Spectroscopic and quantum computational study on naproxen sodium

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 226 (2020) 117614

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Spectroscopic and quantum computational study on naproxen sodium Rinnu Sara Saji a, d, Johanan Christian Prasana a, S. Muthu b, *, Jacob George a, Tintu K. Kuruvilla a, B.R. Raajaraman c a

Department of Physics, Madras Christian College, East Tambaram, 600059, Tamil Nadu, India Department of Physics, Arignar Anna Government Arts College, Cheyyar, 604407, Tamil Nadu, India c Department of Physics, Sri Venkateswara College of Engineering, Sriperumbudur, 602 117, Tamil Nadu, India d University of Madras, Chennai, 600005, Tamilnadu, India b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 29 March 2019 Received in revised form 5 June 2019 Accepted 6 October 2019 Available online 7 October 2019

The spectroscopic (FT-IR, FT-Raman, NMR), electronic (UVe-Vis.), structural and thermodynamical properties of an anti-inflammatory analgesic called Naproxen Sodium, (s)-6-methoxy-a-methyl-2naphthaleneacetic acid sodium salt are submitted by using both experimental techniques and theoretical methods as quantum chemical calculations in this work. The equilibrium geometry and vibrational spectra are calculated by using DFT (B3LYP) with 6e311þþG (d,p) basis set using GAUSSIAN 09. The vibrational wavenumbers are also corrected with scale factor to take better results for the calculated data. The HOMO-LUMO calculations are carried out on the title compound. The theoretical and experimental NMR peaks were found to be in good agreement. In addition, the detailed study on the NonBonding Orbitals, the excitation energies, AIM charges, condensed fukui calculations, thermodynamical properties, Localized Orbital Locator (LOL) and Electron Localization Function (ELF) are also performed. Furthermore, the study is extended to calculate the first order hyperpolarizability and to predict its NLO properties. The docking studies details helped on predicting the binding with different proteins. © 2019 Elsevier B.V. All rights reserved.

Keywords: DFT FT-IR FT-Raman NBO NLO Molecular docking

1. Introduction Naproxen sodium is the sodium salt form of naproxen and is a white to off-white crystalline powder [1].It is an aryl acetate derivative with chemical formula (C14H13NaO3) and molecular weight of 252.245 g/mol. It comes under the category non-steroidal antiinflammatory drugs (NSAIDs), used for pain relief and inflammatory diseases [2] and is commercialized as tablets or liquid filled capsules [3]. It exhibits anti-inflammatory, analgesic and antipyretic activity [4].Both acid and sodium salt form of the drug is used for the treatment of rheumatoid arthritis and other rheumatic or musculoskeletal disorders, dysmenorrhea, and acute gout [5,6]. On intake of naproxen sodium less severe headache was observed in common migraine patients [7]. Naproxen Sodium is used in the treatment of migraine [8]. The strength and capability is nearly the same as that of the parent compound, naproxen, but the salt form is absorbed more rapidly in the gastrointestinal tract than its acid form. Naproxen sodium exhibits prostaglandin biosynthesis, specifically

* Corresponding author. E-mail address: [email protected] (S. Muthu). https://doi.org/10.1016/j.saa.2019.117614 1386-1425/© 2019 Elsevier B.V. All rights reserved.

cyclooxygenase enzyme. It is a COX inhibitor which blocks the conversion of arachidonic acid to pro-inflammatory prostaglandins. This inhibits the formation of prostaglandins that are involved in pain, inflammation and fever [9,10]. Thus naproxen sodium can be used to treat mild to severe pain. Under literature survey it was noted that a complete quantum mechanical study on the above mentioned compound has not been reported yet. So the vibrational, electronic, nonlinear optical properties, intra molecular interactions, thermodynamic and docking studies were done on the compound using DFT technique. 2. Experimental details Naproxen sodium with 99% purity was procured from Sigma Aldrich Company. The FT-IR, FT-Raman, NMR studies were done on this compound without further purification. Using the KBr pellet technique and with a resolution of 1.0 cm1, the FT-IR spectrum of the title compound was recorded in the region 4000-400 cm1 using the PERKIN ELMER FT-IR spectrophotometer from SAIF IITChennai, India. The FT-Raman spectrum of the title compound with a resolution 2 cm1, using Nd:YAG Laser of 100 mW, in the region 4000-100 cm1was obtained using BRUCKER RFS 27 at IIT SAIF, Chennai, India. UV analysis for the title compound was done

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R.S. Saji et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 226 (2020) 117614

Fig. 1. Optimized molecular structure of naproxen sodium.

using DMSO as solvent in SIF, VIT, Vellore, Tamil Nadu, India. The NMR was done on BRUKER in SIF, VIT, Vellore, Tamil Nadu, India.

theory was implemented to compute the non-linear optical (NLO) properties such as dipole moment, polarizability and the first order hyperpolarizability of the title compound. For better understanding of electronic properties and charges, UV analysis, HOMO-LUMO studies, dipole moment and hyperpolarizability calculations were carried out in an even more advanced basis set, cc-pVDZ. NBO calculation were done to understand the delocalization of electron density from occupied(donor) to unoccupied(acceptor) NBOs within the molecule. These transition energies help to evaluate the hyperconjugation interactions and intramolecular interactions. The AIM charges of the title compound is also reported in this paper along with fukui calculations. The variations in the thermodynamical properties such as the heat capacity, entropy and enthalpy was studied for a temperature range of 100e1000K using THERMO.PL software [18]. To study molecular docking simulations AutoDock 4.2.6 was used [19]. 4. Results and discussions

