Vibrational, UV spectra, NBO, first order hyperpolarizability and HOMO–LUMO analysis of carvedilol

Accepted Manuscript Vibrational, UV spectra, NBO, first order hyperpolarizability and HOMO-LUMO analysis of Carvedilol N. Swarnalatha, S. Gunasekaran, M. Nagarajan, S. Srinivasan, G. Sankari, G.R. Ramkumaar PII: DOI: Reference:

S1386-1425(14)01428-0 http://dx.doi.org/10.1016/j.saa.2014.09.070 SAA 12746

To appear in:

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy

Received Date: Revised Date: Accepted Date:

31 July 2014 9 September 2014 18 September 2014

Please cite this article as: N. Swarnalatha, S. Gunasekaran, M. Nagarajan, S. Srinivasan, G. Sankari, G.R. Ramkumaar, Vibrational, UV spectra, NBO, first order hyperpolarizability and HOMO-LUMO analysis of Carvedilol, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2014), doi: http://dx.doi.org/ 10.1016/j.saa.2014.09.070

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Vibrational, UV spectra, NBO, first order hyperpolarizability and HOMO-LUMO analysis of Carvedilol N.Swarnalathaa,g, S.Gunasekaranb, M.Nagarajanc, S.Srinivasand, G.Sankarie and G.R.Ramkumaarf* a

PG and Research Department of Physics, Pachaiyappa’s College, Chennai 600030, TN, India b

Research and Development, St. Peter’s Institute of Higher Education and Research, St. Peter’s University, Avadi, Chennai – 600054, TN, India

c

Department Of Physics , ArulmiguPalani Andavar College Of Arts and Culture, Palani 624601, TN, India. d

PG and Research Department of Physics, Presidency College, Chennai 600005, TN, India

e

Department of Physics, Meenakshi College for women, Chennai- 600024, TN, India.

f

Department of Physics, C. Kandaswami Naidu College for Men in Anna Nagar East, Chennai - 600102, TN, India g

Department of Physics, SCSVMV University, Enathur, Kanchipuram 631561, TN, India.

*Corresponding Author (email: [email protected]) Tel.: +91 9884351008 Abstract In this work, we have investigated experimentally and theoretically on the molecular structure, Vibrational spectra, UV spectral analysis and NBO studies of cardio-protective drug carvedilol. The FT-Raman and FT-IR spectra for carvedilol in the solid phase have been recorded in the region 4000-100 cm-1 and 4000-400 cm-1 respectively. Theoretical calculations were performed by using density functional theory (DFT) method at B3LYP/6-31G(d,p) and B3LYP/6-31++G(d,p) basis set levels. The harmonic vibrational frequencies, the optimized geometric parameters have been interpreted and compared with the reported experimental values. The complete vibrational assignments were performed on the basis of Potential Energy Distribution (PED) of the vibrational modes. The thermodynamic properties and molecular electrostatic potential surfaces of the molecule 1

were constructed. The electronic absorption spectrum was recorded in the region 400–200 nm and electronic properties such as HOMO and LUMO energies were calculated. The stability of the molecule arising from hyper conjugative interactions and charge delocalization have been analyzed from natural bond orbital (NBO) analysis. The first order hyperpolarizability of the title molecule was also calculated. The photo stability of carvedilol under different storage conditions were analyzed using UV–Vis spectral technique. Keywords: FT-IR; DFT; NBO; Topological charge; carvedilol Introduction Carvedilol is a non selective beta blocker/ alpha -1 blocker used for the treatment of mild to severe congestive heart failure. Norepinephrine stimulates the nerve that controls the muscles of the heart by binding to the β1 and β2 –adrenergic receptors. Carvedilol blocks the binding to those receptors, which slows the heart beat rhythm and hence reduces the force of the heart’s pumping. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure [1]. The activation energy of carvedilol was determined using thermogravimetry analysis by Andre Talvani et al. [2]. Also, they used differential scanning calorimetry, Fourier transform infrared spectroscopy, and optical microscopy were used to test binary mixtures of carvedilol and selected excipients. Almeida et al [3, 4] recorded the NMR spectrum of carvedilol and also studied their electronic structure. The Density Functional Theory (DFT) method has proved to be a powerful tool for the investigation of molecular structure and vibrational spectra [5, 6]. Hence, the title molecule is of considerable interest in the field of medicinal and pharmaceutical science. Literature survey reveals that so far there is no complete experimental and theoretical study for the title molecule was carried out. In the present study, detailed vibrational analyses have been made using FT-IR and FT-Raman spectra of carvedilol. A complete vibrational band assignment were made by using DFT method. The electronic parameters such as frontier 2

molecular orbital, Natural bonding orbital (NBO) and first hyperpolarizability analysis of carvedilol were made in the present study. Experimental section The spectroscopic pure sample of carvedilol was obtained from Sigma–Aldrich chemical company, with stated purity of 99% and it was used as such without further purification. The solid phase FT-IR spectrum of this compound was recorded in the region 4000–400 cm-1 in evacuation mode on Nexus 670 DTGS using KBr pellet technique (solid phase) with 4.0

cm-1 resolution. The FT-Raman spectrum was recorded using 1064 nm line of

Nd: YAG laser as excitation wavelength in the region 4000–400 cm-1 on Bruker IFS 66V spectrophotometer equipped with FRA 106 Raman module was used as an accessory. All sharp bands observed in the spectra are expected to have an accuracy of ±1 cm-1. UV–Vis spectral measurements have been made using Cary 5E-UV–Vis spectrophotometer in the wavelength region 200–400 nm. Computational details All the theoretical computations were performed using density functional theory (DFT) at B3LYP level using B3LYP/6-31G(d,p) and B3LYP/6-31++G (d,p) basis sets on a Pentium IV/1.6 GHz personal computer using the Gaussian 09W software [7].The stable molecular structure of carvedilol in the ground state is optimized and the structural parameters have been computed by using Becke’s three parameter hybrid functional(B3) [8] related with gradient corrected correlation functional of Lee-Yang-Parr (LYP) [9] with using B3LYP levels with 6-31G(d,p) and 6-31++G(d,p) basis sets to characterize all stationary points as minima by using Gaussian 09W program package without any constraint on the geometry The optimized molecular geometry, harmonic vibrational spectrum of

carvedilol were obtained using Gaussian 09W resulting IR frequencies

together with intensities of the present compound. The potential energy distributions of the vibrational modes of the compounds are also calculated. The comparison is made between 3

the theoretically calculated frequencies and experimentally measured frequencies [10]. The vibrational frequency assignments were made with a high degree of accuracy with the help of chemcraft software program [11]. Vibrational spectra of carvedilol have been analyzed on the basis of calculated potential energy distribution (PED). The redistribution of electron density in various bonding and antibonding orbitals along with energies have been calculated by natural bond orbital (NBO) analysis using DFT method to give clear evidence of stabilization originating from the hyper-conjugation of various intramolecular interactions. The UV spectroscopic studies along with HOMO, LUMO analysis calculated by DFT method have been used to elucidate information regarding charge transfer within the molecule. The properties of the structural geometry, molecular electrostatic potential (MEP) of the title compound were studied with the aid of DFT studies. The first order hyperpolarizability of the title compound was obtained based on theoretical calculations. Molecular Geometry The optimized molecular structure along with numbering of atoms of carvedilol was obtained from chemcraft program was shown in Fig. 1. The optimized structural parameters (bond length and bond angle) calculated by DFT/B3LYP with 6-31G(d,p) and 6-31++G(d,p) basis sets are compared with experimental data [12] and are presented in Table 1.

