Vibrational spectroscopic study and NBO analysis on tranexamic acid using DFT method

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 129 (2014) 184–192

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Vibrational spectroscopic study and NBO analysis on tranexamic acid using DFT method S. Muthu a,⇑, A. Prabhakaran b,c a

Department of Physics, Sri Venkateswara College of Engg, Sriperumbudur 602 105, India Department of Physics, Pallavan College of Engg, Kanchipuram 631 502, India c Research and Development Center, Bharathiar University, Coimbatore 641 046, 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

 Vibrational assignments with PED of

TA were calculated.  Potential energy surface scan with the

B3LYP/6-311G(d,p) level of theoretical approximations was performed.  NBO and HOMO and LUMO energies of TA were studied.

a r t i c l e

i n f o

Article history: Received 20 December 2013 Received in revised form 1 March 2014 Accepted 20 March 2014 Available online 1 April 2014 Keywords: FT-IR FT-Raman NBO HOMO LUMO DFT

a b s t r a c t In this work, we reported the vibrational spectra of tranexamic acid (TA) by experimental and quantum chemical calculation. The solid phase FT-Raman and FT-IR spectra of the title compound were recorded in the region 4000 cm1 to 100 cm1 and 4000 cm1 to 400 cm1 respectively. The molecular geometry, harmonic vibrational frequencies and bonding features of TA in the ground state have been calculated by using density functional theory (DFT) B3LYP method with standard 6-31G(d,p) basis set. The scaled theoretical wavenumber showed very good agreement with the experimental values. The vibrational assignments were performed on the basis of the potential energy distribution (PED) of the vibrational modes. Stability of the molecule, arising from hyperconjugative interactions and charge delocalization, has been analyzed using Natural Bond Orbital (NBO) analysis. The results show that ED in the r* and p* antibonding orbitals and second order delocalization energies E(2) confirm the occurrence of intramolecular charge transfer (ICT) within the molecule. The electrostatic potential mapped onto an isodensity surface has been obtained. The calculated HOMO and LUMO energies show that charge transfer occurs within the molecule. The thermodynamic properties (heat capacity, entropy, and enthalpy) of the title compound at different temperatures were calculated in gas phase. Ó 2014 Elsevier B.V. All rights reserved.

Introduction Tranexamic acid (TA) is the trans-isomer of 4-aminomethylcyclohexanecarboxylic acid. TA is a white crystalline powder. It is ⇑ Corresponding author. Tel.: +91 9443690138; fax: +91 4427162462. E-mail addresses: [email protected], [email protected] (S. Muthu). http://dx.doi.org/10.1016/j.saa.2014.03.050 1386-1425/Ó 2014 Elsevier B.V. All rights reserved.

freely soluble in water and slightly soluble in ethanol and practically insoluble in ether. The molecular formula is C8H15NO2 and the molecular weight is 157.2. It is a synthetic derivative of the amino acid lysine that exerts it is antifibrinolytic affect through the reversible blockade of the lysine binding sites on plasminogen molecules [1]. TA is frequently used in surgeries with high risk of blood loss such as cardiac, liver, vascular and large orthopedic

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[2,3]. It has been found to decrease the risk of death in people who have significant bleeding due to trauma [4]. In obstetrics, TA is used after delivery to reduce bleeding, often with syntocinon and fundal massage. A major trial is in progress worldwide to establish the efficacy of the drug to arrest postpartum haemorrhage (PPH) [5]. It is an antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin, by binding to specific sites of both plasminogen and plasmin, a molecule responsible for the degradation of fibrin. It has roughly eight times the antifibrinolytic activity of an older analogue, e-aminocaproic acid. To the best of our knowledge, there is no complete vibrational data on TA molecule in the literature. In this work, we have mainly focused on the detailed spectral assignments and vibrational thermodynamic properties basing on the experimental Fourier transform infrared (FT-IR) and Fourier transform Raman (FT-Raman) spectra as well as computational calculations for TA. The redistribution of electron density (ED) in various bonding, antibonding orbitals and E(2) energies have been calculated by natural bond orbital (NBO) analysis to give clear evidence of stabilization originating from the hyper conjugation of various intra-molecular interactions. The study of HOMO, LUMO analysis have been used to elucidate information regarding charge transfer within the molecule. Herein, the investigated results have been reported. 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 TA was purchased from Sigma–Aldrich chemical company (USA) with a stated purity of greater than 97% and it was used as such without further purification. The FT-Raman spectrum of the compound was recorded using 1064 nm line of Nd-YAG laser as excitation wavelength in the region 4000–100 cm1 on BrukerModel IFS 66 spectrophotometer. The FT-IR spectrum of this compound was recorded in the region 4000–400 cm1 on IFS 66 V Spectrophotometer using KBr pellet technique with a scanning speed of 30 cm1 min1 and the spectral resolution of 4.0 cm1. The observed experimental and calculated FT-IR and FT-Raman spectra are shown in Figs. 1 and 2. The spectral measurements were carried out at Sophisticated Analytical Instrumentation Facility (SAIF), IIT, Chennai.

