Research, Volume: 20( 3)
SPECTROSCOPIC STUDIES OF -3-FURAN-2-YL-4-PHENYL-BUTYRIC ACID COMPOUND DFT METHOD (FT-IR AND FT-RAMAN), NBO ANALYSIS, HOMO-LUMO, FIRST ORDER HYPERPOLARIZABILITY, AND DOCKING STUDIES
- P Chakkaravarthy
Department of Chemistry,
Government Thirumagal Mills College Gudiyattam,
Received: June 23, 2022, Manuscript No. tsijcs-22-67457; Editor assigned: June 27, 2022, PreQC No. tsijcs-22-67457; Reviewed: July 11, 2022, QC No. tsijcs-22-67457; Revised: August 22, 2022, Manuscript No. tsijcs-22-67457; Published: August 29, 2022, DOI:10.37532/0972-768X.22.20.430
Citation: P Chakkaravarthy. Spectroscopic Studies of 3-Furan-2-yl-4-Phenyl-Butyric Acid Compound DFT Method (FTIR and FTRaman), NBO Analysis, Homo-Lumo, First Order Hyper polarizability and Docking Studies. Int J Chem Sci. 2022;20(3):430
The goal of this research is to characterize 3-furan-2-yl-4-phenyl-butyric acid. The molecule was created using quantum chemistry and vibrational spectrum techniques. The ideal molecular geometry (bond length, bond angle), whole vibrational frequency, infrared intensities, and Raman scattering activities were determined using the Density Functional Theory (DFT) B3LYP approach with the 6- 311++G (d, p) basis set. The estimated HOMO-LUMO band gap energies confirm charge transport within the molecule. The hyper conjugative interaction energy E (2) and the electron densities of donor I and acceptor (j) bonds were calculated using NBO analysis. Other factors were calculated and analyzed in addition to NLO and MEP. Molecular docking was performed to determine the hydrogen bond lengths and binding energy with numerous different molecules to study the investigation molecule's biological activities.
Hyper conjugative interaction, Density functional theory, HOMO-LUMO band gap
The vibrational spectroscopic studies of anti-inflammatory molecule 3-furan-2-yl-4-phenyl-butyric acid with the help of DFT method. It is used to fever, stiffness, swelling and relieve pain. The title molecule is soluble in water and sparingly insoluble in alcohol.
An extensive literature survey conducted reveals that a great deal of research has been done on aryl propionic acids and its substituted derivatives. Structure characterization investigation of ketoprofen, a propanoic acid derivative by combined quantum chemical calculations and spectroscopic analysis was done by ML Vueba . Various other properties of propionic acids and its substituted derivatives have also been studied to state its uses in biological field. Photo degradation mechanism of Non-steroidal anti-inflammatory drugs containing Thiophene moieties: Suprofen and Tiaprofenic Acid by Klefah AK Musa is one such work . Molecular mobility of ibuprofen and ketoprofen was evaluated with respect to the different inter molecular linear/cyclic hydrogen bonding associations by MT Ottou Abe .
Quantum chemical computational techniques have proved to be an indispensable tool for deducing and predicting the vibrational spectra [4,5]. Sophisticated electron correlation and density functional theory calculations are increasingly available and deliver force field of high precision even for large polyatomic molecules [6,7]. Neither the complete spectroscopy analysis nor the quantum chemical calculations for the title compound have been reported so far on the basis of the literature survey done. The objective of the present study is to give a complete account of the molecular geometry and vibrations of the title molecule. For that purpose, quantum chemical computations were carried out to study conformational stability analysis, molecular structure and FT-IR spectral investigation of 3-furan-2-yl-4-phenyl-butyric acid using Density Functional Theory (DFT). Vibrational spectra have been analyzed on the basis of calculated Potential Energy Distribution (PED). Mean polarizability, dipole moment and first order hyperpolarisability have been investigated by ad initio DFT methods. In addition to this, ab initio and density functional theory calculations using 6-311++G (d, p) basis set were used to determine the HOMO-LUMO energy.
Materials and Methods
The title compound in the solid state was procured from Sigma Aldrich chemical company with a stated purity 98% and it was used without further purification. The FT-IR spectrum was recorded in the region 4000–450 cm-1 with the sample in the KBr pellet, using Perkin Elmer FT-IR spectrometer. The resolution of the spectrum is 4 cm-1. The FT-Raman spectrum was obtained in the range 4000–100 cm-1 using Bruker RFS 100/S FT-Raman spectrophotometer with a 1064 nm Nd: YAG laser source of 100 mW power. All the experimental spectral data (FT-IR, FT-Raman) collected from SAIF, IIT, Chennai, India.