By allowing the relaxation of all parameters, the calculations converge to

optimized geometries, which correspond to true energy minima, as revealed by the lack of imaginary frequencies in the vibrational mode calculation [13]. The vibrationally averaged nuclear positions of carvedilol were used for harmonic vibrational frequency calculations. The bond length between C2-C3 is 1.5248 Å and 1.524 Å in B3LYP/6-31G(d,p) and B3LYP/6-31++G(d,p) methods respectively. The bond length of N1-C2 is 1.4585 Å and 1.4611 Å in B3LYP/6-31G(d,p) and B3LYP/6-31++G(d,p)

methods respectively and

those for N-C is 1.465 Å and 1.468 Å in 6-31G(d,p) and 6-31++G(d,p) methods respectively [14]. The bond angle of the atoms C6-C5-C10 is 119.4° in both methods. 4

Similarly, bond angle of the atoms C7-C8-C9 is 120.0° and 119.9° in B3LYP/6-31G(d,p) and B3LYP/6-31++G(d,p) methods respectively. Further the results of our calculations, the experimental and calculated geometric parameters agree well with remaining geometrical parameters. From the theoretical values, it is found that some of the calculated parameters are slightly deviated from the experimental values, due to fact that the theoretical calculations belong to molecule in the gaseous phase and the experimental results belong to molecule in solid state. Vibrational Analysis In order to obtain the spectroscopic signature of carvedilol, we performed a frequency calculation analysis. The aim of the vibrational assignments is to conclude which of the vibrational modes give rise to each of these observed bands.

The experimental and

theoretical FT-IR and FT-Raman spectra of carvedilol were shown in Figs. 2 and 3 respectively. Theoretically computed frequencies using B3LYP level with 6-31G(d,p) and 6-31++G(d,p) basis sets along with their relative intensities, probable assignments and potential energy distribution (PED) are summarized in Table 2. The molecule carvedilol has 56 atoms and it belongs to C1 symmetry as revealed from its geometry optimization. Theoretical calculations were made for a molecule in vacuum, where experiments were performed in solid phase. Therefore the vibrational analysis obtained for carvedilol with theoretically computed values are generally somewhat greater than the experimental values due to neglect of anharmonicity in real system. C-H Vibrations Heterocyclic aromatic compounds and its derivatives are structurally very close to benzene. The C- H stretching frequency of such compounds falls very nearly in the region 3000 - 3100 cm−1 which is the characteristic region for the ready identification of C–H stretching vibrations. In these regions the bands are not much affected by the nature and position of the substitutions [15]. Gunasekaran et al observed the C-H stretching band at 5

3070 cm-1 and 3082 cm-1 in FT-IR and FT-Raman spectra respectively [16]. In the present work the both FT-IR and FT-Raman bands were observed at 3060 cm−1 and 3070 cm-1 assigned to CH asymmetric stretching. It is noticeable that asymmetric stretching vibrations occurred at higher wave number.

The theoretically calculated harmonic

wavenumber at 3071 cm-1 in B3LYP/6-31G(d,p) and 3073 cm-1 in B3LYP/6-31++G(d,p) basis set respectively with PED contribution of 100%. N-H vibrations It has been observed that the presence of N-H atomic group in various molecules may be correlated with a constant occurrence of absorption bands whose positions are slightly altered from one compound to another. This is because of the reason that the NH group vibrates independently of other groups in the molecule and has its own frequency. Usually in heterocyclic compounds the N-H stretching vibration occurs in the region 3000-3500 cm-1 [17]. Similarly, Muthu et al observed the N-H band at 3500 cm-1 for indole-3aldehyde. In our title molecule the NH vibration occurs at 3524 cm-1 in FT-IR spectrum[18]. The theoretically calculated harmonic wavenumber at 3517 cm-1 in B3LYP/6-31G(d,p) and 3527 cm-1 in B3LYP/6-31++G(d,p) basis set respectively with PED contribution of 100%. C=C vibrations The C=C vibration are more interesting if the double bonds are in conjugation with the ring. The actual positions are determined not so much by the nature of the substituents by the form of the substitution around the ring. Ramkumaar et al observed the values for C=C stretching modes for FT-IR and FT-Raman at 1508 and 1583 cm-1 respectively [19]. In the present study, we observed band at 1590 cm-1 in FT-IR and 1583 cm-1 in FT-Raman spectra. Also it is observed at 1629 cm-1 in both FT-IR and FT-Raman spectra respectively.

6

The theoretically calculated harmonic wavenumber at 1628 and 1618 cm-1 with B3LYP/631G(d,p) and B3LYP/6-31++G(d,p) basis sets respectively.

C-N vibrations The identification of C-N stretching modes in the side chains is a rather difficult task since there are problems in identifying these frequencies from other vibrations.

The C-N

stretching band is assigned at 1319 and 1268 cm-1 in FT-IR and at 1317 and 1266 cm-1 in FT Raman spectrum of propylthiouracil by Seshadri et al [20]. In our present investigation, the vibrational bands observed at 1333 and 1337 cm-1 in FT-IR and FT-Raman spectra are assigned to C-N vibrations. The theoretically calculated harmonic wavenumber at 1335 and 1329 cm-1 with B3LYP/6-31G(d,p) and B3LYP/6-31++G(d,p) basis sets respectively. O-H vibrations The OH Stretching vibrations are sensitive to hydrogen bonding. The non-hydrogenbonded hydroxyl group of phenols absorbs strongly in the 3700–3584 cm-1 region [21]. Sundaraganesan et al observed the O-H stretching mode in the region at 3517 cm-1 in FTRaman spectrum of rosmarinic acid [22]. In our present study the vibrational band at 3851 cm-1 both in FT-IR spectrum is assigned to O-H vibration.

The theoretically computed

values using DFT calculations are 3851 cm-1 and 3831 cm-1 are in good agreement with the experimental values. C-O vibrations The absorption is sensitive for both the carbon and oxygen atoms of the carbonyl group. Both have the same while it vibrates. Normally, the C-O stretching vibrations occur in the region 1260–1000 cm-1 [23]. Amalanathan et al [24] observed the C-O stretching vibration at 1182 cm-1. Hence, the bands at 1120 cm-1 in FT-IR spectrum is assigned to C-O

7

vibration. The theoretically computed values in DFT methods were 1130 cm-1 and 1125 cm-1 coincides with the experimental values.

Topological charge distribution The calculation of effective atomic charges plays an important role in the application of quantum mechanical calculation to molecular systems [25]. The atomic charges of carvedilol calculated by DFT method using the B3LYP/6- 311++G(d, p) method are presented in Table 3.