3. Computational details

4.1. Geometry

Using GAUSSIAN09W program package Becke’s threeparameter hybrid function (B3) for the exchange part combined with Lee-Yang Parr (LYP) correlation function and with DFT (B3LYP) with 6e311þþG (d, p) basis set as the theory level, the spectroscopic measurements and quantum chemical computations were done on the title compound [11,12]. The energy was minimized and the structure was optimized. Using the optimized structure of the title compound, the bond angle and bond length were attained from CHEMCRAFT software and further this optimized structure was used to measure the harmonic vibrational frequencies from VEDA software [13]. When comparing the theoretical and experimental vibrational frequencies, the errors which occurs by neglecting the vibrational anharmonicity and also due to the incompleteness arising from basis set is compensated by including a scaling factor of 0.958 (4000-1700 cm1) and 0.983 (below 1700 cm1) for the vibrational frequencies [14,15]. The HOMOLUMO energies were studied using Gaussum2.2 [16]. The UV analysis for the compound was done using TD-DFT technique with B3LYP/6e311þþG (d, p) basis set. The same basis set was used for NMR studies with gauge-including atomic orbital (GIAO) approach and the chemical shifts calculated for 1H and 13C NMR were compared with the experimental spectra [17]. The same level of

The structure of the molecule was optimized using DFT (B3LYP) with 6e311þþG (d,p) basis set. The theoretical geometric parameters of Naproxen Sodium were compared with the experimental XRD results of the parent compound, Naproxen. The compound can be divided into two aromatic halves, such arylacetates have only the Sconformer known to be active. The optimized structure of (s)-6methoxy-a-methyl-2-naphthaleneacetic acid sodium salt is shown in Fig. 1 with the atom type and number labeling system. The prominent bond parameters are also marked. Table 1 gives selected experimental and theoretical bond parameters of the title compound. Under XRD study the crystal of the compound under study was found to be monoclinic with the carboxylic group nearly perpendicular to the naphthalene ring. The dimensions and similar conformations when compared to naproxen are nearly the same [20]. Since Naproxen sodium has only one extra sodium atom when compared to the parent atom (Naproxen), comparative study can be done for the geometry [21]. These results were comparable to an extend. On analyzing the theoretical data obtained it was found that the O-C bonds are 1.272 and 1.274 and 1.368 Å. The Oxygen attached to methyl group shows bond length 1.420 Å. All the C-H bonds are approx. 1.0 Å as in literature value. The Carbon-Carbon bonds inside

Table 1 Selected bond Lengths and Bond Angles of Naproxen Sodium. Bond length

B3LYP/6e311þþG(d,p)

Experimentala

Bond angle( )

B3LYP/6e311þþG(d,p)

Experimentala

O1-C2 C2-O3 C2-C4 C4-C5 C4-C6 C6-C7 C6-C17 C7-C8 C8-C9 C9-C10 C9-C16 C10-O11 C10-C13 O11-C12 C13-C14 C14-C15 C15-C16 C16-C17 O3-Na31

1.274 1.272 1.541 1.541 1.524 1.423 1.382 1.378 1.42 1.423 1.423 1.368 1.383 1.42 1.419 1.375 1.424 1.422 2.198

1.345 1.225 1.501 1.556 1.523 1.36 1.388 1.37 1.406 1.431 1.419 1.358 1.366 1.454 1.448 1.358 1.408 1.412

O1-C2-O3 O1-C2-C4 O3-C2-C4 C2-C4-C6 C4-C6-C17 C7-C6 -C17 C6-C7-C8 C6-C17-C16 C7-C8-C9 C8-C9-C16 C10-C9-C16 C9-C10-O11 C9-C10-C13 C9-C16-C15 C9-C16-C17 O11-C10-C13 C10-O11-C12 C10-C13-C14 C13-C14-C15 C15-C16-C17

123.4 118.6 117.9 110.2 120.6 118.5 121.1 122.1 120.9 118.8 118.6 115 120.7 119.5 118.6 124.3 118.5 119.8 121.2 121.9

120.7 125.4 113.8 105.7 122.6 119.7 121.9 123.4 120.8 118.3 119.1 114.2 120.9 118.8 123.3 126.6 117.9 119.2 120.1 123.3

a

Taken from Ref. [22].

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Table 2 Experimental and calculated vibrational frequencies of naproxen sodium. Modes

87 86 85 84 83 82 81 80 79 78 77 76 75 74 73 72 71 70 69 68 67 66 65 64 63 62 61 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17

Frequencies (cm1)

IR intensity

Raman activity

Experimental

Theoretical

IR

Raman

Unscaled

Scaleda

Relative

Absoluteb

Relative

Absoluteb

3158 e e e e e e e e 2957 e e e 1629 e e 1546 1502 1483 e e e e e e e 1396 e 1366 e 1303 e 1254 e 1212 e e 1162 e e e 1060 e 1027 e e 957 e 923 889 856 e e e 813 e 746 e e 688 660 e e 530 e 497 471 e e e e

e e e e 3055 e 3013 e e e e e e 1630 e 1578 e e 1483 e e e e e 1445 1414 e 1388 e e e e 1250 e 1211 e 1167 e e e 1119 e e 1023 e e e 958 e 877 e e e 820 e 794 746 e e e e e e e 523 e e e 403 376 e

3223 3221 3202 3195 3178 3171 3147 3138 3105 3084 3078 3041 3015 1673 1644 1620 1590 1546 1510 1503 1501 1495 1494 1485 1466 1430 1420 1415 1398 1386 1332 1300 1285 1274 1249 1219 1200 1190 1184 1171 1134 1101 1095 1082 1013 1006 994 967 939 909 884 862 857 838 821 799 756 741 719 692 663 620 607 563 528 518 481 444 437 376 353

3088 3085 3067 3061 3044 3038 3015 3006 2975 2954 2949 2913 2889 1645 1616 1592 1563 1520 1484 1477 1475 1469 1468 1460 1441 1405 1396 1391 1375 1363 1310 1278 1263 1252 1228 1198 1180 1170 1164 1151 1114 1082 1076 1063 996 989 977 950 923 893 869 848 842 823 807 785 743 728 707 681 652 609 596 553 519 509 473 437 430 370 347

13 6 0 30 4 11 23 18 42 10 39 45 76 23 21 56 480 9 20 19 0 8 22 19 54 199 34 14 76 7 17 117 6 69 48 8 6 4 1 1 101 6 25 8 3 3 0 1 21 10 7 1 16 5 10 30 43 9 13 2 2 1 7 13 4 5 3 6 6 39 1