Fig. 1. The experimental and calculated FT-IR spectrum for TA.

Computational details The optimized geometrical parameters, atomic charge, vibrational frequencies with their IR intensity and Raman scattering activities of the TA molecule were calculated by DFT method with the hybrid functional (B3LYP) [6–9] and basis set 6-31G(d,p). The entire calculations were performed using Gaussian 03W program package [10]. The optimized geometries corresponding to the minimum on the potential energy surface have been obtained by solving self consistent field (SCF) equation iterative. Harmonic vibrational wavenumber have been calculated using analytic second derivatives to confirm the convergence to minima on the potential surface and to evaluate the zero-point vibrational energy [11]. Multiple scaling of the force field has been performed by the SQM procedure [12,13] to offset the systematic errors caused by basis set incompleteness, neglect to electron correlation and vibrational anharmonicity [14]. Normal coordinate analysis of TA has been performed to obtain full description of the molecular motion pertaining to the normal mode using the MOLVIB-7.0 program [15,16]. The calculated analytic force constant was used by MOLVIB in the calculation of vibrational frequencies by diagonalization of dynamical matrix. These force fields obtained

Fig. 2. The experimental and calculated FT-Raman spectrum for TA.

in cartesian coordinates and dipole derivatives with respect to atomic displacements were extracted from the archive section of the Gaussian 03 output and transformed to a suitable defined set

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of internal coordinates. The natural bonding orbital (NBO) calculation [17] were performed using NBO 3.1 program as implemented in Gaussian 03W [10] package at B3LYP/6-31G(d,p) level in order to understand various second-order interaction between the filled orbitals of one subsystem and vacant of another subsystem, which is measure of the intermolecular delocalization or hyper conjugation. The Raman scattering activities (Si) calculated by Gaussian 03W program were suitably converted to relative Raman intensity (Ii) using the following relationship derived from the basis theory of Raman scattering [18,19].

Ii ¼

f ðm0  mi Þ4 Si mi ½1  expðhcmi =ktÞ

ð1Þ

Fig. 4. Atom numbering scheme adopted in the optimized structure of TA.

where v0 is the exciting frequencies (cm ), vi is the vibrational wavenumber of the ith normal modes, h, c, and k are fundamental constants and f is suitably chosen common normalization factor for all the intensities. For the plots of simulated IR and Raman spectra, pure Lorentzian band shapes were used with a bandwidth (FWHM) of 10 cm1. The theoretically simulated spectra are more regular than the experimental ones, because many vibrations presenting in condensed phase leads to strong perturbation of infrared intensities of many other modes.

calculations were performed for an isolated molecule in gaseous phase and the experimental results are for a molecule in a solid state. The cyclohexane ring appears to be small distorted from its regular position. It is due to effect of substitution of carboxylic acid and amino methyl group at 1 and 4 positions on cyclohexane ring. The bond length CAC bond in cyclohexane ring are varied between 1.51 and 1.53 Å for B3LYP/6-31G(d,p) method and experimental values are varied in the range between 1.48 and 1.53 Å.

Results and discussion

Vibrational assignments

Molecular geometry

The present molecule consists of 26 atoms, thus assuming C1 point group of symmetry and 72 normal modes of vibration, all modes are active in infrared and Raman spectra. A detailed vibrational assignment has been carried out with the assist of normal coordinate analysis. The specific assignment to each frequency was assigned through potential energy distributation (PED). For this purpose, internal valence coordinate of TA was defined according to Pulay’s recommendations [21] and listed in Table S2 (supplementary material). The computed wavenumber are selectively scaled according to the SQM procedure comprising set of multiple scale factor suggested by Rauhut and Pulay [12] and are presented in Table S3 (supplementary material). The observed FT-IR and FTRaman bands with their relative intensities are shown in Table 1 along with detailed assignments. Modes are numbered from highest frequency to smallest frequency within each fundamental wavenumbers. The experimental frequency were calculated for solid sample, only while theoretical calculation were performed for free molecule in vacuum, so there are some disagreements between calculated and observed vibrational frequency. All frequencies are calculated, however some of them are not observed in the FT-IR and FT-Raman spectra.

1

The potential energy surface (PES) scan was carried out with dihedral angle C6AC1AC7AO9 for TA molecule. During the calculation all the geometrical parameters were simultaneously relaxed while the C6AC1AC7AO9 dihedral angle were varied in step of 10°, 20°, 30°–360°. For this rotation minimum energy was obtained at 289.6° as shown in Fig 3. The structure was further re-optimized with B3LYP/6-31G(d,p) basis set. The optimized structure of the molecule with numbering scheme for the atoms as shown in Fig. 4. The optimized geometry shows that the benzene ring was most stable conformer has a cyclohexane ring as chair form. The optimized structural parameters of TA calculated by B3LYP method with 6-31G(d,p) basis set and compared with the available experimental data for similar compound [20] are listed in Table S1 (Supplementary material). From theoretical values we can find that most of the optimized bond lengths and bond angles are slightly longer than experimental values, this is due to the theoretical

Fig. 3. The potential energy curves of TA along the CCCO dihedral angle, calculated by B3LYP/6-31G(d,p) level of theory.