The atomic charges computed B3LYP/6-31++G(d,p) method for

carvedilol are shown in the Fig. 4. All hydrogen atoms have almost same net positive charge except H31(0.37762) and H48(0.47193), because of highly electronegative oxygen and nitrogen atoms attached to those hydrogen atoms. The carbon atom C23 possesses high positive charge. This may be due to the reason that it is connected to highly electronegative oxygen O17. It may be noted that the oxygen atoms O4, O11 possesses large net negative charge may be due to electronegative character. Also, C14 (0.10871) and C19 (0.18549) have positive charges because of neighbouring atoms such as O16(-0.75533) and N18(0.55093). The nitrogen atoms N1(-0.7309) and N18 (-0.55093) possess highly negative charge because both are connected to positively charged hydrogen atoms H31 and H49. Donor acceptor interactions: perturbation theory energy analysis Natural bond orbital analysis provides the most accurate possible ‘natural Lewis structure picture of Ф, because all the orbital details are mathematically chosen to include the highest possible percentage of the electron density. A useful aspect of the NBO method is that it gives information about interactions in both filled and virtual orbital spaces that could enhance the analysis of intra- and intermolecular inter actions. The second-order Fock matrix was calculated to evaluate the donor–acceptor interactions in NBO analysis 8

[25]. The interactions result in a loss of occupancy from the localized NBO of the idealized Lewis structure into an empty non-Lewis orbital. For each donor (i) and acceptor (j), the stabilization energy E(2) associated with the delocalization i→j is estimated as E2 = ∆Eij= qi(F(i.j)2/(εj-εi) where qi is the donor orbital occupancy, εj and εi are diagonal elements and F (i, j) is the off diagonal NBO Fock matrix element. NBO analysis gives a convenient basis for investigating charge transfer or conjugative interaction in molecular systems. 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. Delocalization of electron density between occupied Lewis-type (bond or lone pair) NBO orbital and formally unoccupied (antibond or Rydberg) non-Lewis NBO orbital correspond to a stabilizing donor–acceptor interaction. NBO analysis has been performed on the molecule at the B3LYP/6-31++G(d,p) level in order to elucidate the intramolecular, rehybridization and delocalization of electron density with the molecule. NBO analysis shows that intra molecular charge transfer in carvedilol from π(C5-C10) to π*(C8-C9) with stabilization energy of 231.72 kcal mol-1 and from π (C6-C7) to π*( C8-C9) with stabilization energy of 207.8 kcal mol-1 and from σ( C7-C8) to σ *(C6-O11) with stabilization energy of 4.83 kcal mol-1 and from σ( C21-C22) to σ*(O17-C23) with stabilization energy of 5.1 kcal mol-1 From π(C25-C30) to π*(C19C24) and π*(C26-C27) anti bonding orbitals with stabilization energies of 18.49 and 261.61 kcal mol-1 respectively. From π(C26 - C27) to π*(C25-C30) and π*C28-C29) anti bonding orbitals with stabilization energies 17.89 kcal mol-1

and 21.66 kcal mol-1

respectively. From π(C26 - C27) to π*(C25-C30) and π*C28-C29) anti bonding orbitals with stabilization energies 17.89 kcal mol-1 and 21.66 kcal mol-1 respectively are listed in Table 4. 9

The energy contribution of LP (1) of N1 → σ * (C13-H43) and σ *(C13-H44) have the stabilization energy 1.36 and 8.32 kcal mol-1

respectively and hence there is a

possibility of delocalization of lone pair of electrons between N1 and C13-H43. The energy contribution of O4 → π*(C5-C10) is 31.4 kcal mol-1 indicates that the possibility of delocalization between O4 and C5-C10.

First order hyperpolarizability The first hyperpolarizability (β0) and related properties (β, α0 and ∆α) of carvedilol, are calculated based on the finite-field approach. In the presence of an applied electric field, the energy of a system is a function of the electric field. First hyperpolarizability is a third rank tensor that can be described by a 3 x 3 x 3 matrix. The 27 components of the 3D matrix can be reduced to 10 components due to the Kleinman symmetry [26,27]. It can be given in the lower tetrahedral format. It is obvious that the lower part of the 3 x 3 x 3 matrices is a tetrahedral. The components of b are defined as the coefficients in the Taylor series expansion of the energy in the external electric field. When the external electric field is weak and homogeneous, the expansion becomes: 1 1 E = E  − μ F − α F F − β  F F F + ⋯ 2 6

where E0 is the energy of the unperturbed molecules, F the field at the origin µα, ααβ and βαβγ

are

the

components

of

dipole

moment,

polarizability

and

the

first

hyperpolarizabilities, respectively. The total static dipole moment µ, the mean polarizability α0, the anisotropy of the polarizability ∆α and the mean first hyperpolarizability β0, using the x, y, z components are defined as: µ = (µ x2+µ y2+µ z2)1/2 α =

α + α + α 3

10

First hyperpolarizability is a third rank tensor that can be described by 3 × 3×3 matrix. The 27 components of 3D matrix can be reduced to 10 components due to the Kleinman symmetry β = β = β = β = β = β ; likewise other permutations also take same value). The output from Gaussian 09W provides 10 components of this matrix as β , β , β , β , β , β , β , β , β , β respectively. The components of the first hyperpolarizability can be calculated using the following equation: 1 β = β + (β + β + β ) 3 

Using the x, y and z components of β, the magnitude of the first hyperpolarizability tensor can be calculated by: β = (β!  + β!  + β!  ) The complete equation for calculating the magnitude of β from Gaussian 09W output is given as follows: β =

(β + β + β )! + (β + β + β )! + (β + β + β )! β = β + β + β β" (β + β + β β#" β + β + β

Hyperpolarizabilites are very sensitive to the basis sets and levels of theoretical approach employed [28, 29]. Since the values of the hyperpolarizability (β ) of the Gaussian 09W output are reported in atomic units (a.u.), the calculated values have been converted into electrostatic units (esu) (1 a.u. = 8.639 x10-33 esu) and given in Table 5. UV-visible Spectral Analysis The nature of the transitions in the observed UV–Visible spectrum of the title compound has been studied by the time dependent density functional theory (TD-DFT) with in 11

GAUSSIAN 09W program. The experimental [30] and calculated results of UV-Vis spectral data were compared in Table 6. The experimental UV-Vis data at 203.6 nm and 238.6 nm with theoretically computed data at 278.1 nm, 296.0 nm and 306.3 nm respectively, which was obtained by TD-B3LYP/6-31++G(d,p) method. These excitations corresponds to π-π*, π-π* and n→ $* and electronic transitions. The analysis of the wave function indicates that the electron absorption corresponds to the transition from the ground to the first excited state. It is mainly described by an electron excitation from the highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO). The HOMO energy characterizes the ability of electron donating, LUMO characterizes the ability of electron accepting, and the gap between HOMO and LUMO characterizes the molecular chemical stability [31]. Gauss-Sum 2.2 Program [32] has been used to calculate group contributions to the molecular orbitals and prepare the density of the state (DOS) as shown in Fig. 5. The DOS spectra were created by convoluting the molecular orbital information with GAUSSIAN cures of unit height. The HOMO and LUMO surfaces are sketched in Fig. 6(a) and (b). Frontier molecular orbitals In principle, there are several ways to calculate the excitation energies. The simplest one involves the difference between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of a neutral system, and is a key parameter determining molecular properties. Both HOMO and LUMO are the main orbital taking part in chemical reaction. The HOMO energy characterizes the ability of electron giving, the LUMO characterizes the ability of electron accepting, and the gap between HOMO and LUMO characterizes the molecular chemical stability [33]. The energy gap between the HOMOs and LUMOs is a critical parameter in determining molecular electrical transport properties because it is a measure of electron conductivity [34]. Surfaces for the frontier orbitals were drawn to understand the bonding scheme of present compound. The features 12

