FT-IR , Laser-Raman , UV-Vis , and NMR Spectroscopic Studies of Antidiabetic Molecule Nateglinide

+e quantum chemical calculations and spectroscopic and theoretical characterizations of nateglinide molecule, a derivative of meglitinide and an oral antidiabetic drug, were performed using FT-IR, Laser-Raman, and NMR chemical shift and UV-Vis analysis methods. +e other parameters including geometric structures, optimized geometry, vibrational frequencies, dipole moments, infrared and Raman intensities, and HOMO and LUMO energies of nateglinide molecules were studied using the density functional theory. In addition, the C and H NMRs were calculated using Gaussian 09 program with the DFT/B3LYP method at the 6-31G+ (d, p) basis set. TD-DFTcalculations were performed to examine the electronic transitions including orbital energies, absorption wavelengths, oscillator strengths, and excitation energies inmethanol.+e research was performed to provide detailed spectroscopic information of antidiabetic nateglinide molecule’s monomer conformations.

Jain et al. carried out a work on spectrophotometric determination of nateglinide in bulk and tablet dosage forms [9].Babu et al. investigated nateglinide with visible spectrophotometry and spectrophotometric methods [10,11].Bruni et al. developed a method for the quantification of the polymorphic purity of nateglinide in mixtures formed by polymorphs H and B [12].Guardado-Mendoza et al.
explained that nateglinide and repaglinide are effective in reducing postprandial glucose excursion and HbA1c levels from 0.8% to 1% in T2DM [13].Rani et al. described two spectrophotometric methods for the determination of nateglinide [14].Goyal et al. determined the crystal structure and crystallographic parameters of experimentally crystallized polymorphs of nateglinide.Crystallographic parameters of nateglinide polymorphs were given as Form H, Form B, Form MS, and Form S (space groups are P-1, C2, P-4, and P-42C), and the forms were found to exist in triclinic, monoclinic, tetragonal, and tetragonal, correspondingly [15].Remko [16] used the methods of theoretical chemistry to elucidate the molecular properties of the hypoglycemic sulfonylureas and glinides (acetohexamide, tolazamide, tolbutamide, chlorpropamide, gliclazide, glimepiride, glipizide, glibenclamide, nateglinide, and repaglinide) which are known as antidiabetic molecules.
e geometry and energy of these drugs were computed using the Beck-e3LYP/6-31G + (d, p) method.Karakaya et al. [17] investigated the vibrational and structural properties of tolazamide molecule.Ozdemir and Gokce studied the glimepiride molecule as a sulfonylurea compound using FT-IR, Raman and NMR spectroscopy, and DFT theory [18].
Few studies have been encountered on investigation of nateglinide molecule, which is effectively used against diabetes mellitus.In this regard, the present research was carried out to perform a detailed theoretical and experimental investigation of nateglinide, which is the active ingredient of an antidiabetic drug commonly prescribed as Starlix, using spectroscopic analyses such as FT-IR, Laser-Raman, UV-Vis, and NMR.In the present study, density functional theory study was theoretically performed to obtain the vibrational wavenumbers, FT-IR, Laser-Raman, and NMR chemical shifts and UV-Vis of nateglinide molecule.e recorded experimental data were supported with the computed parameters using theoretical methods at DFT/B3LYP/6-31G + (d, p) level.e obtained theoretical and experimental results were used to give detailed information of the molecular electronic structure of nateglinide.