3 1 0 6 1 2 5 4 9 2 8 9 16 5 4 12 100 2 4 4 0 2 5 4 11 42 7 3 16 2 4 24 1 14 10 2 1 1 0 0 21 1 5 2 1 1 0 0 4 2 2 0 3 1 2 6 9 2 3 0 0 0 2 3 1 1 1 1 1 8 0

170 97 51 184 78 51 115 32 138 56 78 214 185 32 13 68 7 11 6 21 47 15 7 13 36 45 340 120 23 5 4 9 7 8 13 12 5 14 4 3 24 11 13 4 2 13 2 1 8 1 33 1 1 20 1 1 1 23 6 3 1 0 2 4 3 7 2 2 0 5 2

50 29 15 54 23 15 34 9 41 16 23 63 54 9 4 20 2 3 2 6 14 4 2 4 11 13 100 35 7 2 1 3 2 2 4 3 1 4 1 1 7 3 4 1 1 4 1 0 2 0 10 0 0 6 0 0 0 7 2 1 0 0 1 1 1 2 1 1 0 1 0

Vibrational Assignments (%PED)

sym. ʋCH(89) asym ʋCH(90) asym. ʋCH(91) asym. ʋCH(91) asym. ʋCH(90) asym. ʋCH(91) asym. ʋCH(91) asym. ʋCH(90) asym. ʋCH(96) sym. ʋCH(97) asym. ʋCH(100) sym. ʋCH(96) sym. ʋCH(91) asym. ʋCC(64) asym. ʋCC(58) sym. ʋCC(62)þ bHCC(10) asym. ʋOC(85) bHCC(28)þ asym. ʋCC(35) bHCH(79)þ bHCC(11) bHCC(84) bHCH(13)þ bHCC(26) bHCH(83)þ bHCH(14) bHCH(72) bHCH(60) bHCC(55) sym. ʋCC(26)þ bHCC(22)þ sym. ʋOC(22) asym. ʋCC(68) asym. ʋCC(45) bHCC(52)þ sym. ʋOC(11) bHCH(33)þ asym. ʋCC(26)þ asym.ʋCC(10) asym. ʋCC(12)þ bHCC(37) bHCC(47) bHCC(51) bHCC(41)þ asym. ʋCC(12) bHCC(10)þ sym. ʋCC(49)þ sym ʋCC(10) bHCC(11)þ bHCC(26)þ bHCC(15) bHCC(48) bHCC(37)þ asym. ʋCC(19) bHCC(54) bHCH(14)þ bHCH(81) bHCC(13)þ asym. ʋCC(48) asym. ʋCC(36)þ bHCC(13) sym. ʋCC(50) bHCC(41) asym. ʋCC(43)þ HCC(14) sym. ʋCC(17) tHCCC(88) tHCCH(93) bHCC(10)þ asym. ʋCC(41) tHCCH(80) bHCC(36)þ sym. ʋOC(30) tHCCC(91) tHCCC(84) asym. ʋCC(19)þ bHCC(46) tHCCO(52) tHCCC(83) tHCCC(79) sym. ʋCC(12)þ bHCC(29)þ asym. ʋNaO(11) bHCC(52) tHCCO(10)þ uHCC(47) tHCCC(77) tHCOC(61)þ uHCC(11) tHCOC(15) bHCC(48) bHCC(32)þ tHCOC(11)þ tHCCO(12) bHCC(50) bHCC(65) bHCC(28) tHCCC(81) asym. ʋNaO(40)þ asym. ʋCC(22) sym. ʋNaO(31) (continued on next page)

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Table 2 (continued ) Modes

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1

Frequencies (cm1)

IR intensity

Raman activity

Experimental

Theoretical

IR

Raman

Unscaled

Scaleda

Relative

Absoluteb

Relative

Absoluteb

e e e e e e e e e e e e e e e e

e e e e e e 205 e e e 127 e 80 e e e

336 289 285 247 231 228 217 186 166 145 129 102 69 49 32 25

330 284 280 243 227 224 214 183 163 142 127 101 68 48 31 25

2 8 9 9 1 2 3 13 10 3 6 14 11 3 5 3

0 2 2 2 0 0 1 3 2 1 1 3 2 1 1 1

6 2 2 2 1 0 2 1 1 2 0 1 0 2 3 6

2 1 1 1 0 0 1 0 0 1 0 0 0 0 1 2

Vibrational Assignments (%PED)

uHCH(11)þ uHCC(13)

sym. ʋNaO(10)þ tHCOC(12)þ tHCCC(41) asym. ʋNaO(15)þ tHCOC(41) bCONa(51)þ tHCCC(14) tHCOC(65) bCONa(16)þ tHCCC(34) tHCCC(45) asym. ʋNaO(19)þ bCONa(59) tHCCO(32) tHCCC(78) bCCC(63) tHCOC(70) tHCOC(71) tHCOC(15)þ tCCCO(70) tHCOC(28)þ tHCCO(12)þ uCCCO(21) tCCCC(79)þ uCCC(15)

ʋ-stretching, sym.-symmetric, asym.- asymmetric, b -in plane bending, u -out of plane bending and t-torsion. a scaling factor 0.958 for wavenumbers 4000-1700 cm1 and 0.983 for lower than 1700 cm1 for B3LYP/6e311þþG(d,p) basis set. b Normalised to 100.

the ring is in the range 1.375e1.423 Å. The C-C-C angles inside the ring are in the range118.5
-122.1. The C-C-H angles outside the ring are 118.3
-120.3 range. All the H-C-H angles in the methyl group are 109.4 . The experimental bond lengths and bond angles are in good agreement with the theoretical data obtained. There is a deviation in the theoretical values as the experimental values denoted are of a compound that is comparable with the title compound and not the exact one. Also variations occur due to the fact that the experimental studies are carried out in solid state while the theoretical calculations are on an isolated molecule in gaseous state [22]. 4.2. Vibrational spectral analysis For a non-linear molecule with N atoms the fundamental modes of vibrations are given by (3N-6) apart from 3 translational and 3 rotational degrees of freedom [23,24]. Naproxen sodium has 31 atoms and so it should show 87 modes of vibrations. The assignment for selected modes of vibrations of the title compound with PED contribution is shown in Table 2. Figs. 2 and 3 show the comparative graphs of theoretical and experimental FT-IR and FT Raman spectra.

