 C24 F25 F26 H27 H28 H29 H30 H31 H32 H33 H34 H35 H36 H37 H38 H39 H40 H41
0.1931 0.5482 0.6058 0.3059 0.3023 0.3710 0.1471 0.1484 0.1855 0.2275 0.2144 0.1422 0.1476 0.1778 0.1588 0.1605 0.1594 0.1732 0.1858 0.1852
Table 9 Molecular properties of pantoprazole. Molecular properties
B3LYP/631G(d, p)
EHOMO (eV)
5.95308
ELUMO (eV) EHomo–Lumo gap (eV)
0.92737 5.02571
Ionization potential (I) eV Electron affinity (A) eV
5.95308 0.92737
Molecular properties Chemical hardness (g) Softness (S) Chemical potential (l) Electronegativity (v) Electrophilicity index (x)
B3LYP/631G(d, p) 2.51285 0.39795 3.44022 3.44022 5.91757
bonding orbital with maximum electron density. The NBOs are one of a sequence of natural localized orbital sets that include ‘‘natural atomic orbitals’’ (NAO), ‘‘natural hybrid orbitals’’ (NHO), ‘‘natural bonding orbitals’’ (NBO) and ‘‘natural (semi-)localized molecular orbitals’’ (NLMO). These natural localized sets are intermediate between basis atomic orbitals (AO) and molecular orbitals (MO):
Atomic orbital ! NAO ! NHO ! NBO ! NLMO ! Molecular orbital
Fig. 5. UV–Vis spectrum of pantoprazole.
Natural population analysis Atomic charges of PPZ, calculated by natural population analysis at the B3LYP/6-31G(d, p) level of theory, are given in Table 8. In quantum chemistry, a natural bond orbital or NBO is a calculated
Natural (localized) orbitals are used in computational chemistry to calculate the distribution of electron density in atoms and in bonds between atoms is shown in Fig. 6. They have the ‘‘maximum-occupancy character’’ in localized 1-center and 2-center regions of the molecule. Natural bond orbitals (NBOs) include the highest possible percentage of the electron density. It can be seen from Table 8, the magnitudes of the carbon atomic charges were
Table 7 The UV–Vis excitation energy of pantoprazole. States
TD-B3LYP/6-31G(d, p) Gas phase
S1 S2 S3
Expt. kobs
Major contributions
290 263 240
HOMO ? LUMO (68%) H 1 ? LUMO (70%) H 1 ? L + 1 (21%), H ? L (24%)
Water
kcal
E (eV)
kcal
E (eV)
280.22 260.26 257.18
4.4245 4.7639 4.8210
282.98 269.25 240.38
4.3217 4.7071 4.9785
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8
P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx
B3LYP/6-31G(d,p)
1.0
0.4 0.2
0.0 -0. 2 -0. 4 -0. 6 -0. 8
0 H4 36 2 H 3 8 H 2 4 H 2 0 C 2 C 16 AT C 12 OM C C8
S
Charges (eV)
0.8 0.6
Fig. 8. Frontier molecular orbitals of pantoprazole.
in which ZA is the charge of nucleus A, located at RA and q(r0 ) is the electronic density function for the molecule and r0 is the dummy integration variable [39,40]. At any given point r (x, y, z) in the vicinity of a molecule, the MEP, V(r) is defined in terms of the interaction energy between the electrical charge generated from the molecule, electrons and nuclei and a positive test charge (a proton) located at r [41]. The MEP is related to electron density and a very useful descriptor for determining sites for electrophilic attack and nucleophilic reactions as well as hydrogen-bonding interactions [42,43]. The different values of the electrostatic potential at the surface are represented by different colours is shown in Fig. 7. Potential increases in the order red < orange < yellow < green < blue. The colour code of these maps is in the range between 0.105 a.u. (deepest red) to 0.0676 a.u. (Deepest blue) in compound, where blue indicates the strongest attraction and red indicates the strongest repulsion. The negative (red, orange and yellow) regions of the MEP are related to electrophilic reactivity. The maximum positive region is localized on the HFF bonds, indicating a possible site for nucleophilic attack. The MEP map shows that the negative potential sites are on electronegative oxygen atoms (O11) and the positive potential sites are around the hydrogen atoms. These sites give information about the region from where the compound can have intermolecular interactions. This predicted the most reactive site for both electrophilic and nucleophilic attack.
B
C4
Fig. 6. Natural population analysis chart of pantoprazole.