of these MO can be seen in Fig. 6(a) and (b). It establishes correlation in various chemical and biochemical systems [35, 36]. There are lot of applications available for the use of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energy gap as a quantum chemical descriptor. The HOMO energies, the LUMO energies and the energy gap for carvedilol molecules have been calculated using B3LYP level with 6-31G(d,p) and 6-31++G(d,p)

basis set for carvedilol. Both the highest

occupied molecular orbitals and the lowest unoccupied molecular orbitals are mainly localized on the rings indicating that the HOMO–LUMO are mostly the %- anti-bonding type orbitals. The HOMO–LUMO energy gap of carvedilol was calculated at the DFT (B3LYP)/6-31++G(d,p) level reveals that the energy gap reflects the chemical activity of the molecule. The calculated energy values for HOMO, LUMO and energies are -5.3130 eV, -0.58749844 eV respectively. The difference in energies of HOMO and LUMO is 4.7255 eV. The 3D plots of HOMO and LUMO are shown in Fig. 6(a) and (b). Molecular electrostatic potential Molecular electrostatic potential (MEP) generally present in the space around the molecule by the charge distribution is very useful in understanding the sites of electrophilic attacks and nucleophilic reaction for the study of biological recognition process [37] and hydrogen bonding interactions [38]. The mapping of electrostatic potential onto iso -electron density surface simultaneously displays molecular shape, size, and dipole moments. And also it explores the polarization and charge transfer effects within the molecule [39, 40]. It provides a visual method to understand the reactive polarity [41]. In order to predict the molecular reactive sites, the MEP for our title molecule is calculated by B3LYP/631G(d,p) method as shown in Fig. 7. The charges derived from the electrostatic potential computation the information about the chemical reactivity of the compound. 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 13

negative (red, orange and yellow) regions of the MEP are related to electrophilic reactivity. These sites give information about the region from where the compound can have intermolecular interactions. Thermodynamic properties On the basis of vibrational analyses and statistical thermodynamics, the standard thermodynamic functions such as entropy(S), heat capacity(Cp) and enthalpy (∆H) were calculated using perl script THERMO.PL [42] and are listed in Table 7. It is observed that the values of S, Cp and ∆H all increase with the increase of temperature from 100 to 1000 K, which is attributed to the enhancement of the molecular vibration as the temperature increases. Fig. 8 depict the correlation of entropy (S), heat capacity (Cp) at constant pressure and enthalpy change (∆H) with temperature along with the correlation equations. From Table 7, one can find that the entropies, heat capacities, and enthalpy changes are increasing with temperature ranging from 10 to 1000 K due to the fact that the molecular vibrational intensities increase with temperature [43]. These observed relations of the thermodynamic functions vs. temperatures were fitted by quadratic formulas, and the corresponding fitting regression factors (R2) are all not less than 0.9990. The corresponding relations for carvedilol are S = 300.07248 + 1.76109 T - 3.5987 X 10-4 T2

R2=0.9999

Cp= 10.26288 + 1.71904 T - 6.86127 X 10-4 T2

R2=0.9990

∆H = -18.27988 + 0.18171 T + 4.86616 X 10-4 T2

R2=0.9994

Quality analysis Pharmaceutical chemistry focuses on the quality of aspects of medicines and aims to assure fitness for the purpose of medicinal products too. The stability and quality of the drug products could only be assured by continual testing and systematic evaluation. In order to maintain optimum efficacy and safety of the drugs correct storage of the drug at every stage are essential. It is a must and mandatory to store any drug in the prescribed storage 14

condition. The violation may give rise to reduced benefits. This gives the maximum benefits of the drug. The UV spectrum of the compound was recorded in the wavelength region 200 nm to 400 nm with suitable spectrophotometer with various concentrations. To analyze the behavior, the drug is purposely exposed to different violation of storage condition. Exposed to sunlight, ice point, IR radiation, hot air oven. By purposely exposing the drug to different violation it was observed that there is a variation in absorbance. UV– Vis spectral investigation has been carried out to study the variation of absorbance under different storage conditions and is tabulated in Table 8. The overlay spectra of UV-Visible spectra at different storage conditions is shown in Fig. 9. By Maintaining proper storage conditions for drugs plays important role to maintain the quality of the drug. Drug expiry dates are based on ideal storage conditions and protecting drug quality until their expiration date is important for serving customers and conserving resources. Medications last only as long as their storage conditions are favorable. In order to maintain their potency drugs should be stored in a place that is dry, cool and dark. Conclusion FT-IR, FT-Raman, UV spectra and DFT quantum chemical calculations studies were performed on carvedilol, in order to identify its structural and spectroscopic features. On the basis of experimental results and PED calculations, assignments of all the fundamental vibrational frequencies were done. NBO analysis was made and it is indicating the intramolecular charge transfer between the bonding and antibonding orbitals. NBO analysis revealed that the π(C5-C10) to π*(C8-C9) with stabilization energy of 231.72 kcal mol-1 interaction gives the strongest stabilization to the system. Natural atomic charge analysis shows that charge distribution on different atoms in the title molecule. The energies of MOs, absorption wavelength (λmax), oscillator strength excitation energies of the compound were determined and compared with experimental values. The lowering of HOMO and LUMO energy gap supports the bioactivity of the molecule. First-order 15

hyperpolarizability of the compound have been calculated in order to get insight into the compound. The present study predicts that the vibrational frequencies of carvedilol could be successfully elucidated by DFT methods. From the UV–Vis spectra recorded for the drug sample at different storage conditions, it is found that the absorbance values changes with storage condition implies the fact that the drug must be stored at proper prescribed conditions to retain their potency.

Acknowledgement The author acknowledges Indian Institute of Technology (IIT), Chennai, India for allowing her to utilize the facilities necessary for the present research work. The author thanks the management of Department of Physics, SCSVMV University, Enathur, Kanchipuram for the encouragement and support rendered for the present work.

16

References [1]

W.S. Colucci, M. Packer, M.R. Bristow, E. Michael Gilbert, J.N. Cohn, M.B. Fowler,

S.K. Krueger, R. Hershberger, B.F. Uretsky, J.A. Bowers, Jonathan D.

Sackner-Bernstein, Sarah T.Young, Circulation 94(11)(1996) 2800-2806. [2]

A. Talvani, M.T. Bahia, L.C. Lira de Sá-Barreto, E.M. Lima, M. Sérgio Soares da Cunha-Filho, J. Therm. Anal. Calorim. 115(3) (2013) 2501-2506.

[3]

D.R.P. Almeida, D.M. Gasparro, T.A. Martinek, F. Fulop, and I.G. Csizmadia J. Phys. Chem.A108(38) (2004) 7719–7729.

[4]

D.R.P. Almeida, D.M. Gasparro, L.F. Pisterzi, L.L. Torday, A. Varro, J.Gy. Papp, B. Penke, and I.G. Csizmadia J. Phys. Chem. A 107(29) (2003), 5594–5610.

[5]

R.G. Parr, W. Yang, Density Functional Theory of atoms and molecules, Oxford University Press, New York, 1989.

[6]

B.A. Hess, J. Schaad, P. Carsky, R. Zahradnik, Chem. Rev. 86 (1986) 709–730.

[7]

M.J. Frisch, G.W. Trucks, H.B. Schlegel, et al., Gaussian 09, Revision A.O2, Gaussion Inc., Wallingford, CT, 2009.