Fig. 2. Theoretical and experimental FT-IR

4.2.1. C-H vibrations In aromatic compounds usually weak multiple bands due to C-H stretching is observed in the region 3100-3000 cm1 [25,26]. The peaks at 3094 and 2955 cm1 in the FT-IR spectrum and 3051 and 3012 cm1 in the FT Raman spectrum are assigned to C-H stretching vibrations. At 2955 cm1 the PED contribution is 100% and at 3051 and 3012 cm1 90% PED contribution is observed [27,28]. The bands of C-H bending vibrations are observed in the region 1000-1300 cm1 [29,30]. For the title compound the C-H bending was assigned to 1344, 1280, 1249, 1224, 1200, 1171, 1153, 1126, 1058 and 1040 cm1, out of which 1249,1200,1171 cm1 peaks were observed in FT Raman spectrum and all other peaks in FT eIR spectrum. 4.2.2. C-C vibrations C-C vibrations are observed in the region 1650 and 1100 cm1 which is irrespective of the substituent [31,32]. The ring stretching vibrations are expected in the range 1300-1000 cm_1 [33] The vibrations 1608,1580,1557,1486,1374,1364,1280,1224,1200,1058 cm1 in FT-IR spectra and FT Raman spectra of naproxen sodium were assigned to C-C stretching vibrations. Vibrations at 1486,1444,1409,1249,1224,1171 cm1 are assigned to C-C-C

Fig. 3. Theoretical and experimental FT-Raman.

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Fig. 4. HOMO-LUMO, H- > Lþ1, H- > Lþ2, L- > H-1,L- > L-2 plots for Naproxen Sodium.

bending. This shows that the experimental result is in well agreement with the literature value. 4.2.3. C-O vibrations C¼O stretching vibrations in the expected region of 18501550 cm 1 [34]. For C-O the absorption peaks will be between 1310 and 1095 cm 1 [35]. The peak at 1590 cm1 for FT-IR spectra corresponds to the stretching vibrations of C]O bond of the title compound and 1344 cm1 for FT-IR spectra and 1374 cm1 for FT Raman spectra can be assigned to C-O bonds. The bending vibrations are also observed in the theoretically expected region. 4.2.4. O-Na vibrations The very weak peak at 361 cm1 in FT Raman spectrum can be assigned to the stretching vibrations of Na-O bond in the compound. No peaks corresponding to Na-O vibrations are seen in FT-IR

spectrum since it is expected in the far-infra red region and Na-O shows very weak absorption peaks in the lower range 170e300 cm1 [36]. Other theoretically calculated vibrations for Na-O bond for stretching and bending are 339,278,274 cm1 and 237,219, 178 cm1 respectively. 4.3. Frontier molecular orbitals and UV analysis Theoretical UV calculations were done using TD-DFT method by B3LYP/6e311þþG (d, p) and dunning cc-pDVZ basis sets with DMSO as a solvent. The spectrum obtained is compared with the experimental UV spectrum and is shown in Fig. 5. The peak is seen at 262 nm for experimental spectrum and at 250 nm and 251 nm for the theoretical spectrum obtained using B3LYP/6e311þþG (d, p) and cc-pDVZ respectively. The corresponding band gaps are calculated and tabulated and is given in Table 4.

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1 Global hardnessðhÞ ¼ ðELUMO  EHOMOÞ 2 Electrophilicity ¼

SoftnessðSÞ ¼

Fig. 5. Experimental and Theoretical UV spectrum of molecule using DMSO as solvent.

Energy gap is the energy difference between highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital(LUMO) [37]. This is important for the explaining stability of structure and bioactivity of the molecule [38]. Ionization potential and electron affinity are related HOMO and LUMO respectively [39]. Table 3 gives details of HOMO and LUMO and other related parameters. The parameters that can be obtained from HOMO-LUMO values are given in the following equations:

1 Chemical PotentialðmÞ ¼ ðELUMO þ EHOMOÞ 2 1 Electro negativityðcÞ ¼  ðELUMO þ EHOMOÞ ¼  m 2

Table 3 Calculated Energy Values of Naproxen Sodium using B3LYP/6e311þþG(d,p) and ccpVDZ basis sets. PROPERTY

B3LYP/6e311þþG(d,p)

cc-pVDZ

EHOMO(eV) ELUMO(eV) Ionization potential Electron affinity Energy gap Electronegativity Chemical potential Chemical hardness Chemical softness Electrophilicity index