The spectroscopic analysis and the quantum chemical calculations which comprises of the optimized structure of the title compound, corresponding energy and vibrational harmonic frequencies were calculated by using DFT (B3LYP) with 6-311++G (d,p) basis set using GAUSSIAN 03W program package . 6-311++G is a split-valence triple-zeta basis and adds one Gaussian Type Orbitals (GTO) to 6-31G that uses three sets of contracted functions for each valence orbital type [9,10]. The geometric structure as well as parameters, namely bond angle and bond length were obtained from CHEMCRAFT software.
Vibrational frequencies are scaled 0.9461 for B3LYP/6-311++G (d,p). The symmetry considerations and the vibrational assignments are made with a high degree of accuracy using the Vibrational Energy Distribution Analysis (VEDA) software . The GABEDIT software and ORIGIN6.1 software were used to generate the theoretical and experimental IR and RAMAN spectrum and the spectra were compared. The hyperpolarisability for the title molecule was also calculated at B3LYP level using the basis set 6-311++G (d,p) Polar = enonly. By using the Gaussian 03W output the thermodynamical variables were found out using THERMO.PL . The correlation graphs of the thermodynamical variables (entropy, enthalpy and heat capacity) vs. temperature were plotted for the title compound. The Molecular Electrostatic Potential (MEP) was also calculated using Gauss View. The Natural Bond Orbital (NBO) was calculated of the title molecule at B3LYP level using the basis set 6-311++ G (d,p) POP=NBO test. This analysis is done to give clear evidence of stabilization originating from hyper conjugation of various intra molecular interactions [13-15]. The Raman activities (Si), calculated with the GAUSSIAN 03W program, were subsequently converted to relative Raman intensities (Ii) using the following relationship derived from the theory of Raman scattering using raint program [16,17].
Where υ0 is the laser excitation frequency in cm−1 (in this work, the excitation wave number, υ0=9398.5 cm-1, which corresponds to the wavelength of 1064 nm of a Nd: YAG laser, υi is the vibrational wavenumber of the ith normal mode in cm−1, h, kbc and T are the fundamental constants Planck constant, Boltzmann constant, speed of light and temperature in Kelvin, respectively.
Results and Discussion
The optimized structure parameters of the title compound were calculated at B3LYP levels and are recorded in (Table 1). In accordance with the atom numbering scheme as obtained from CHEMCRAFT software and represented in (Figure 1). This molecule has fourteen C-C bond lengths, four C-O bond lengths, thirteen C-H bond lengths and one O-H bond length. The molecular geometry in the gas phase may differ from the solid phase, owing to the extended hydrogen bonding and staking interactions. From theoretical values, any variation in the optimized bond lengths is because the theoretical values belong to the isolated molecules in gas phase and the experimental values belong to the molecules in solid state . It is observed that the calculated C-C bond lengths and the O-C bond lengths are found to be nearly identical at all calculation levels. The average value of the bond distances of C-C and C-H in the benzene ring calculated by density functional theory method with same basis sets are 1.529 A and 1.098 A, respectively. Inclusion of OH and CH atoms brings a strong electron withdrawing nature to the compound and thus is expected to contribute to the formation of a resonance structure. This is the reason for the shortening of bond lengths O2-H31=0.981 Å and C9-H23=1.08 Å obtained by DFT method compared to other bond lengths like C4-C5=1.535 Å. In this title molecule the bond angle C7-O1-C14= 104.3° is smaller than the other bond angle C16-C17-H30=120° calculated.
bond length (Å)
bond angle (0)
TABLE 1. Optimized geometrical parameters of 3-Furan-2-yl-4-Phenyl-Butyric Acid (2F4PBA).
Figure 1: Optimized geometric structure with atom numbering of 3-Furan-2-yl-4-Phenyl-Butyric Acid (2F4PBA).
Donor acceptor interactions
In quantum chemistry, a calculated bonding orbital with maximum electron density forms a natural bond orbital or NBO. In computational chemistry the localized orbitals are used to calculate the distribution of electron density in atoms and in bonds between atoms. The details obtained about the interactions in both filled and virtual orbital space can complement the study of both inter and intra molecular interactions, which is the basis of studying NBO. That is why NBO analysis is proved to be an important tool for chemical analysis of hyper conjugative interaction and electron density transfer from filled lone electron pairs of the Lewis base (an electron pair donor) Y into the unfilled anti bond σ* (X-H) of the Lewis acid (an electron pair acceptor) X- in X-Y….Y hydrogen bonding systems . The magnitude of energy of hyper conjugative interactions, E (2) forms the basis of studying the strength of the interaction between electron donors and electron acceptors, or the donating affinity from electron donors to acceptors and hence the degree of conjugation of the entire system. The second-order Fock matrix was done to evaluate the donor–acceptor interactions in NBO analysis . The interactions cause loss of occupancy from the localized natural bond orbitals of the idealized Lewis structure into an empty non-Lewis orbital. For each donor (i) and acceptor (j), the stabilization energy E (2) related with the delocalization i → j is estimated as
Where qi is the donor orbital occupancy
εj and εi are diagonal elements
Fij is the off diagonal NBO Fock matrix element.