[8]

A.D. Becke, Phys. Rev. 38 (1988) 3098–3100.

[9]

C. Lee, W. Yang, R.G. Parr, Phys. Rev. 37 (1988) 785–789.

[10] W.J. Hehre, L. Radom, P.V.R. Schleyer, A.J. Pople, Ab initio Molecular Orbital Theory, Wiley, New York, 1989. 17

[11] G.A. Zhurko, D.A. Zhurko, Chemcraft Program, Academic version 1.5, 2004. Available at Cybulski J., Acta Crytallogr. Sect E: Structure (2004) online 60, O66-O68 [12] A. Carpy, A.K. Saxena, Acta Crystallogr. C47 (1991) 227–229. [13] G.R. Ramkumaar, S. Srinivasan, T.J. Bhoopathy, S. Gunasekaran, J. Spectrochim. Acta Part A Mol. Biomol. Spectrosc, 99 (2012) 189–195. [14] S. Renuga, S. Muthu , J. Spectrochim. Acta Part A Mol. Biomol. Spectrosc, 118 (2014) 702–715 [15] G. Varsanyi, Assignments for Vibrational spectra of Seven Hundred Benzene derivatives, ½ Academic Kiaclo, Budapest, 1973. [16] T. Gnanasambandan, S. Gunasekaran, S. Seshadri, IJCR, 4(2) (2012) 324-332. [17] Y. Wang, S. Saebo, C.U. Pittman, J. Mol. Struc. 281 (1993) 91-288. [18] S. Muthu, J. Uma Maheswari, Tom Sundius, Spectrochimica Acta Part A,106, (2013), 299-309. [19] G.R. Ramkumaar, S. Srinivasan, T.J. Bhoopathy, S. Gunasekaran, J. Spectrochim. Acta Part A Mol. Biomol. Spectrosc., 98 (2012) 265–270 [20] T. Gnanasambandan, S. Gunasekaran, S. Seshadri, IJCR, 3(7) (2012) 590 – 597. [21] R.M. Silverstein, F.X. Webster, D.J. Kiemle, Spectrometric Identification of Organic Compounds, Seventh ed., John Wiley & Sons, New York, 2005. [22] G. Mariappan, N. Sundaraganesan, S. Manoharan, J. Spectrochim. Acta Part A Mol. Biomol. Spectrosc, 97 (2012) 340–351. [23] D. Lin-Vien, N.B. Colthup, W.G. Fateley, J.G. Grasselli, The Handbook of Infrared and Raman Characteristic Frequencies of Organic Molecules, Academic Press, Boston, MA, 1991. [24] M. Amalanathan, V.K. Rastogi, I. Hubert Joe, M.A. Palafox, Rashmi Tomar Spectrochim. Acta Part A Mol. Biomol. Spectrosc.78 (2011) 1437–1444. 18

[25] M. Szafran, A. Komasa, E.B. Adamska, J. Mol. Struct. Theochem. 827 (2007) 101– 107 [26] C. James, A. Amal Raj, R. Reghunathan, I.H. Joe, V.S. Jayakumar, J. Raman Spectrosc. 37 (2006) 1381–1392. [27] J. Liu, Z. Chen, S.F. Yuan, J. of Zhejing Univ. Sci. 6B (2005) 584–591. [28] C.J. Cramer, Essentials Comput. Chem., Theor. Methods (2002) 278–289. [29] D.A. Kleinman, Phys. Rev. 126 (1962) 1977-1979. [30] L. Jagannathan, R. Meenakshi, S. Gunasekaran and S. Srinivasan, Molecular Simulation (2009) 1–8. [31] B.Kosar, C.Albayrak, Spectrochim. Acta.A 87 (2011) 160-167. [32] N.M. O’Boyle, A.L. Tenderholt, K.M. langer, J. Comput. Chem. 29 (2008) 839–845. [33] I. Fleming, Frontier Orbital and Organic Chemical Reactions, Wiley, London, 1976. [34] M. Karabacak, M.Cinar, M. Kurt, Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 74 (2009) 1197–1203. [35] D.F.V. Lewis, C. Loannides, D.V. Parke, Xenobiotica 24 (1994) 401–408. [36] Z. Zhou, R.G. Parr, J. Am. Chem. Soc. 112 (1990) 5720–5724. [37] P. Politzer, P.R. Laurence, K. Jayasuriya, Molecular electrostatic potentials: an effective tool for the elucidation of biochemical phenomena Environ, Health Perspect. 61 (1985) 191–202. [38] P. Politzer, P. Lane, Molecular electrostatic potentials: concepts and applications, Struct. Chem. 61 (1990) 159–164. [39] B.M. Draskovic, G.A. Bogdanovic, M.A. Neelakandan., A.C. Chamayou, S. Thalamuthu, Y.S. Avadhut, S. Banerjee, D. Janiak, Cryst. Grow. Design, 10 (4), (2010) 1665–1676. [40] T. Brinck, P.Jin, Y .Ma, J.S. Murray, P .Politzer, J. Mol. Model. 9 (2003) 77-83.

19

[41] I. Fleming, Frontier Orbitals and Organic chemical reactions, John Wiley and sons, New York, (1976) 5-27. [42] K.K. Irikura, THERMO. PL, National Institute of Standards and Technology, Gaithersburg, MD, 2002. [43] A.E. Reed, F. Weinhold, J. Chem. Phys. 83 (1985) 1736–1740.

20

Fig.1 Numbering system adopted in the molecular structure of carvedilol

21

Fig. 2 Experimental and Theoretical IR spectrum of carvedilol

22

Fig. 3 FT-Raman spectrum of carvedilol

23

Fig. 4. Atomic charges computed B3LYP/6-31++G(d,p) method of carvedilol

24

Fig. 5. Density of energy states of carvedilol

Fig. 6(a) HOMO plot of carvedilol

Fig. 6(b) LUMO plot of carvedilol

25

Fig. 7 Molecular electrostatic potential map of carvedilol

26

Fig. 8 Correlation graphs of thermodynamic properties at different temperatures for carvedilol

27

Fig. 9 Overlay of UV-Visible spectra of carvedilol at different storage conditions

28

Table(s)

Table 1

Optimized geometrical parameters for carvedilol by B3LYP with 6-31G(d-p) and 6-31++G(d-p) basis sets Geometrical Parameter

Experimental

B3LYP/6-31G(d-p)

B3LYP/6-31++G(d-p)