5.7220 1.1877 5.7220 1.1877 4.5343 3.4548 3.4548 2.2671 0.2205 0.7618

5.6322 1.0163 5.6322 1.0163 4.6159 3.3242 3.3242 2.3079 0.2166 0.7201

m2 2h

1

h

HOMO-LUMO energy gap of the title compound is calculated as 4.5343eV(B3LYP/6e311þþG(d,p) and 4.6159eV (cc-pVDZ) and is comparable to the experimentally obtained band gap energy of 4.73eV. The small energy gap means that the molecule is reactive, polarizable and is a soft molecule [40]. The chemical hardness indicates the chemical stability and the chemical softness predicts toxicity of the molecule [41]. In the present study, the low softness value 0.2205(B3LYP/6e311þþG(d,p) and 0.2166(cc-pVDZ) using the two basis sets indicates that theoretically the molecule is nontoxic. The high chemical hardness 2.2671(B3LYP/6e311þþG(d,p) and 2.3079(cc-pVDZ) denotes the stable nature. Fig. 4 shows the HOMO/LUMO, HOMO/(Lþ1), HOMO/(Lþ2), LUMO/(H-1) and LUMO- > -(H-2) plots obtained using B3LYP/6e311þþG (d, p) basis set where HOMO/(Lþ2) and LUMO/(H-2) transitions arises from intra molecular charge transfer(ICMT) and the others including HOMO/LUMO transistion are due to p/ p* transistion. 4.4. Electron localization function and localized orbital locator The two dimensional representation of Localized Orbital Locator (LOL) Electron Localization Function (ELF) and are given in Fig. 6 and Fig. 7 respectively. The electron localization in molecular system can be studied using electron localization function [42]. LOL is also a similar study about the localized electron cloud. The electron localization can be calculated by applying Pauli repulsion on two like-spin electrons [43]. The bonding, reactivity and chemical structure can be studied in detail using this data [44]. 1 and 0 are the upper and lower limits of ELF respectively and red colour denotes the high values and blue colour the low values of ELF [45]. For the title compound the maximum Pauli repulsion was found around the Hydrogen atoms with single electrons are indicated by red and the minimum is for Carbon and Oxygen atoms indicated by blue region. High LOL values are indicated by red colour and can be assigned to covalent regions while blue coloured areas in the figure can be explained as regions of electron depletion between valence shell and inner shell [46]. 4.5. NBO NBO studies was done on the title compound to explain the intermolecular and intramolecular bonding, stability, transfer of

Table 4 Comparison of electronic properties obtained experimentally and theoretically by TD-DFT/B3LYP. EXPERIMENTAL

TD-B3LYP/6e311þþG(d,p)

Wavelength

Band gap

Wavelength

Band gap

max(nm)

(eV)

(nm)

(eV)

262

4.73

306.745 292.483 258.827 250.002 248.056

4.04 4.24 4.79 4.96 5.00

oscillatory strength

Energy (cm1)

Assignments

0.1086 0.0346 0.0452 0.4378 0.1271

32600.34864 34190.0784 38635.83712 39999.73008 40313.48192

HOMO- > LUMO(95%) HOMO- > Lþ1 (61%) HOMO- > Lþ2 (71%) H-1- > LUMO (43%) H-2- > LUMO (68%)

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Fig. 6. LOL representation of Naproxen Sodium.

Fig. 7. Colour Filled Mapping of Electron Localization function of the Molecule

charge and conjugative interactions [47,48]. The electron donor and acceptor reactions and thereby the extent of conjugation can be analysed using the value of E (2). The higher the E (2) value, the higher is the extent of conjugation [49]. The mathematical expression for each and every donor (I) and acceptor (j), the stabilization energy E(2) linked with the delocalization value of i, j as estimated by:

Eð2Þ ¼ DEij ¼ qi

Fði; jÞ2 Ei  Ej

where qi is the donor orbital occupancy status, Ei and Ejare donor and acceptor orbital energy values and F(i,j) is Fock matrix elements [50].This stabilization energy will give details on intermolecular hydrogen bonding, intermolecular charge transfer and delocalization of electron density [51].

In the present study the NBO calculations were carried out using B3LYP/6e311þþ G(d,p) basis set and is presented in Table 5. C9-C16 shows the highest E (2) value of 20.95 kcal/mol in p to p* transition. C15-C29 shows the highest E (2) value of 4.19 kcal/mol in s to s* transition. Another data obtained by the NBO analysis of the title compound was marked for LP (2) to s* transition with an E (2) value of 27.81 kcal/mol followed by 23.41 kcal/mol for C2 - O3 and C2 - C4 respectively. A stabilization energy of 19.67 kcal/mol is observed for C7-C8(p) to C6-C17(p*) transition and 19.49 kcal/mol for C10C13(p) to C14-C15(p)* transition. Other important p to p* transitions are observed at C6-C17 to C9-C16, C6-C17 to C7-C8 and C9C16 to C7-C8 with 19.27 kcal/mol, 19.1 kcal/mol and 18.39 kcal/ mol respectively. For transitions C17-H30(s) to C9-C16(s*) and C8H23(s) to C9-C16(s*) stabilization energies are 4.18 kcal/mol and 4.17 kcal/mol respectively. It is interesting to note that the lone pairs in the oxygen atoms participate in the stabilization of the

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Table 5 Second order perturbation theory analysis of fock matrix in NBO basis. Donor

C 6 - C 17 C 6 - C 17 C7-C8 C7-C8 C 7 - H 22 C8-C9 C 8 - H 23 C 9 - C 16 C 9 - C 16 C 9 - C 16 C 9 - C 16 C 10 - C 13 C 10 - C 13 C 13 - H 27 C 14 - C 15 C 14 - C 15 C 15 - H 29 C 16 - C 17 C 17 - H 30 C 17 - H 30 O1 O1 O3 O3 O3 O 11 O 11 O 11 O 11

Type

p p p p s s s p p p p p p s p p s s s s LP LP LP LP LP LP LP LP LP

(2) (2) (1) (2) (2) (1) (2) (2) (2)

ED/e

Acceptor

1.68137 1.68137 1.72663 1.72663 1.98173 1.97413 1.98334 1.52738 1.52738 1.52738 1.52738 1.71993 1.71993 1.98016 1.73617 1.73617 1.98326 1.97482 1.9817 1.9817 1.84867 1.84867 1.96069 1.90099 1.90099 1.95079 1.8981 1.8981 1.8981

Type

C7-C8 C 9 - C 16 C 6 - C 17 C 9 - C 16 C 6 - C 17 C 9 - C 16 C 9 - C 16 C 6 - C 17 C7-C8 C 10 - C 13 C 14 - C 15 C 9 - C 16 C 14 - C 15 C 9 - C 10 C 9 - C 16 C 10 - C 13 C 9 - C 16 C 9 - C 16 C6-C7 C 9 - C 16 C2-O3 C2-C4 O1-C2 O1-C2 C2-C4 C 10 - C 13 C 9 - C 10 C 10 - C 13 C 12 - H 26

p* p* p* p* s* s* s* p* p* p* p* p* p* s* p* p* s* s* s* s* s* s* s* s* s* s* s* p* s*

ED/e

0.2891 0.50069 0.28193 0.50069 0.01953 0.03124 0.03124 0.28193 0.2891 0.32762 0.28527 0.50069 0.28527 0.03512 0.050069 0.32762 0.03124 0.03124 0.02277 0.03124 0.08251 0.09473 0.04601 0.04601 0.09473 0.02905 0.03512 0.32762 0.018

E(2)

E(j)-E(i)

F(i,j)

kcal/mol

a.u.

a.u.