Delocalization of electron density between occupied Lewis type (lone or bond pair) natural bonding orbitals and previously unoccupied non Lewis (anti bond or Rydberg) natural bonding orbitals correspond to a stabilizing donor–acceptor interaction. In order to interpret the intermolecular hydrogen bonding, Intermolecular Charge Transfer (ICT) and delocalization of electron density, NBO analysis was performed on the title molecule using B3LYP/6-311++G (d,p) Pop=NBO test basis set and the corresponding results are presented in Table 2. Intensity of the interaction between electron donors and electron acceptors is directly dependent on E (2) value, i.e. more the donating tendency from electron donors to electron acceptors, greater is the extent of conjugation of the whole system. The intra-molecular interaction is formed by the orbital overlap between σ(C-C) and σ*(C-C) bond orbital which results in Intra-molecular Charge Transfer (ICT) causing stabilization of the system. These interactions are observed as increase in Electron Density (ED) in C-C, C-H, C-O and O-H anti-bonding orbital that weakens the respective bonds. NBO analysis was performed on the molecule at the DFT/B3LYP6-31++G (d,p) level in order to explicate the delocalization of electron density within the molecule. The delocalization of σ electron from σ (C1-C2) distribute to anti-bonding σ* (C2-C3), σ * (C3-C14), σ* (O6-H23) leading to the stabilization energy of 0.84 kJ/mol, 1.99 kJ/mol, 2.95 kJ/mol, respectively due to conjugative interactions.
A strong interaction has been observed due to the electron density transfer from the Lone Pair (LP) (1) of Oxygen atom (O5) to anti-bonding orbital σ*(C1-C6) with a large stabilization energy of 32.76 kJ/mol. In the case of LP (1) of Oxygen atom (O13) to the anti-bonding acceptor σ*(C14-C15) and σ*(C16-C17) has low stabilization energy of 5.82 kJ/mol and 6.67 kJ/mol respectively as shown in Table 2. The interaction energy, related to resonance in the molecule, is electron withdrawing from the ring through π* (C16-C17) of the NBO conjugated with π*(C14-C15) resulting with large stabilization energy of 86.64 kJ/mol. Similarly, π* (C16-C17) of the NBO conjugated with π*(C14-C15) resulting with l stabilization energy of 22.916 kJ/mol. Therefore, the maximum energy delocalization takes place in the π*-π* transition (Table 2).
TABLE 2. Second order perturbation theory analysis of Fock matrix in NBO basis of 3-Furan-2-yl-4-Phenyl-Butyric Acid (2F4PBA).
Vibrational spectral analysis
The title molecule consists of 31 atoms, so it has 3N-6 i.e. 87 modes of vibration. The Vibrational frequencies are scaled 0.9642 for B3LYP/6-311++G (d,p) in order to compensate for the errors arising from the basis set incompleteness and neglect the vibrational anharmonicity. The vibrational assignments were made using the VEDA software. For the IR and Raman spectrum plots Lorentzian band is used. Figure 2 and 3 shows comparative representations of theoretically spectra at B3LYP level of theory along with experimental spectra. The calculated wavenumber, Raman activities, IR intensities are represented in Table 3. Plotting a correlation graph between the scaled frequency and the IR and Raman frequencies represented in Figure 4 shows a corresponding fitting factor of 0.9987 and 0.9998 respectively (Table 3).