1.438

1.4585

1.4611

N1-C13

1.438

1.4619

1.4602

C2-C3

1.523

1.5248

1.524

C3-O4

1.402

1.4238

1.4254

O4-C5

1.355

1.3648

1.3639

C5-C6

1.3948

1.4187

1.4193

C5-C10

1.3948

1.3931

1.3952

C6-C7

1.3949

1.3931

1.3948

C6-O11

1.355

1.365

1.3655

C7-C8

1.3948

1.402

1.4037

C8-C9

1.3948

1.3871

1.389

C9-C10

1.3949

1.4018

1.4035

O11-C12

1.402

1.4165

1.4198

C13-C14

1.523

1.5319

1.5313

C14-C15

1.523

1.535

1.5348

C14-C16

1.402

1.4287

1.4331

C15-O17

1.402

1.4281

1.4284

O17-C23

1.355

1.3734

1.3701

N18-C19

1.375

1.3842

1.3858

N18 --C30

1.375

1.3861

1.3878

C19--C20

1.4001

1.3983

1.4006

C19--C24

1.3943

1.4187

1.4172

C20--C21

1.398

1.3884

1.3908

C21--C22

1.3929

1.4062

1.4092

C22--C23

1.3997

1.397

1.3967

C23--C24

1.4105

1.4088

1.4075

C24--C25

1.4318

1.4493

1.4492

C25--C26

1.4105

1.4003

1.4036

C25--C30

1.3943

1.4209

1.4224

C26--C27

1.3997

1.3924

1.3948

Bond length(Å) N1-C2

C27--C28

1.3929

1.4054

1.4076

C28--C29

1.3981

1.3932

1.3949

C29--C30

1.4001

1.3962

1.3973

Bond Angle(deg) C2-N1-C13

120.0

113.7

113.1

N1-C2-C3

109.5

109.5

109.8

C2-C3-O4

109.5

107.2

107.2

C3-O4-C5

120.0

118.4

118.5

O4-C5-C6

120.0

115.4

115.7

O4-C5-C10

120.0

125.1

124.8

C6-C5-C10

120.0

119.5

119.5

C5-C6-C7

120.0

119.5

119.5

C5-C6-O11

120.0

115.4

115.7

C7-C6-O11

120.0

125.1

124.8

C6-C7-C8

120.0

120.5

120.5

C7-C8-C9

120.0

120.0

120.0

C8-C9-C10

120.0

120.1

120.0

C5-C10-C9

120.0

120.5

120.5

C6-O11-C12

120.0

117.9

118.2

N1-C13-C14

109.5

110.2

112.5

C13-C14-C15

109.5

114.5

114.4

C13-C14-C16

109.4

107.6

105.7

C15-C14-C16

-

107.4

108.0

C14-C15-O17

109.5

110.6

108.8

C15-O17-C23

120.0

118.5

119.0

C19-N18-C30

111.1

109.8

109.8

N18-C19-C20

130.2

129.0

129.3

N18-C19-C24

107.0

108.3

108.2

C20-C19-C24

122.8

122.7

122.5

C19-C20-C21

117.6

116.9

117.0

C20-C21-C22

121.0

122.1

122.1

C21-C22-C23

120.6

120.5

120.1

O17-C23-C22

120.3

124.4

124.7

O17-C23-C24

120.3

116.6

115.9

C22-C23-C24

119.5

118.9

119.4

C19-C24-C23

118.5

118.8

118.8

C19-C24-C25

107.4

106.9

107.2

C23-C24-C25

134.1

134.3

133.9

C24-C25-C26

134.1

134.6

134.5

C24-C25-C30

107.4

106.6

106.3

C26-C25-C30

118.5

118.8

119.2

C25-C26-C27

119.5

119.5

118.9

C25-C26-C53

120.3

119.8

120.4

C27-C26-C53

-

120.7

120.7

C26-C27-C28

120.6

120.6

121.0

C27-C28-C29

121.0

121.2

121.2

C28-C29-C30

117.6

117.7

117.6

N18-C30-C25

107.0

108.4

108.5

N18-C30-C29

130.2

129.6

129.5

C25-C30-C29

122.8

122.0

122.0

Table 2. Observed and calculated vibrational frequencies of carvedilol at B3LYP method with 6-31G(d,p) and 631++G(d,p) basis sets. Experimental B3LYP/631G(d,p)

DFT IR Intensity

B3LYP/631++G(d,p)

IR Intensity

FT-IR

FT-Raman

3851

-

3851

18.2

3831

34.8

γOH(100)

-

-

3686

60.8

3682

65.0

γNH(100)

3524 3398

-

3517 3251

8.9 4.1

3527 3229

19.8 7.2

γNH(100)

3344 -

-

3236 3227

11.3 0.7

3225 3222

0.3 16.8

γCH(94) γCH2(87) γCH2(95)

-

-

3223 3206

23.0 18.3

3219 3204

4.0 20.0

γCH2(89) γCH2(95)

-

-

3205 3202

27.5 28.9

3203 3202

23.6 21.3

γCH3(91) γCH2(86)

-

-

3193 3187

13.4 4.6

3190 3188

17.9 3.3

γCH2(94) γCH2(97)

-

-

3186 3182 3147

1.0 2.9 23.4

3186 3180 3148

1.6 0.6 21.3

-

-

3078 3077

96.2 3.2

3077 3076

71.5 1.1

γCH2(95) γCH3(99) γCH(92) γCH3(90) γCH2(85)

3060 -

3070 -

3071 3070

42.2 43.0

3073 3063

38.6 43.2

γCH2(100) γCH2(87)

-

-

3056 3019 3016

15.5 22.5 48.4

3057 3036 3011

11.9 17.1 62.3

γCH3(100) γCH(87) γCH2(90)

2995 2922 2877 2836 -

3001 2880 2835 -

3010 3006 2963 2952 1676

58.0 43.2 57.6 40.3 7.2

3007 3006 2960 2933 1666

45.5 66.7 70.6 64.2 15.1

γCH4(92) γCH(87) γCH(96) γCH(97) γCC2(44)

-

-

1660 1650

78.3 4.3

1652 1640

77.6 6.1

γCC3(39) γCC(39)+δ(CCC)2(21)

1629

1629

1649 1635

68.7 55.1

1636 1628

75.5 68.7

γ(CC)4(70) γ(CC)2(34)

1590

1583

1628 1559

15.3 149.4

1618 1549

14.5 163.5

γ(CC)2(29) δ(CC)2(35)

-

-

1552 1538

67.4 12.7

1544 1528

58.6 6.3

δ(CC)2(23)+δ(HCC)4(26) δ(HCH)3(83)

-

-

1533 1528 1524 1521

5.3 45.0 7.0 39.2

1524 1521 1516 1513

3.7 34.3 16.3 32.9

-

-

1520 1512

39.2 20.1

1509 1505

40.8 6.8

γ(CC)2(26)+δ(HCC)(16) δ(HCH3)(74) δHNC(22)+δ(HCH)2(47) δHNC(29)+δ(HCH)2(28) δ(HCH)3(79)+τHCOC(10) δ(HCH)2(70)

1503

1497

1505

4.9

1495

7.3

δ(HCH)2(77)+τHCOC(15)

Vibrational Band Assignment PED(%)

-

-

1501

27.2

1491

37.1

δ(HCC)2(40)

-

-

1497 1482

48.9 18.9

1490 1472

28.1 11.1

γCC(11)+δ(HCC)2(34)+δHCH(10) δHCC(12)+δ(HCH)3(53)

1454 1403 1383

1451 -

1476 1466 1446 1439 1418 1391 1386

55.2 20.9 3.3 15.4 3.0 43.6 35.5

1471 1452 1437 1429 1415 1389 1379

65.2 15.6 3.8 12.7 1.3 45.2 31.7

δ(HCC)2(34) τHCNC(10) + σCCCH(10) δHNC(11) σCCCH(14) δHCC(33)+τHCOC(15) γCC(12) γ(CC)2(32)