19.1 19.27 19.67 15.72 3.69 3.82 4.17 15.13 18.39 20.95 15.92 15.04 19.49 3.87 17.32 17.29 4.19 3.61 3.95 4.18 27.81 23.41 3.59 11.86 11 6.35 5.17 12.62 6.46

0.26 0.27 0.29 0.28 1.08 1.24 1.08 0.28 0.26 0.25 0.26 0.3 0.28 1.07 0.28 0.26 1.08 1.23 1.06 1.07 0.67 0.64 1.32 0.86 0.64 1.05 0.9 0.38 0.76

0.063 0.068 0.067 0.063 0.056 0.061 0.06 0.061 0.065 0.068 0.061 0.063 0.066 0.058 0.067 0.061 0.06 0.06 0.058 0.06 0.124 0.111 0.062 0.091 0.075 0.073 0.062 0.065 0.064

molecule by n/ s* and n/ p* interactions with considerable stabilization energies.

H ¼ 11.5273 þ 0.12524 T þ 2.59051  104 T2 (R2 ¼ 0.99945)

4.6. Thermodynamic properties

4.7. AIM charges and FUKUI calculations

These studies help to determine the direction of the reaction according to the second law of thermodynamics [52,53]. Thermodynamic energies can also be computed using the above data. The variation of the thermodynamic properties such as entropy, enthalpy and specific heat for a temperature range of 0-1000k is given in Table 6 and the graphical representation of the same is shown in Fig. 8. Vibrational zero-point energy was calculated as 629.90 kJ/mol. The correlation equation between thermodynamic properties and temperature are given below. The fitting factors R2 corresponding to S, Cp and H are 0.99991, 0.99957, 0.99945 respectively.

Bader’s atoms in molecules(aim) theory has been used to study the bonding nature of weak interactions [54,55]. In this, the electron density r(r) is used to analyze the bonding and non-bonding interactions in a chemical system by measuring its strength at BCPs and Laplacian of electron density V2 r(r) gives the nature of the bond [56]. Aim study helps in studying the non-covalent interactions in the molecule [57]. Both high value of ED and the

S ¼ 260.23229 þ 1.07833T - 2.62023  104T2 (R2 ¼ 0.99991) Cp ¼ 24.81096 þ 0.94931 Te3.9262  104 T2 (R2 ¼ 0.99957) Table 6 Thermodynamic functions of naproxen sodium. T

S0m

C0pm

H0m

(K) 100 200 298 300 400 500 600 700 800 900 1000

(J/mol.K) 361.482 468.305 560.189 561.861 649.881 733.313 811.818 885.298 953.964 1018.182 1078.345

(J/mol.K) 120.071 195.713 269.638 271.03 343.079 405.092 455.867 497.137 531.006 559.155 582.8

(kJ/mol) 7.363 23.479 46.307 46.807 77.576 115.081 158.217 205.937 257.398 311.948 369.079

Fig. 8. Thermodynamic properties.

R.S. Saji et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 226 (2020) 117614

negative value of V2r indicates a covalent bond [58]. Hydrogen bond energy is calculated by the formula EH

… X ¼ 1/2Vc;

the rth atomic site is the neutral (N), anionic (Nþ1), cationic (N-1) chemical species [66]. The local softness is related to Fukui function as follows:

where Vc ¼ 1/4 V2r -2Gc

sr-Gr- ¼ Sf

where Vc is the local potential electron energy density and Gc is the local kinetic electron energy density. Fig. S1 gives the AIM molecular graph of the title compound and Table 7 presents the details on the major interactions of the atoms in the molecule that are covalent in nature. It also summarizes the kinetic energy(G), potential energy(V), total electron density(H) in atomic units along with ellipticity and interaction energies, in kcal/mol, of the major interactions in the molecule. The values of MOD(V/G) > 1 indicates that all the interactions are covalent in nature. The Fukui function is a local reactivity descriptor which shows preferred regions where a chemical species will change its density when the number of electrons is altered. This helps to study chemical reactivity and selectivity [59e61]. By changing the charge and multiplicity, fukui calculations were done. This also helps to study the electronic structure, molecular polarizability and electrostatic potential surface [62e65]. Fukui functions can be calculated using the following equations f r-¼ q

r (N)-q r (N-1)

9

for electrophilic attack

fþ r ¼q r (Nþ1)-qr (N) for nucleophilic attack f 0r ¼ 1/2 [q r(Nþ1)-q r (N 1)] for radical attack In these equations, qr is the atomic charge (evaluated from Mulliken population analysis, electrostatic derived charge, etc.) at



k

for electrophilic attack

srþ Grþ ¼ Sfþk for nucleophilic attack sr0 Gr0 ¼ Sf0k for radical attack Table gives data of fukui function and local softness of all the atoms, excluding hydrogen atoms, under study. From the dual descriptor analysis, the nucleophilic and electrophilic sites of the molecule have been studied. It is seen from Table 8 that all oxygen atoms and C4, C6, C9 and C11 atoms have values greater than zero and so are sites of nucleophilic attack while atoms C2, C5, C7, C8, C10, C12, C13, C14, C15 and the sodium atom are sites of electrophilic attack as they have values less than zero. 4.8. NLO properties NLO studies are an important part in present world researches as NLO active materials find applications in telecommunication, potential applications in modern communication technology, optical signal processing and data storage [67]. Urea is used to study the NLO properties of the compounds [68]. The non-linear optical response of an isolated molecule in the electric field Ei (u) can be given as a Taylor series expansion of total dipole moment, mtot, induced by the field:

mtot ¼ m0þaijEjþ bijkEjEk

Table 7 Parameters obtained from AIM analysis of the title compound. Sl. No.