CAH vibration The hetero aromatic structure shows the presence of CAH stretching vibration in the region 3100–3000 cm1 which is the characteristic region for the ready identification of CAH stretching vibration [22]. In this region, the bands are not affected appreciably by the nature of substituent. Accordingly, in the present study, the CAH stretching band not appeared in FT-Raman and FT-IR spectrum, where as theoretical computed values at 2885 cm1 in B3LYP/6-31G(d,p) method was assigned to CAH stretching vibrations in the aromatic ring. The CAH in-plane and out-of-plane bending vibrations generally lie in the regions 1300–1000 cm1 and 1000–675 cm1 [23,24], respectively. The bands due to CAH in-plane ring vibration interacting somewhat with CAC stretching vibration are observed as many medium and weak intensity sharp bands in the region 1300–1000 cm1. In accordance with above literature data in our present study, the band observed at 1330 cm1 in FT-IR spectrum was assigned to CAH in-plane bending vibrations. The theoretically

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Table 1 Comparison of the experimental FT-IR and FT-Raman bands, and the theoretical frequencies (cm1), IR intensities and Raman scattering activities of TA calculated by B3LYP method with 6-31G(d,p) basis set. Mode No.

Experimental frequency (cm1) FT-IR

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

FT-Raman 3481(w) 3362(w) 3052(w) 2980(w)

2921(m)

2937(w)

2867(m)

1635(m)

2835(vw) 1751(w) 1584(w)

1453(m)

1458(vw)

1385(s)

1379(m)

1330(w)

1295(m) 1280(w)

1227(m) 1197(w) 1170(w)

1184(w)

1098(w) 1080(w)

1010(w)

1018(vw)

970(w)

961(m)

921(s) 888(vw) 845(w) 806(vw) 769(m) 758(vw) 615(w) 536(s) 472(m)

486(w)

403(w) 345(w) 289(w) 247(w)

Characterization of normal modes with PED (%)c

Calculated using B3LYP/6-31G(d,p) Scaled frequency (cm 3666 3447 3364 3000 2992 2962 2960 2948 2941 2921 2908 2902 2885 2874 2843 1804 1608 1470 1462 1454 1448 1442 1383 1366 1362 1345 1329 1305 1303 1298 1287 1266 1257 1241 1220 1197 1161 1138 1099 1080 1066 1048 1039 1009 1007 972 930 917 885 882 847 808 773 756 696 631 527 473 472 450 437 404 342 279 246 228 226 192

1

)

IIRa 10 0 1 8 13 42 4 5 18 17 21 5 5 6 36 100 11 1 1 4 1 0 6 3 8 0 1 32 8 12 19 11 62 17 40 0 1 0 9 0 0 3 1 9 0 2 3 4 5 4 23 24 1 4 2 3 3 36 3 3 1 4 3 2 16 2 1 6

IRAb 6 16 23 21 16 12 28 18 11 21 22 2 18 22 23 8 12 20 8 2 1 24 4 1 12 4 4 1 2 3 18 8 6 42 9 1 7 13 6 11 2 5 1 4 32 3 3 6 2 1 7 11 7 31 16 8 2 11 11 12 5 5 3 31 24 10 4 4