Experimental and Computational Procedures
Nateglinide was purchased from Sigma-Aldrich Corporation in powder form.e melting point of nateglinide is in the range of 137 °C-141 °C.e chemical name of nateglinide (NTG) is N-(trans-4-isopropylcyclohexyl carbonyl)-Dphenylalanine. is molecule is almost insoluble in water, and highly soluble in methylene and methanol chloride.It shows polymorphism [19].
e optimized monomer structures of antidiabetic molecule are given in Figure 1. e FT-IR spectrum of nateglinide molecule was recorded within 400-4000 cm −1 region at room temperature, using the potassium bromide (KBr) pellet, on a Fourier-transform infrared spectrometer in the solid phase of the sample as shown in Figure 2. e Laser-Raman spectrum was recorded at room temperature in 100-4000 cm −1 region as shown in Figure 3. e 1 H and 13 C NMR chemical shift spectra of the compound solved in dimethyl sulfoxide (DMSO-d6) were recorded with TMS as the internal standard using the Premium Compact NMR device at 600 MHz frequency and 14.1 Tesla field power.e chemical shifts were reported at ppm level as given in Figures 4 and 5. e ultraviolet visible spectrum of nateglinide dissolved in methanol was recorded using a UV-Vis spectrophotometer in 200-400 nm range at room temperature as given in Figure 6.B3LYP (Becke, three-parameter, Lee-Yang-Parr) level with 6-31G + (d, p) basis set was used to compute the electronic structure properties of nateglinide molecule [20,21].Vibrational wavenumbers, geometric parameters, and molecular properties were calculated using Gaussian 09W software and GaussView5 molecular visualization program on a computer system [22][23][24].Veda 4 program was used to compute the potential energy distribution of vibrational wavenumbers as given in Table 1 [25].e major contributions for the computed electronic wavelengths were obtained by GaussSum 3.0 program as listed in Table 2 [26].

Geometric Structure.
e experimental data explain the crystallographic structure of nateglinide [27], and these findings were compared with the calculated results as given in Table 3. e other geometric parameters such as bond lengths, bond angles, and torsion angles with the corresponding literature information are given in Table 3. Zeropoint, relative energy values, and dipole moments are given in Table 4. Tessler and Goldberg investigated bis(nateglinide) hydronium chloride, in addition to its self-assembly into extended polymeric arrays with O-H e title compound contains four dissimilar moieties which are conformationally different in the asymmetric unit [27].
e C-C bond lengths of the title molecule were calculated at the interval of 1.395-1.558Å, while they were recorded between 1.352 and 1.543 Å in the literature [27].

Vibrational Frequency Analyses.
In the following discussion, nateglinide is experimentally examined using FT-IR, Laser-Raman, UV-Vis spectroscopy, and NMR. e observed and calculated vibrational frequencies, observed and calculated FT-IR intensities, Raman scattering activities, and vibrational assignments of the title molecule are given in Table 1.Nateglinide consists of 50 atoms, and accordingly, it has 144 modes of vibrations according to the relation 3N-6 (for N � 50).In the present research, C-H, C-O, O-H, N-H, and C-C vibrations were examined.As shown in Figures 2  and 3 and Table 1, the experimental and calculated vibrational wavenumbers are in good agreement.
e computations of harmonic wavenumbers, IR intensities, and Raman activities were performed with the ere is strong symmetric stretching between carbon and hydrogen (]CH) at 2800-3000 cm −1 frequency range for the Raman spectrum [31].

1 H and 13 C NMR Chemical Shift
Analyses.e experimental shielding ranges for 1 H NMR and 13 C NMR are given as 0-13 ppm and 0-180 ppm, respectively. 1H and 13 C NMR chemical shift calculated with gauge-including atomic orbital (GIAO) approach using Gaussian 09 software shows good agreement with the experimental chemical shift.Figures 4 and 5 show the experimental 1 H and 13 C NMR   5 and 6. 1 H chemical shift values for Monomer 1 were computed at the intervals of 0.8078-8.1579ppm in DMSO. 1 H chemical shift values for Monomer 2 were computed at the intervals of 0.8144-8.089ppm in DMSO.
e experimental chemical shifts of 1 H are measured in the range of 0.69-12.58ppm.e largest deviation between the calculated and experimental 1 H NMR chemical shifts (δ exp -δ cal. ) was obtained for H16 with 0.6135 ppm, whereas the smallest deviation was found for H37 with 0.0009 ppm for Monomer 1. e largest deviation between the calculated and experimental 1 H NMR chemical shifts (δ exp -δ cal. ) was obtained for H22 with 1.4 ppm, whereas the smallest deviation was found for H34 with 0.0028 ppm for Monomer 2.   Journal of Spectroscopy e 13 C chemical shifts for Monomer 1 were calculated in the range of 7.0408-163.551ppm in DMSO ppm, and the 13 C chemical shifts for Monomer 2 were calculated in the range of 6.1516-161.592ppm, while they were experimentally recorded in the range of 20.07-175.54ppm.e largest deviation between the calculated and experimental 13 C NMR chemical shifts (d exp -d cal. ) was obtained for C17 with 14.022 ppm, whereas the smallest deviation was found for C33 with 0.6225 ppm for Monomer 1. e largest deviation between the calculated and experimental 13 C NMR chemical shifts (d exp -d cal. ) was obtained for C23 with 13.948 ppm, whereas the smallest deviation was found for C33 with 0.4279 ppm for Monomer 2.