Atoms

rBCP

V 2rBCP

Ellipticity

G (a.u)

V (a.u)

H (a.u)

MOD(V)/G

Eint kcal/mol

1 2 3 4 5 6 7 8 9 10

O1 - C2 C2 - O3 C7 - C8 C8 - C9 C10 - C13 C9 - C16 C16 - C17 C14 - C15 C8 - H23 C15 - H29

0.364 0.367 0.319 0.296 0.317 0.292 0.296 0.321 0.284 0.280

0.454 0.449 0.909 0.797 0.893 0.776 0.800 0.917 0.983 0.954

0.582 0.588 0.338 0.288 0.336 0.281 0.288 0.342 0.284 0.279

0.020 0.026 0.236 0.164 0.288 0.168 0.164 0.254 0.018 0.025

0.469 0.476 0.110 0.089 0.113 0.087 0.088 0.113 0.038 0.040

1.051 1.063 0.448 0.378 0.448 0.369 0.376 0.454 0.321 0.319

2.242 2.236 4.059 4.233 3.982 4.225 4.275 4.039 8.495 7.967

1380.278 1395.927 588.256 495.765 588.599 483.800 493.318 596.432 421.880 418.221

Table 8 Fukui function and local softness for the title compound. Atoms

fþ r

f r

f 0r

△f

þ sþ r fr

 s r fr

s0r f 0r

1C 2C 3O 4C 5C 6C 7C 8C 9C 10 C 11 O 12 C 13 C 14 C 15 C 16 C 17 C 31 Na

0.106557 0.804270 0.236961 0.778689 0.362364 0.746099 0.483003 0.037379 0.082862 0.146099 0.426976 0.210380 0.115156 0.327944 0.099129 0.032865 0.054754 0.067349

0.239921 0.951090 0.164013 0.379141 0.090624 0.429459 0.470955 0.244274 0.271587 0.671512 0.393866 0.206654 0.081803 0.284165 0.296765 0.304995 0.009386 0.756969

0.066682 0.073410 0.036474 0.199774 0.135870 0.158320 0.006024 0.140827 0.177225 0.262707 0.016555 0.001863 0.098480 0.021890 0.098818 0.136065 0.032070 0.344810

0.346478 1.755360 0.400974 1.157830 0.452988 1.175558 0.953958 0.206895 0.188725 0.817611 0.820842 0.417034 0.033353 0.612109 0.395894 0.337860 0.045368 0.824318

0.069443 0.524143 0.154427 0.507472 0.236153 0.486233 0.314773 0.024360 0.054001 0.095213 0.278260 0.137105 0.075047 0.213721 0.064602 0.021418 0.035683 0.043891

0.156357 0.619825 0.106887 0.247086 0.059060 0.279878 0.306921 0.159193 0.176993 0.437624 0.256682 0.134676 0.053311 0.185190 0.193402 0.198765 0.006117 0.493317

0.043457 0.047841 0.023770 0.130193 0.088546 0.103177 0.003926 0.091777 0.115497 0.171206 0.010789 0.001214 0.064179 0.014265 0.064400 0.088674 0.020900 0.224713

10

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Table 9 Calculated values of dipole moment, polarizability, first order hyperpolarizability components of Naproxen sodium using B3LYP/6e311þþG(d,p) and cc-pVDZ basis sets. Parameter

B3LYP/6e311þþG(d,p)

B3LYP/cc-pVDZ

Parameter

B3LYP/6e311þþG(d,p)

B3LYP/cc-pVDZ

mx my mz m (D) axx axy ayy axz ayz azz a(a.u) a(e.s.u) Da (a.u) Da (e.s.u)

1.578 2.348 2.046 3.492 258.037 17.388 173.801 11.362 3.151 95.420 175.753 2.6047*10¡23 468.606 6.9447*10¡23

1.117 1.506 1.401 2.341 255.546 2.957 171.458 17.124 15.927 110.963 179.322 2.657*10¡23 460.140 6.8193*10¡22

bxxx bxxy bxyy byyy bzxx bxyz bzyy bxzz byzz bzzz btot (a.u) btot (e.s.u)

540.665 230.151 248.137 211.897 579.332 111.724 147.187 671.732 200.562 971.873 2330.373 2.0133*10¡29

842.845 541.971 474.558 292.721 550.171 292.628 294.111 410.712 289.030 449.245 2433.588 2.1025*10¡29

Fig. 9. Experimental 13C NMR graph of Naproxen Sodium.

where a is the linear polarizability, m0 the permanent dipole moment and bijk are the first hyperpolarizability tensor components [69]. The first order hyperpolarizability, is a tensor of rank 3 denoted by a 3  3 x 3 matrix and the components of this 3D matrix is reduced to 10 from 27 components by the Kleinman symmetry [70]. The m, a and b of the compound, computed using B3LYP/ 6e311þþG (d, p) basis set, was found to be 3.491946 D, 2.6047  1023 esu and 2.0133  1029 esu respectively and using cc-pVDZ is 2.341 D, 2.657  1023 esu and 2.1025  1029 esu respectively, which is given in Table 9. On comparing the computed first hyperpolarizability value of the title compound with the prototypical Urea (bo ¼ 0.928  1030 esu) [71], the very high value of bo ¼ 2.0133  1029 esu and bo ¼ 2.1025  1029 esu using the two basis sets indicates that the compound can be a good NLO material. 4.9. NMR spectral analysis The table comaparitive study of peaks obtained for 13C and 1H NMR experimentally and chemical shift values theoretically

obtained using B3LYP/6e311þþG(d,p) basis set using GIAO method and taking DMSO as the solvent [72], which are in good agreement. Gauge Invariant Atomic Orbital method is one important technique to calculate isotropic nuclear magnetic shielding tensors [73,74]. The chemical shifts are taken relative to the internal standard reference TMS, dTMS ¼ 0 ppm.The experimental graphs are shown in Figs. 9 and 10. Table 10 gives the comparison between theoretical and experimental chemical shift values. In 13C, the chemical shift value of 192.50 ppm corresponds to C]O which agrees well with the theoretical range of 190e200 ppm. C5 and C12 are methyl groups that shows values 55.26 and 22.69 ppm which is good agreement with the theoretical range of 10e40 ppm. C12 shows a little high value as it is also connected to an Oxygen atom. The peaks of aromatic carbon are expected in the range of 120e170 ppm and it comes in expected range for the title compound. In 1H, the expected range of aromatic group is in the range of 6e9 ppm and that of methyl group is in the range less than 2 ppm which is seen in H19, H20 and H21. For methyl group that has an