mOH (100) masNH2 (92) mssNH2 (90), masCH2(89) masCH2 (88) masCH2 (67) mCH(46) masCH2(52) mssCH2(72) mssCH2(89) mssCH2(71), masCH2(13) mssCH2 (70), masCH2(22) mCH(87) mssCH2(meth) (62), masCH2(meth)(35) mssCH2 (70) mC@O(82) NH2 sci (75) CH2sci(meth) (82) CH2sci (93) CH2sci (92) CH2 sci (91) CH2 sci (82) CH2 wag(meth) (59) CH2 wag (60),CHopb(22), mCC(11) CH2 wag (43), CHopb(15), mCC(17) CH2 wag (43), CH2 twi(meth) (12), CH2 twi(11) CHipb(31), mCC(17), CH2 wag (14) CH2 wag (66) CHipb(20), CH2 wag (18), CH2 twi (19),CHopb(15) CH2 twi (36),CHopb(26) OHipb(30), mCO(34), CH2twi(53) CHopb(21), CH2twi(21), CH2wag(10) CH2twi(45), mCC(15), CH2wag(17) tCNH2(25), CH2 twi(meth)(13) COipb(20),CH2roc(11) mCC(26),COHipb(12),NH2sb(10) mCC(58) mCC(54), CH2twi(46) NH2sb(20), mCC(17), CH2twi(meth)(11) mCC (71) mCC(39), mCN(30) mCC(59), mCN(20) Rtri (20), NH2roc(16), CH2roc(14) mCC (41) CHopb(51) mCC(39), mCN(30) Rtri(20), NH2roc(16), CH2roc(14) mCC(36), mCN(14) mCC(32), VCC(19), CH2roc(10) mCC(28), CH2roc (13) mCC (51) mCC(37), CH2roc(32) OHopb(58), mCC(30) CNopb(37), tCNH2(15) CO2sci(62), Rtri(10) Rtri (30), NH2roc(13), CH2roc(11) CCCsci(28), Rtri(14), tCNH2(10) CO2roc(30), Rsym(15), mCC (10) Rasy(58),CH2sci (33) CCCsci(34), tCNH2(19) tCNH2(38), CCCsci(13), CHopb(13) tRasy(43), CCCsci(23), Rasy(38),CH2sci (33) CCCsci(28), Rtri(24), tCNH2(10) CCCsci(18), Rtri(10), tCNH2(10) Rsym(42), tRasy(13), mCC(12), CH2sci(11) CCipb(22), CCCsci(20), tCNH2(10) (continued on next page)

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Table 1 (continued) Mode No.

Experimental frequency (cm1) FT-IR

69 70 71 72

FT-Raman 102(w)

Characterization of normal modes with PED (%)c

Calculated using B3LYP/6-31G(d,p) Scaled frequency (cm 145 110 64 41

1

)

IIRa 3 0 0 3

IRAb 8 10 5 100

CCCsci(44), tCNH2(19) tCNH2(57), CCipb(38) tRasy(53), CCipb(22), CCCsci(20)

Abbreviations: m, stretching; ipb, in-plane bending; opb, out-of-plane bending; t, torsion; ss, symmetric stretching; asy, asymmetric stretching; sb, symmetrical bending; roc, rocking; sci, scissoring; wag, wagging; twi, twisting; vs very strong; s, strong; ms, medium strong; w, weak; vw, very weak. a Relative absorption intensities normalized with highest peak absorption equal to 100. b Relative Raman intensities calculated by Eq. (1) and normalized to 100. c Only PED values greater than 10% are given.

computed wavenumber for this mode falls at 1329 cm1. The bands observed at 970 cm1 in the FT-IR spectrum and 961 cm1in the FT-Raman were assigned to CAH out-of-plane bending vibrations. While The theoretically computed values at 972 cm1 in B3LYP/6-31G(d,p) method were assigned to CAH out-of-plan bending vibration. Carboxylic acid group vibrations The OAH group gives rise to three vibrations, viz. stretching, inplane bending and out-of-plane bending vibration. The OAH group vibrations are likely to be most sensitive to the environment, so they show pronounced shifts in the spectra of the hydrogen bonded species. The hydroxyl stretching vibrations are generally observed in the region around 3500 cm1 [25]. On the other hand, the hydrogen bonding in the condensed phase with the other acid molecules makes vibrational spectra more complicated. Therefore, we could not observe the strong and sharp bands of the OAH vibration in the FT-IR and FT-Raman spectrum and the calculated value at 3666 cm1 was assigned to OAH stretching modes of the carboxylic groups. The OAH in-plane bending vibration in the phenols, in general lies in the region 1150–1250 cm1 and is not much affected due to hydrogen bonding unlike to stretching and out-of-plane bending frequencies [26]. The medium band in FTIR spectrum at 1280 cm1 was assigned OAH in-plane bending vibration. Theoretically computed value at 1287 cm1 by B3LYP method shows a good agreement with recorded spectrum. The OAH out-of-plane bending mode for the free molecule lies below 300 cm1 and it is beyond the infrared spectral range of the present investigation. However, for the associated molecule the OAH outof plane bending mode lies in the region 517–710 cm1 [27] in both intermolecular and intramolecular association, the frequency is at a high value than in free OAH. In our present investigation a strong band observed in FT-Raman spectrum at 758 cm1 was assigned to OAH out-of-plan bending vibration, the theoretically computed value by B3LYP shows the same kind of vibration at 756 cm1 was assigned to OAH out-of-plane bending vibration. The CO stretching bands of acids are considerably more intense than the ketonic CO stretching bands. The CO stretching vibration in the spectra of carboxylic acid gives rise to a strong band in the region 1675–1750 cm1 [28]. The very strong bands observed in the FT-Raman spectra at 1751 cm1 were assigned to CO stretching vibration. The same value is predicted at theoretical calculation. Ring vibration Many ring modes are affected by the substitution in the ring of TA. In addition, there are several in-plane and out-plane bending vibrations of the ring carbons. However, empirical assignments of vibrational modes for peaks in the fingerprint region are difficult. In general the band around 1400 and 1650 cm1 in benzene derivatives are assigned to CAC stretching vibrations [29]. In the fingerprint region there are five variable intensity band are observed at