UV-Vis Analyses.
e obtained and simulated UV-Vis spectrum of nateglinide dissolved in methanol was recorded in the region of 190-350 nm.UV-Vis calculation was performed in methanol using the TD-DFT method with Gaussian 09W software and GaussView5 molecular visualization program.
e measured and simulated UV-Vis electronic absorption spectra are given in Figures 6 and 7. Additionally, the experimental and computed electronic absorption wavelengths, electronic transitions, oscillator strengths, excitation energies, and major contributions are listed Table 2. Rajasekaran et al. determined a method in which the absorbance of pure drug and tablet extract in 95% ethanol was measured at 210 nm [33].Xavier studied the UV
e calculated dipole moments are 5.1216 and 2.3479 debye for Monomer I and Monomer II, respectively.By considering Monomer II, the structural, spectroscopic (IR, Raman, NMR, and UV-Vis), and HOMO-LUMO analyses for nateglinide were performed using theoretical computational methods.e relative energy between the two monomers is considerably low, and it has a value of −0.99582 kcal/mole.Owing to its more stable structure, dipole moment of monomer 2 is lower than monomer 1. e simulated HOMO and LUMO surfaces, energy values, and their shapes for the title molecule are given in Figure 8. e calculated HOMO and LUMO energy values were computed as −6.9449 eV and −0.8923 eV for Monomer 1 and −6.8336 eV and −0.8101 eV for Monomer 2 at the DFT/B3LYP/6-31G + (d, p) level, respectively.

Conclusion
e structural, spectroscopic (IR, Laser-Raman, NMR, and UV-Vis), and HOMO-LUMO analyses for nateglinide were performed using theoretical computational methods.e computed spectral properties were compared with the experimental data.After the conformational analysis, two molecular geometric forms at the lowest energies were optimized with the DFT/B3LYP/6-31G + (d, p) level.e results can be summarized as follows: (i) e linear correlation coefficient (R 2 ) value between the calculated and experimental [27] molecular geometric parameters was found as 0.975 for bond lengths ( Å) and 0.9605 for bond angles ( °), respectively, as given in Table 3. (ii) As a result of the performed analyses, the linear correlation coefficient (R 2 ) values between the experimental and computed vibrational frequencies of Monomer 1 and Monomer 2 for IR wavenumbers were found as R 2 � 0.9981 and R 2 � 0.9980, respectively.(iii) e R 2 and RMSD values between the experimental and computed 1 H NMR chemical shifts were found

Figure 2 :
Figure 2: e experimental IR spectrum of nateglinide (a) and simulated IR spectra of nateglinide for Monomer 1 and for Monomer 2 (b).

Figure 3 :
Figure 3: e experimental Laser-Raman spectrum of nateglinide (a) and simulated Raman spectra of nateglinide for Monomer 1 and for Monomer 2 (b).

Figure 4 :
Figure 4: e experimental 13 C NMR chemical shift spectra of nateglinide.

Table 2 :
e experimental and computed UV-Vis parameters and electronic transitions in methanol of nateglinide.

Table 3 :
e optimized molecular geometric parameters of nateglinide.

Table 4 :
Zero point, relative energy and dipole moment of nateglinide.

Table 5 :
e experimental and computed 1 H NMR isotropic chemical shifts (with respect to TMS, all values in ppm) of nateglinide.

Table 6 :
e experimental and computed13C NMR isotropic chemical shifts (with respect to TMS, all values in ppm) of nateglinide.