1347

-

1380 1375 1372

10.1 44.5 14.8

1373 1370 1350

0.4 55.4 0.6

1333 -

1337 -

1343 1335

2.8 28.4

1339 1329

2.3 53.6

1304 1284 -

1286 -

1321 1317 1315 1302 1297 1288 1267

23.2 22.6 8.2 205.2 42.3 144.8 321.4

1317 1314 1311 1298 1295 1287 1262

36.7 8.2 12.3 80.3 185.2 116.4 320.0

γ(CC)2(20)+τ(HCNC)2(20) γ(CC)2(26)+δHCC(13) δ HCC(26)+τHCOC(13)+σCCCH(25) τ(CNC)2(35) γNC(12) δ(HCC)2(47)

-

-

1261

3.3

1257

4.5

δ(CO)2(38)

-

-

1251

30.1

1246

42.7

δ(HCC)2(32)+δCCC(11)

-

-

1245 1237

67.1 52.8

1235 1228

18.9 49.3

δHNC(38)

-

1223

1222

12.7

1213

23.0

δHCC(10)+δHCO(21)+δHCN(15)

1215 -

-

1212 1201 1192 1185 1183

30.5 4.8 0.1 0.5 4.1

1204 1198 1188 1183 1178

32.1 4.8 1.6 10.5 6.3

1177 -

1162

1179 1164

0.7 68.7

1170 1160

1.0 71.3

δHCH(17)+γ(HCOC)2(60) δ(HCC)3(45) γCC(10)+δ(HCC)2(65) γNC(10)+δHCO(18) γCC(11)+δ(HCC)3(63) δ(HCH)2(27)+τ(HCOC)3(72) γ(NC)2(77)

1156 -

-

1155 1140

84.3 7.5

1150 1137

94.6 6.7

γ(CC)2(32)+δ(HCC)2(24) γ(CC)2(32)+δ(HCC)2(30)

1120 -

-

1130 1125 1110

125.2 87.1 54.8

1125 1112 1107

172.2 6.6 21.3

-

1105 -

1106 1103 1088 1074 1069

3.4 40.0 13.4 5.4 8.2

1098 1088 1081 1068 1060

8.6 78.5 8.0 25.5 47.5

1045

1058 -

1067 1046

84.2 4.9

1058 1042

49.7 3.1

γOC(29)+δHCC(12) γCC(30)+δOCC(10) γCC(22)+δHCN(14) δ(HCC)2(32)+δCCN(13) γCC(30)+γNC(16)+γOC(12) γCC(18)+γ(OC)2(35)+δHCC(10) γ(CC)2(22)+γOC(32) γOC(32) γ(OC)2(24)

1022 1001

1012

1036 1017 1012

28.0 2.1 12.8

1036 1015 1005

53.2 4.2 22.5

δHCC(27) γCC(13)+γNC(10)+δHCC(12) δHCN(15) γCC(10)+γOC(13) γNC(16)+γOC(20)+δHCC(14) γ(CC)2(32)

δ(HOC)2(56)+σCCCH(15)

γCC(27)+δ(HCC)2(25) γ(NC)2(39)+γ(OC)2(24) δ(CCC)2(33) γCC(11)+γOC(39)

980

-

989

1.1

986

0.1

τ(HCCC)3(83)

957 -

955 -

956 944 940

0.0 0.6 1.2

963 953 949

0.0 0.1 1.5

-

-

934 929

0.4 21.3

933 921

2.8 17.2

τ(HCCC)2(65)+τCCCC(20) τ(HCCC)3(74)+τCCCN(11) τ(HCCC)2(55)+τHCCN(20)+τCCCC(15) δHCC(97)+τ(HCNC)2(33)+τ(HCOC)2(29) γ(CC)2(47)

914 -

916 -

905 881

5.1 1.2

914 877

5.1 0.5

τ(HCCC)4(87) δ(CCC)2(46)

870 -

869 -

869 856

2.5 5.1

865 853

0.9 2.0

τ(HCCC)2(35)+τHCCN(40) τ(HCCC)2(30)+δCCC(35)

850 -

-

844 837

7.5 0.0

844 844

2.7 6.9

γOC(10)+δCCC(14)+γ(HCCC)4(68) γOC(10)+δCCC(14)+γ(HCCC)4(68)

783 747

766 -

836 821 810 790 790 768 762 753

8.2 47.1 7.2 29.5 15.1 55.3 5.1 62.6

837 816 806 798 785 765 756 750

7.2 51.2 21.6 13.2 27.5 67.5 16.8 76.4

728 720

725 -

733 729 716

9.5 28.2 0.0

745 732 729

1.0 21.9 61.3

δ(HCCC)2(20)+τHCNC(11)+τHCOC(12) τHNCC(41) δCCC(29) τCCCC(11)+τCCNC(13)+σOCCC(15) γOC(16)+δCCC(35) τHCCC(10)+τCCCC(25) τ(HCCC)3(54)+τHCCN(19) τ(HCCC)4(90) τHCCC(10)+τ(CCCC)3(62)+σOCCC(16) δCCC(15) τ(HCCC)2(30)

654 633 620 580 -

-

665 631 618 612 594 586 583 574 561 557

1.1 6.4 7.1 4.7 2.6 1.3 1.9 0.0 0.2 3.6

663 630 619 610 593 585 584 575 561 554

1.1 5.3 7.9 4.5 2.7 1.5 1.2 0.0 0.2 0.7

537 507 473 -

543 468 424 -

542 510 486 474 450 445 427 411 397 367 325

4.6 14.0 3.3 0.0 4.6 3.7 1.4 3.4 5.4 75.4 0.2

544 512 477 476 461 446 433 397 392 353 322

5.9 6.5 3.5 1.8 4.4 7.3 2.7 0.2 5.3 58.4 1.5

-

-

322 317 307 292

1.8 8.5 12.9 7.7

317 315 305 290

0.1 4.4 3.2 9.8

δCC(18)+δ(CCC)2(30)+δCNC(11) τHCCC(10)+σOCCC(34)+σCNCC(18) δCCC(13) δCCO(17)+δCCC(26) δ(COC)2(21)+δOCC(20) δCCC(23)+δCCO(17)+δCCC(24) τHCCC(11)+τ(CCCC)2(31)+σCCCC(16) τHCCC(10)+τCCCC(29)+τCCCO(19)+σOCCC(17) δCCC(23)+δCCO(19) δCCC(10)+δCCN(30) σ(CC)2(10)+δ(HCC)2(20)+τCCCN(12)+τCCNC(14) σOCCC(20) δCNC(14)+δOCC(19) τCCCC(33)+σOCCC(25) δCCC(29) τ(CCCC)2(48)+σNCCC(21) γCC(10)+γNC(10 ) δOCC(11)+δCCC(17) δ(COC)2(29)+δOCC(10) δOCC(11)+δCCC(17)+δCCC(29) τCCCN(11)+σCNCC(12) δ(HCC)2(47)+τHCOC(10)+τCCCC(29)+τCCCO(27)+σOCCC(12) δCCC(29) δCOC(28) τHNCC(16)+τCCCC(15)+τ(CCNC)2(36)+σCCCC(12)

-

-

263 260 249

83.4 4.7 24.3

251 249 242

0.7 56.2 49.8

τ(HCOC)3(56)+τCCCO(17) τHOCC(46) τHOCC(43)

238 0.8 230 4.4 197 2.3 187 0.6 180 1.3 174 2.2 162 0.3 146 1.7 129 3.9 122 4.1 104 3.5 97 0.7 92 5.6 69 0.3 49 1.3 43 0.7 37 0.1 17 0.1 14 0.1 -stretching; δ-bending; τ-torsion. σ-Out of plane bending