1625–1590, 1590–1575, 1540–1470, 1460–1430 and 1380– 1280 cm1 [22]. By referring the above literature values, the frequencies observed in the FT-IR spectrum at 1330, 1170 and 1098 cm1 have been assigned to CAC stretching vibration. The theoretically predicted frequencies at 1066, 1099, 1130, 1161 and 1329 cm1 by B3LYP/6-31G(d,p) method shows an excellent agreement with experimental data. Methylene group vibration For the assignments of CH2 group frequencies, basically six fundamentals can be associated to each CH2 group namely, CH2 symmetric stretch, CH2 asymmetric stretch, CH2 scissoring and CH2 rocking modes which belong to polarized in-plane vibrations. In addition to that CH2 wagging and CH2 twisting modes of CH2 group would be expected to be depolarized for out-of-plane bending vibrations. The CAH stretching vibrations of the methylene group are at lower frequencies than those of the aromatic CAH ring stretching. The CH2 antisymmetric stretching vibrations are generally observed in the region 3000–2900 cm1, while the CH2 symmetric stretch will appear between 2900 and 2800 cm1 [30,31]. The CH2 antisymmetric symmetric stretching vibration was observed at 3052, 2980 in FT-Raman spectrum and symmetric stretching vibration was observed at 2921 and 2867 cm1 in FTIR and 2937 and 2835 cm1 in FT-Raman. The theoretically computed values falls in the region 2992–2843 cm1 for assigned to CH2 antisymmetric and symmetric stretching vibrations. The CH2 bending modes involving hydrogen atom attached to the central carbon fall into the 1450–875 cm1 range. For cyclohexane, the CH2 scissoring mode has been assigned to the medium intensity IR band at about 1450 cm1 [32]. In these molecule the scaled vibrational frequencies computed by B3LYP/6-311G (d,p) method at 1470, 1462, 1454, 1448 and 1442 cm1 were assigned to CH2 scissoring modes vibration which shows good correlation with recorded spectrum at 1453 cm1 in FT-IR and 1458 cm1 in FT-Raman spectrum. From the theoretical calculations, the CH2 wagging modes are predicted at 1383, 1366 and 1362 cm1. It shows excellent correlation with the FTIR and FT-Raman bands at 1385, 1379 cm1, respectively. The CH2 twisting is observed at 1295 cm1 in FT-Raman spectrum. The CH2 rocking vibrations are also predicted at lower wavenumbers with good correlation of experimental data. NH2 vibration The molecule under investigation possesses only one NH2 group and hence one expects one symmetric and asymmetric NAH stretching vibration in NH2 group. In all the primary aromatic amines, the NAH stretching frequency occurs in the region 3300–3500 cm1 [33], 1700–1600 cm1 for scissoring and 1150– 900 cm1 for rocking deformations. In the present study, the asymmetry and symmetric stretching mode for NH2 are assigned at 3447 and 3364 cm1 by B3LYP method. These assignments agree

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well with the earlier report [33]. The band at 1635 cm1 in FT-IR and 1584 cm1 in FT-Raman are assigned to NH2 scissoring mode vibration. The theoretically calculated frequency for this mode at 1608 cm1 for B3LYP/6-31G(d,p) method shows good agreement with experimental value as shown in Table 1. The wavenumber obtained at 1010 cm1 by FTIR spectra and 1018 cm1 by FT-Raman spectra was assigned to NH2 rocking mode vibration. These amino group vibrations were also in good agreement with literature values. It is a difficult task to identify the CAN stretching band, since overlapping of bands is possible in the region. However, the normal coordinate nanlysis result will be very useful to study CAN stretching vibration. Silverstein et al. [34] assigned CAN stretching vibration in the region 1350–1000 cm1 for amines. For the title compound, CAN stretching vibrations are not observed, while DFT calculation gives the CAN stretching vibrations at 1048 and 1039 cm1.

NBO analysis Natural bond orbital analysis has been used to identify important conformation specific orbital interaction, determine atomic charge, and obtain desaription of orbital hybridations [35]. The NBO analysis transforms canonical delocalized Hartree–Fock molecular orbitals (MOs) into localized orbitals via sequential transformation of nonorthogonal atomic orbitals into sets of natural atomic orbitals, natural hybrid orbitials, and natural bond orbitals (NBOs). The natural bond orbital (NBO) method of Weinhold et al. [36,37] provides a scheme appropriates to the analysis of Lewis acid/base interactions [36,38] as it emphasizes the calculation of delocalization of electron density into unoccupied orbitals. The NBO analysis is carried out by examining all possible interactions between ‘filled’ (donor) Lewis-type NBOs and ‘empty’ (acceptor) non-Lewis NBOs. Delocalizing interactions are determined by a second-order perturbation approach. Using this perturbation approach it is possible to calculate stabilization energies for orbital interactions between filled donor NBOs and empty or partially filled acceptor NBOs. The stabilization energy DEij is the difference in energy between the donor orbital and the new lower energy