Local reactivity descriptors Fig. 7. Molecular electrostatic potential of pantoprazole.
noted to change from 0.1931 to 0.6058. The magnitudes of the carbon atom attached to the oxygen atoms (O19, O21, O23) have corresponding negative value, whereas the carbon atoms attached to the hydrogen atoms (H27 to H41) were calculated to be generally positive. In fact, S10 connected to oxygen atoms (O11) have the maximum charge magnitude 0.8944 at B3LYP/6-31G(d, p) calculation level. Molecular electrostatic potential (MEP) MEP and electrostatic potential are useful quantities to illustrate the charge distributions of molecules and used to visualize variably charged regions of a molecule. Therefore, the charge distributions can give information about how the molecules interact with another molecule. MEP is widely used as a reactivity map displaying most probable regions for the electrophilic attack of charged point-like reagents on organic molecules [39]. The molecular electrostatic potential V(r) that is created in the space around a molecule by its nuclei and electrons is well established as a guide to molecular reactive behaviour. It is defined by:
VðrÞ ¼
X A
ZA ðRA rÞ
Z
qðr0 Þ ðr 0 rÞ
dr
0
ð3Þ
The energy gap between HOMO and LUMO is a critical parameter to determine molecular electrical transport properties. By using HOMO and LUMO energy values for a molecule, the global chemical reactivity descriptors of molecules such as hardness, chemical potential, softness, electronegativity and electrophilicity index as well as local reactivity are being defined [44–48]. Pauling introduced the concept of electronegativity as the power of an atom in a molecule to attract electrons to it. Hardness (g), chemical potential (l) and electronegativity (v) and softness are defined follows.
1 @2E 1 @l VðrÞ ¼ VðrÞ 2 @N 2 2 @N @E l¼ VðrÞ @N @E VðrÞ v ¼ l ¼ @N
g¼
ð4Þ ð5Þ ð6Þ
where E and V(r) are electronic energy and external potential of an N-electron system respectively. Softness is a property of molecule that measures the extent of chemical reactivity. It is the reciprocal of hardness.
S¼
1
g
ð7Þ
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P. Rajesh et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy xxx (2014) xxx–xxx
Using Koopman’s theorem for closed-shell molecules, g, l and v can be defined as
g¼
1A ðI þ AÞ IþA l¼ v¼ 2 2 2
ð8Þ
where A and I are the ionization potential and electron affinity of the molecules respectively. The ionization energy and electron affinity can be expressed through HOMO and LUMO orbital energies as I = EHOMO and A = ELUMO. Electron affinity refers to the capability of a ligand to accept precisely one electron from a donor. The ionization potential calculated by B3LYP/6-31 G(d, p) method for PPZ is 5.9530 eV respectively. Considering the chemical hardness, large HOMO–LUMO gap means a hard molecule and small HOMO–LUMO gap means a soft molecule. One can also relate the stability of the molecule to hardness, which means that the molecule with least HOMO–LUMO gap means it is more reactive. Recently Parr et al. [44] have defined a new descriptor to quantify the global electrophilic power of the molecule as electrophilicity index (x), which defines a quantitative classification of the global electrophilic nature of a molecule Parr et al. [47] have proposed electrophilicity index (x) as a measure of energy lowering due to maximal electron flow between donor and acceptor. They defined electrophilicity index (x) as follows:
x¼
l2 2
ð9Þ
Using the above equations, the chemical potential, hardness and electrophilicity index are being calculated for PPZ and their values are shown in Table 9. The usefulness of this new reactivity quantity has been recently demonstrated in understanding the toxicity of various pollutants in terms of their reactivity and site selectivity [49–51]. Conclusion In this paper we have reported on complete structural, vibrational and electronic properties of PPZ by using experimental techniques FT-IR and FT-Raman. The vibrational frequencies of the fundamental modes of the compound have been precisely assigned and analyzed and theoretical results were compared with the experimental vibrations. Close agreement between the experimental frequencies were achieved. The energies of important MOs and the kmax of the compound are also evaluated from TD-DFT method. Moreover, HOMO and LUMO orbitals have been visualized. The intermolecular contacts have been interpreted by NBO/NLMO analysis. The MEP map shows that the negative potential sites are on electronegative atoms as well as the positive potential sites are around the hydrogen atoms. References [1] M.A. Wahbi, O.A. Razak, A. Azza, J. Pharm. Biomed. Anal. 30 (2002) 1133–1142. [2] G.M. Reddy, B.V. Bhaskar, P. Pratap, J. Pharm. Biomed. Anal. 45 (2007) 201–210. [3] P. Mansell, K. Robinson, D. Minck, E. Hurtt, Original Art. Birth Defects Res. (Part B) 92 (2011) 345–352. [4] M. Sudheer, A. Quraishi, Arab. J. Sci. Eng. 38 (2013) 99–109. [5] Jai Moo Shin, Marie Besancon, Alexander Simon, George Sachs, Biochimica et Biophysica Acta 1148 (1993) 223–233. [6] F. Salama, N. El-Abasawy, S.A. Abdel Razeq, M.M.F. Ismail, M.M. Fouad, J. Pharm. Biomed. Anal. 33 (2003) 411–421. [7] Gaussian 03, Revision C.02, M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E.Scuseria, M.A. Robb, J.R. Cheeseman, J.A. Montgomery Jr., T. Vreven, K.N. Kudin, J.C.
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Please cite this article in press as: P. Rajesh et al., Experimental, quantum chemical and NBO/NLMO investigations of pantoprazole, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2014), http://dx.doi.org/10.1016/j.saa.2014.09.029