237 227 186 184 181 175 152 137 130 118 103 90 87 66 55 43 33 16 13

1.2 13.2 13.0 0.7 1.7 0.4 2.7 5.4 1.2 1.5 5.6 1.2 4.0 0.3 0.4 0.4 0.4 0.0 0.1

τCCC(35) δCOC(15) τNCCC(22)+τOCCN(11) τCCCC(25)+τOCCN(25) δCOC(15)+δCNC(12) δCCO(11) τCCCC(10 )+τCNCC(11)+τCCCO(14)+τCOCC(14) τ(CC)2(32)+τHCC(14)+τCNCC(22)+τOCCN(13) τCCOC(14) τCCOC(25)+τNCC(23)+τCCCO(14) τCNCC(15)+σNCCC(18) τCOCC(15)+τCCCO(11) τCOCC(59) δOCC(16)+δCOC(15)+δCCO(10) δCOC(11)+δCCO(11)+τCOCC(13)+δCCOC(16) δCOC(15)+δCCN(17)+δOCC(17)+δHOCC(43)+δCOCC(14) τ(COCC)2(33)+τCCOC(33) τCCCO(23) τCOCC(10)+τNCCC(17)+τCCNC(23)+τOCCN(12)

Table 3 Natural atomic charges of carvedilol by B3LYP/6-31++G(d,p) method Atom with numbering N1 C2 C3 O4 C5 C6 C7 C8 C9 C10 O11 C12 C13 C14 C15 O16 O17 N18 C19 C20 C21 C22 C23 C24 C25 C26 C27 C28 C29 C30 H31 H32 H33 H35 H34 H36 H37

Charge -0.7309 -0.1657 -0.0300 -0.5374 0.2844 0.2801 -0.2647 -0.2253 -0.2158 -0.2740 -0.5326 -0.2076 -0.1789 0.1087 -0.0175 -0.7553 -0.5598 -0.5509 0.1855 -0.2687 -0.1857 -0.2644 0.3527 -0.1470 -0.0954 -0.1294 -0.2101 -0.2010 -0.2359 0.1730 0.3776 0.1766 0.1808 0.1704 0.1755 0.2133 0.2047

H38 H39 H40 H41 H42 H43 H44 H45 H46 H47 H48 H49 H50 H51 H52 H53 H54 H55 H56

0.2051 0.2158 0.1951 0.1679 0.1681 0.1920 0.1715 0.1756 0.1655 0.1151 0.4719 0.4055 0.2091 0.2082 0.2173 0.1931 0.2072 0.2065 0.2102

Table 4 Second order petrurbation theory analysis of Fock matrix in NBO basis of carvedilol studied with B3LYP/631++ basis set

Donor (i) π π σ σ π π σ π σ π

C5 - C10 C6 - C7 C7 - C8 C9 - C10 C19 - C24 C20 - C21 C21 - C22 C22 - C23 C23 - C24 C25 - C30

Acceptor(j) π* π* σ* σ* π* π* σ* π* σ* π*

C8 - C 9 C 8 - C9 C6 - O11 O4 - C5 C20 - C21 C22 - C23 O17 - C23 C20 - C21 C24 - C25 C19 - C24

E (2 )(Kcal/mol)a

(Ej-Ei)b a.u

F(I,j)c a.u

231.72 207.8 4.83 4.86 16.77 15.26 5.1 21.69 5.17 18.49

0.01 0.01 1.03 1.03 0.27 0.27 1.01 0.29 1.23 0.26

0.079 0.079 0.063 0.063 0.061 0.059 0.064 0.072 0.071 0.064

π π π π

C25 - C30 C26 - C27 C26 - C27 C28 - C29

π* π* π* π*

LP(1) LP(1)

N1 N1

LP(1)

C26 - C27 C25 - C30 C28 - C29 C25 - C30

261.61 17.89 21.66 20.94

0.01 0.27 0.27 0.27

0.081 0.065 0.069 0.071

σ* C13 - H43 σ* C13 - H44

1.36 8.32

0.72 0.69

0.028 0.068

O4

σ* C5 - C10

6.82

1.09

0.077

LP(2) LP(2)

O4 O4

σ* C3 - H34 π* C5 - C10

5.18 31.4

0.72 0.33

0.057 0.096

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

O16 O16 O17 N18

σ* σ* π* π*

3.12 7.42 29.94 36.99

0.75 0.66 0.34 0.29

0.043 0.062 0.096 0.095

C14 - H45 C14 - C15 C22 - C23 C19 - C24

Table 5 Calculated first order hyperpolarizability β0 (x 10−30 esu) values for carvedilol by B3LYP/6-31++G(d,p) Parameters βxxx βxxy βxyy βyyy βxxz βxyz βyyz βxzz βyzz βzzz β0

B3LYP 127.667 -126.273 -73.454 -353.944 43.795 92.841 6.152 27.025 -23.19 -11.266 4.417 x 10-30 esu

Table 6 Experimental and calculated absorption wavelength(λmax), excitation energies(E), singlet A, oscillator strength(f), Assignment and Transition of carvedilol by TD- DFT method Singlet A

Excited state-1 106 ->109 106 ->112 107 ->109 Excited state-2

0.15733 -0.22923 0.62734

4.0478

306.3

0.70300

4.1881 238.6 296.0

108 ->109 Excited state-3 106 ->109 107 ->109 107 ->112

0.57703 -0.14168 0.30263

E(eV)

Wavelength(nm) Exp Calc

Excitation

-

Oscillator Strength(f)

4.4577 203.6 278.1

Assignment

Transition

0.0640

π→π *

H-2->L+3 (11%) H-1->LUMO (79%) H-2->LUMO (5%)

0.0006

n→π *

HOMO->LUMO (99%)

n→ *

H-2->LUMO (67%) H-1->L+3 (18%) H-1->LUMO (4%)

0.1183

Table 7 Thermodynamic properties for carvedilol obtained by B3LYP/6-31++G (d,p) density functional calculations Entropy(S) Temperature(K) (J/mol.K) 100 470.87 200 641.43 298.15 792.97 300 795.77 400 945.32 500 1089.83 600 1227.43 700 1357.19 800 1479.07 900 1593.49 1000 1701.02

Heat Capacity (Cp) (J/mol.K) 189.46 317.46 451.96 454.55 589.51 706.53 802.46 880.45 944.51 997.86 1042.79

Enthalpy(∆H) (kJ/mol) 11.66 36.99 74.68 75.52 127.83 192.81 268.42 352.7 444.05 541.25 643.34

Table 8 Carvedilol stored at different conditions

Absorbance at Wavelength( nm) 268 284 298 332

Storage condition Ideal 0.577 0.916 0.138 0.382

Sunlight 0.628 0.994 0.156 0.42

Ice point 0.597 0.954 0.142 0.4

IR Radiation 0.62 0.985 0.151 0.415

Hot Air Oven 0.605 0.958 0.145 0.403

GRAPHICAL ABSTRACT

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HIGHLIGHTS

► FT-IR, FT-Raman and UV-Vis spectra of carvedilol was examined. ► The optimized geometry and vibrational wavenumbers were computed using DFT methods. ► HOMO – LUMO and MEP analysis were made. ► Topological charge distribution explained the intramolecular hydrogen bonding.

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