189

orbital formed from the mixing of the donor and acceptor orbitals. The stabilization energy was obtained from following equation; 2

Eð2Þ ¼ DEij ¼ qi

Fði; jÞ ej  ei

where qi, F(i, j), and ej  ei represent the donor orbital occupancy, the off-diagonal NBO Fock matrix element, and the energies of the donor (ei) and acceptor (ej) orbitals (diagonal elements of the NBO Fock matrix), respectively. The larger the E(2) value, the more intensive is the interaction between electron donors and electron acceptors, i.e., the more donating tendency from electron donors to electron acceptors and the greater the extent of conjugation of the whole system. NBO analysis has been performed on the TA molecule at the B3LYP/6-31G(d,p) level in order to elucidate, the intra molecular rehybridization and delocalization of electron density within the molecule. The intramolecular interactions are formed by the orbital overlap among n ? r*, n ? p* and r ? r* bond and orbital which results intramolecular charge transfer (ICT) causing stabilization of the system is listed in Table 2. The interaction between the lone pair N11, O8 and O9 with antibonding orbital of r* and p* are presented in Table 2. The lone pair N11 lead to delocalized to the antibonding r* (C10AH24) with stabilization energy 7.50 kJ/mol. Further LP(2)O8 and LP(2)O9 leads to strong delocalized to the antibonding r*(C7AO9) and p*(C7AO8) with stabilization energy 35.95 and 44.38 kJ/mol, respectively. HOMO and LUMO analysis The frontier molecular orbitals; both the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) and their properties such as orbital energy is very useful for chemical reactivity and kinetic stability of the molecules, and are important parameters for quantum chemistry. While the energy of the HOMO is directly related to the ionization potential, LUMO energy is directly related to the electron affinity [39]. In order to evaluate the energetic behavior of the title compound. The HOMO and LUMO energy are calculated by B3LYP/6-31G(d,p) method and listed in Table 3. The 3D plots of the frontier energies of the title compound as shown in Fig. 5. The electronic absorption

Table 2 Second-order perturbation theory analysis of Fock matrix in NBO basis corresponding to the intramolecular bonds of TA. Donar

a

c

Energy

LP(1)O8

1.9768

0.6671

LP(2)O8

1.8458

0.2421

LP(1)O9

1.9759

0.5926

LP(2)O9 LP(1)N11

1.8262 1.9598

0.3222 0.3050

r(N11AH26) r(N11AH25) r(C10AH24) r(C10AH23)

1.7551 1.7680 1.9922

0.2871 0.2745 0.9358

1.9638

0.3341

1.9214 1.9923

0.3336 0.9324

r(C10AN11) r(O9AH22) r(C7AO9) r*(C1AC2)

b

ED/e

Acceptor (j) ⁄

r (C1AC7) r⁄(C7AO9) r⁄(C1AC7) r⁄(C7AO9) r⁄(C1AC7) r⁄(C7AO8) p⁄(C7AO8) r*(C4AC10) r*(C5AH18) r*(C10AH24) r*(C10AH23) r*(C4AC10) r*(C4AC5) r*(N11AH26) r*(C4AH17) r*(C3AC4) r*(C7AO8) r*(C1AH12) r*(C1AC6) r*(C1AH12) r*(C2AC3)

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

Energy

E(2)a

E(i)–E(j)b

F(I,j)c

0.3803 0.3500 0.3803 0.3500 0.3803 0.6289 0.0241 0.3874 0.4816 0.4397 0.4479 0.3874 0.3844 0.4700 0.4356 0.3821 0.6289 0.4579 0.3624 0.4579 0.3820

2.92 0.95 18.81 35.95 5.39 1.31 44.38 1.49 0.54 7.50 2.46 2.93 3.32 3.09 2.79 1.78 5.43 0.67 0.84 0.67 0.64

1.05 1.02 0.62 0.59 0.97 1.22 0.35 0.69 0.79 0.74 1.05 0.99 0.88 0.97 0.93 1.08 1.38 1.37 0.96 1.05 0.98

0.50 0.028 0.099 0.132 0.065 0.036 0.111 0.029 0.019 0.067 0.045 0.048 0.048 0.049 0.046 0.039 0.077 0.027 0.025 0.024 0.22