R.S. Saji et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 226 (2020) 117614

11

Fig. 10. Experimental 1H NMR of naproxen sodium.

Oxygen atom in the near surrounding, the values will be in the range 3e4, which is observed in the title compound as well. 4.10. Drug likeness To check the potential to be considered as a pharmaceutical product, the drug likeness of title compound is studied using

Table 10 Theoretical and experimental 1H and13C chemical shifts. Atoms

Chemical Shift Calculated

Experimental(ppm)

23-H 22-H 30-H 28-H 29-H 27-H 24-H 26-H 25-H 18-H 20-H 21-H 19-H 2-C 10-C 6-C 16-C 14-C 17-C 7-C 9-C 8-C 15-C 13-C 4-C 12-C 5-C

8.477 8.315 7.885 7.61 7.592 6.873 6.327 5.914 3.889 3.575 1.891 1.359 0.99 185.506 159.397 151.277 139.754 130.885 130.606 128.696 128.374 125.826 123.437 105.718 56.428 55.266 22.694

8.283 7.695 7.673 7.628 7.498 7.193 7.076 7.058 3.851 3.409 2.514 1.363 1.347 177.72 156.82 141.56 132.95 129.2 128.92 128.05 126.09 125.2 118.35 105.95 55.44 49.21 20.48

Lipinski’s rule of five [75,76]. Table 11 shows the parameters studied to check the possibility of considering as a drug. The acceptable values of HBA and HBD should be less than 5 and 10 respectively, which is 3 and 1 for the title compound. One important parameter is MlogP that gives an idea about the lipophilic character of the molecule, which is 2.57 for the molecule under study. This is in the acceptable range as it is less than 4.15. The number of rotatable bonds should be less than 10 and is 3 in this case. The calculated molar refractivity is 66.79 which is in well desired range of 40e130 [77]. The title compound shows drug likeness property as all the necessary datas calculated are in well favoured region.

4.11. Ramachandran plot Ramachandran plot is one way of finding out the forbidden regions in the protein by viewing the distribution of torsion angles of the protein structure. It is a two dimensional representation of dihedral angles j against f of amino acid residues in protein structure. It can be used to assess the quality of the protein 3D structure. This is given in Fig. 11. For the protein taken has a total number of 512 residues with only 0.4% in disallowed region. A total of 99.5% comes in the allowed and additional allowed region.

Table 11 Drug Likeness parameters for the title compound. Descriptor

Value

Hydrogen Bond Donor(HBD) Hydrogen Bond Acceptor(HBA) MlogP Molar Refractivity Number of Atoms Number of Rotatable Bonds

1 3 2.57 253.25 g/mol 31 3

12

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Fig. 12. Molecular docking of naproxen sodium.

5. Conclusion

Fig. 11. Ramachandran plot showing the favoured regions of Protein selected.

4.12. Docking To predict the possibilities of protein ligand binding, molecular docking study was done on the molecule using AutoDock. It reduces the time and cost and also improves the efficiency by helping drug designing. The exact location of binding and the binding energy can also be theoretically calculated using this [78]. The title compound was chosen as the ligand and docking studies were done taking 5K0X as the protein [79]. The 3D structure for the protein 5K0X was taken from Protein Data Bank. Calculations were carried out to predict the binding of the ligand and the protein and thus to obtain bond distance and Binding energy for various conformations and is given in Table 12. Fig. 12 gives the top pose of binding of the molecule with the protein possessing a binding energy of 40.46 kcal/mol. This study shows theoretically that the molecule can be potential drug for treating blood clots in human beings as the protein comes under fibrinolytic category.

The vibrational spectroscopic (FT-IR, FT Raman studies, UV), NMR (13C and 1H), NLO, NBO, LOL, ELF and docking studies were carried out in the present study. The structure was optimized using B3LYP/6e311þþG(d,p) basis set and the geometric parameters were obtained. Vibrational assignments were done using VEDA software and the %PED was also obtained. The HOMO-LUMO energy gap was calculated and is 4.5343Ev which was comparable with the experimental result. The high electrophilicity value indicates that the compound is biologically active. Two dimensional graphical representations of LOL and ELF were also attained for the molecule and the properties were studied using the variation in the colour. The intramolecular charge transfer between the bonding and anti-bonding orbitals were studied using NBO analysis. The thermodynamic properties like specific heat, entropy and enthalpy for a temperature range was studied and the correlations were also obtained. From the first order hyperpolarizability calculations it was theoretically found that the molecule can be used to achieve NLO properties. AIM study was done to analyze the non covalent interactions in the molecule. By varying charge and multiplicity fukui calculations were also carried out and the electrophilic and nucleophilic sites were studied. Molecular docking was also done to predict the possibilities of protein-ligand binding and the title compound may be used for treating blood clots in human beings. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.saa.2019.117614. References

Table 12 Molecular Docking of Naproxen Sodium with 5K0X protein. Protein

Bonded Residues

Bond Distance

Binding Energy

5K0X

2Z00 245 GLY’193 SER’214 2Z00 245 SER’195 ASP’189

3 3.2 3 3 2.9 2.7

40.46

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