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corresponds that is mainly described by one electron excitation from HOMO to LUMO, for these values increase molecular becomes more stable, and decreases the intermolecular charge transfer which makes the compound to be NLO active. The energy difference between HOMO and LUMO orbital which is called as energy gap is a critical parameter in determining molecular electrical transport properties because it is a measure of electron conductivity, calculated 6.89 eV for title molecule. The HOMO a charge density localized over the NH2 and CH2 atoms, but the LUMO is characterized by a charge distribution on COOH group atoms. . By using HOMO and LUMO energies, the nucleophilicity, chemical hardness (g), chemical potential (l) and electrophilicity index (x) of the title molecule have been calculated and listed in Table 3. The chemical hardness, which is an index of reactivity, is given by:

g¼

ðI  HÞ 2

and chemical potential that measure the escaping tendency of electron cloud is given by:

l¼

ðI þ HÞ 2

Parr et al. [40] 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 2g

where I is ionization potential and H is electron affinity of molecular system. Using the above equations, the chemical potential, hardness and electrophilicity index have been calculated for TA and their values are shown in Table 3. The calculated value of electrophilicity index describes the biological activity of the TA.

Table 3 Calculated energy values of TA molecule using B3LYP/6-31G(d,p) method. Parameter

B3LYP/6-31G(d,p)

HOMO (eV) LUMO (eV) Energy gap (eV) Chemical hardness (g) Chemical potential (l) Electrophilicity index (x)

6.49 0.4 6.89 3.445 3.04 1.341

Fig. 5. The frontier molecular orbital for TA by using B3LYP/6-31G(d,p) method.

Total, partial, and overlap population density-of-states In the boundary region, neighboring orbitals may show quasi degenerate energy levels. In such cases, consideration of only the HOMO and LUMO may not yield a realistic description of the frontier orbitals. For this reason, the total (TDOS), partial (PDOS), and overlap population (OPDOS or COOP (Crystal Orbital Overlap Population)) density of states [41–43], in terms of Mulliken population analysis were calculated and created by convoluting the molecular orbital information with Gaussian curves of unit height and full width at half maximum (FWHM) of 0.3 eV by using the GaussSum 2.2 program [44]. DOS, PDOS and OPDOS spectra was calculated for TA molecule using B3LYP/6-31G(d,p) method as shown in Figs. 6–8. Calculated density of states (DOS) spectra has been shown to be a useful method to visualise the spatial distribution of the electronic structure of complexes [45]. In particular, where there are several close-lying energy levels in the frontier region, it gives a better picture of the contributions of the various moieties to the HOMO and LUMO, compared to examination of individual energy levels. The OPDOS shows the bonding, anti-bonding and nonbonding nature of the interaction of the two orbitals, atoms or groups. A positive value of the OPDOS indicates a bonding interaction (because of the positive overlap population), negative value means that there is an antibonding interaction (due to negative overlap population) and zero value indicates nonbonding interactions [46]. Additionally, the OPDOS diagrams allow us to determine and compare of the donor–acceptor properties of the ligands and ascertain the bonding, non-bonding. The partial density of state (PDOS) spectrum are mainly presents of the composition of NH2 atoms, ring atoms, CH2 atoms and COOH group atoms which is seen in Fig. 7. The OPDOS diagram of TA molecule shows that bonding and anti-bonding character of selected among the group atoms as shown in Fig. 8. Molecular electrostatic potential The molecular electrostatic potential is a well established tool to explain the reactive behavior of a wide variety of chemical systems in both electrophilic and nucleophilic reactions, the study of biological recognition processes and hydrogen bonding interactions [47]. The electrostatic interaction between a molecule and a test charge of magnitude (that is a proton) placed at a point r is well represented by the molecular electrostatic potential V(r) using the equation:

VðrÞ ¼

X A

ZA  jRA  rj

Z

nðr 0 Þ dr 0 jr  r 0 j

Fig. 6. Molecular orbital energy level and density of state spectrum of TA.

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a very useful descriptor for determining sites for electrophilic attack and nucleophilic reactions as well as hydrogen-bonding interactions [50]. To predict reactive sites for electrophilic and nucleophilic attack for the investigated molecule, the MEP at the B3LYP/631G(d,p) optimized geometry was calculated. The different values of the electrostatic potential at the surface are represented by different colors. Potential increases in the order red < orange < yellow < green < blue. The negative (red, orange and yellow) regions of the MEP are related to electrophilic reactivity. The maximum positive region is localized on cyclohexane ring, indicating a possible site for nucleophilic attack. The MEP map (Fig. 9) shows that the negative potential sites are on electronegative N and O atoms and the positive potential sites are around the hydrogen atoms. These sites give information about the region from where the compound can has intermolecular interactions. This predicted the most reactive site for both electrophilic and nucleophilic attack. Statistical thermodynamic properties Fig. 7. The calculated PDOS diagrams for TA.

Fig. 8. The calculated OPDOS diagrams for TA.

where ZA is the charge on nucleus A located at RA, n(r0 ) is the electronic density function for the molecule and r0 is the dummy integration variable [48,49]. At any given point r (x, y, z) in the vicinity of a molecule, the molecular electrostatic potential (MEP), the molecular electrostatic potential is related to electron density and

Statistical thermodynamics calculations are necessary to compute properties as function of temperature. It is meant to include the method used to convert molecular energy levels into macroscopic properties, especially enthalpies, entropies, and heat capacities. Molecular energy level arises from molecular translation, rotation, vibration and electronic excitation. The energies and thermodynamic parameters of the compound have been computed at B3LYP methods with 6-3G(d,p) basis set and listed in Table S4 (Supplementary material). On the basis of vibrational analyses and statistical thermodynamics, the standard thermodynamic Functions, heat capacity at constant pressure (Cp), entropy (S) and enthalpy (H(T)  H(0) for TA were obtained different temperature using Perl script THERMO.PL [51] and listed in Table S5. The anharmonicity effects have been eliminated by scaling the thermodynamic properties by a scale factor of 0.96. Fig. S1 (supplementary material) depicts the correlation of heat capacity at constant pressure (Cp), entropy (S) and enthalpy change (H(T)  H(0) with temperature. The entropies, heat capacities, and enthalpy changes are increasing with temperature ranging from 100 to 1000 K due to the fact that the molecular vibrational intensities increase with temperature. The quadratic equations show the observed relations between the thermodynamic functions and temperatures. The corresponding regression factors (R2) are all not less than 0.9989. Cp = 5.78383 + 0.73266T  2.7192  104T2 (R2 = 0.9989) S = 228.96525 + 0.75709T  1.45922  104T2 (R2 = 0.9999) H(T)  H(0) = 6.57374 + 0.07295T + 2.19502  104 (R2 = 0.9998)

Fig. 9. Molecular electrostatic potential mapped on the isodensity surface in the range from 6.699  102 (red) to 6.699  102 (blue) for TA. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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Conclusion The spectral studies such as FT-IR, FT-Raman for TAmolecule was carried out for the first time. A complete vibrational and molecular structure analysis has been performed based on the quantum mechanical approach by B3LYP calculations with 631G(d,p) basis set. The difference between the observed and scaled wave number values of the most of the fundamental is very small. The complete vibrational assignment with PED was calculated using SQMF method. NBO analysis was made and it is indicating the intra molecular charge transfer between the bonding and antibonding orbitals. The calculated HOMO and LUMO energy gap were confirm the presence of charge transfer within the molecule. The calculated HOMO and LUMO energies can be used to semi quantitatively estimate the electro philicity index, chemical hardness, and chemical potential. The predicted MESP contour map shows the negative regions at carboxylic acid, it is subjected to the electrophilic attack of this compound. The theoretically constructed FT-IR and FT-Raman spectra shows good correlation with experimentally observed FT-IR and FT-Raman spectra. The thermodynamic properties to the title compound have been calculated for different temperatures, revealing the correlations among Cp, S, H(T)  H(0) and temperatures were obtained. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.saa.2014.03.050. References [1] S. Thorsen, I. Clemmenson, L. Sottrup-Jensen, S. Magnusson, Biochim. Biophys. Acta 668 (1981) 377–387. [2] R.S. Brown, B.K. Thwaites, P.D. Mongan, Anesth. Analg. 85 (5) (1997) 963–970. [3] K. Ido, M. Neo, Y. Asada, et al., Arch. Orthop. Trauma Surg. 120 (9) (2000) 518– 520. [4] D. Cherkas, Emerg. Med. Pract. 13 (11) (2011) 1–19. [5] J.E. Anderson, D. Etches, Am. Fam. Phys. 75 (6) (2007) 875–882. [6] J.M. Seminario, P. Politzer (Eds.), Modern Density Functional Theory: A Tool for Chemistry, vol. 2, Elsevier, Amsterdam, 1995. [7] A.D. Becke, J. Chem. Phys. 98 (7) (1993) 5648–5652. [8] A.D. Becke, Phys. Rev. A 38 (6) (1988) 3098–3100. [9] C. Lee, W. Yang, R.G. Parr, Phys. Rev. B 37 (2) (1988) 785–789. [10] 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. Burant, J.M. Millam, S.S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G.A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J.E. Knox, H.P. Hratchian, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, P.Y. Ayala, K. Morokuma, G.A. Voth, P. Salvador, J.J. Dannenberg, V.G. Zakrzewski, S. Dapprich, A.D. Daniels, M.C. Strain, O. Farkas, D.K. Malick, A.D. Rabuck, K. Raghavachari, J.B. Foresman, J.V. Ortiz, Q. Cui, A.G. Baboul, S. Clifford, J. Cioslowski, B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y. Peng, A. Nanayakkara, M. Challacombe, P.M.W. Gill, B. Johnson, W. Chen, M.W. Wong, C. Gonzalez, J.A. Pople, Gaussian 03, Revision C.02, Gaussian Inc., Wallingford CT, 2004. [11] V. Mukherjee, N.P. Singh, R.A. Yadav, J. Mol. Struct. 988 (2011) 24–34.

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