|Sl. No||Frequency (cm-1)||Intensity||dAssignments (PED ≥ 10%)|
|4||3192 (vvw)||3068 (m)||3261||3134||5||1||177||53||υCH (53)|
|7||-||3042 (vw)||3185||3061||7||2||62||19||υCH (98)|
|10||3000 (vw)||3004 (w)||3131||3009||6||2||35||10||υCH (97)|
|11||2973 (vw)||2978 (w)||3081||2961||17||4||70||21||υCH (50)|
|12||2938 (vw)||2940 (m)||3067||2947||2||1||161||48||υCH (58)|
|13||-||2908 (vw)||3063||2944||6||1||88||26||υCH (87)|
|14||2843 (m)||2884 (vw)||3036||2918||23||6||161||48||υCH (93)|
|15||1786 (s)||1726 (vw)||1813||1742||381||100||21||6||υOC (60)|
|16||1603 (vvw)||1629 (m)||1654||1589||7||2||21||6||υOC (11)+υCC (34)|
|19||1481 (m)||1487 (w)||1541||1481||16||4||14||4||υCC(28)+βHCC(13)|
|20||1454 (w)||1455 (vw)||1533||1474||11||3||5||2||βHCH(60)|
|25||-||1419 (w)||1386||1332||11||3||12||4||β HCH(53)|
|26||1417 (m)||1391 (vs)||1377||1323||7||2||42||13||υCC(20)+βHCC(28)|
|31||1302 (s)||1295 (vw)||1294||1244||3||1||4||1||βHCC(34)+τHCCO(22)|
|32||1264 (w)||1266 (vw)||1266||1217||2||1||4||1||βHOC(12)+τHCCO(19)|
|37||1175 (vvw)||1174 (w)||1194||1147||17||4||10||3||βHCC(17)+τHCOC(30)|
|43||1089 (w)||1092 (vw)||1071||1029||10||3||20||6||βCCC(13)|
|44||1071 (w)||1071 (vw)||1053||1012||4||1||1||0||υCC(14)|
|49||963 (s)||961 (w)||989||951||15||4||1||0||τHCCC(57)|
|51||894 (w)||895 (w)||934||898||7||2||2||1||βCCC(27)|
|56||793 (w)||793 (w)||872||838||0||0||20||6||τHCCC(21)+ωOCOC(23)|
|59||741 (s)||741 (m)||810||778||19||5||0||0||υCC(11)|
|62||641 (m)||643 (vw)||732||703||27||7||1||0||τHCCC(11)+τCCCC(25)+ωCCCC(15)|
|67||527 (vs)||523 (w)||610||586||17||5||1||0||τCCCC(15)+ωCCCC(14)|
|83||-||117 (m)||60||57||0||0||0||0||βCCC(27)+τ CCCC(13)+ωCCCC(14)|
a scaling factor: 0.962 for B3LYP/6-311++G(d,p).
b Relative absorption intensities normalized with highest peak absorption equal to 100.
cRelative Raman intensities normalized to 100.
υ-stretching, β- in plane bending, ω- out plane bending, τ- torsion, vvw- very very weak, vw- very weak,
w-weak, m-medium, s-strong, vs-very strong
TABLE 3. Observed and calculated vibrational frequency of 3-furan-2-yl-4-phenyl-butyric acid.at B3LYP method with 6-311++G(d,p) basis set.
Figure 2: FT-Raman spectra of (+)-(S)-2-(6-methoxynaphthalen-2-yl) propanoic acid using DFT/6-311++G (d,p) and experimental data.
Figure 3: FT-IR spectra of 3-furan-2-yl-4-phenyl-butyric acid using DFT/6-311++G (d,p) and experimental data.
Figure 4: Correlation graph representing scaled, IR and Raman frequencies of 3-furan-2-yl-4-phenyl-butyric acid.
O-H vibrations: The Oxygen-Hydrogen stretching vibrations are expected in the region 3300-3500 cm-1. These bands are stronger and broader than those of the amine N–H stretches which appear in the same region. For the 3-furan-2-yl-4-phenyl-butyric acid. Observed at 3753 cm-1 by B3LYP/6-311++G (d,p) method. This pure mode shows 100% PED contribution.
C-H vibrations: The aromatic compounds and its derivatives show C-H stretching vibrations generally in the region above 3000 cm-1 for the benzene and less than 3000 cm-1 for non-aromatic compounds. In the experimental frequency, C-H stretching vibrations were observed at 3067 cm-1 to 2882 cm-1 in FT-Raman spectrum and 3180-2852 in the FT-IR spectra. The peak corresponding to C-H stretching vibration at the range 3170.-2918 cm-1 by theoretical method shows excellent agreement with experimental spectral values. The PED corresponding to this vibration contributes to 87-98%.
C-C vibrations: The aromatic ring modes are influenced more by C-C bands. The ring stretching vibrations (C-C) are expected within the region 1300-1000 cm-1. In the present study, the bands which are of different intensities were observed at 1608, 1509, 1489, 1419, 1356, 1079 and 1037 cm-1 in FT-IR spectrum and Raman bands were identified at 1629, 1579, 1488, 1391, 1199 1127, 1078 and 1014 cm-1. The theoretical values were obtained in the range of 1654-1012 cm-1 by B3LYP/6-311++G (d,p) method. It shows that the theoretical values are in good agreement with experimental data.
O-C Vibrations: The Oxygen-Carbon stretching modes generally exist in the region 1300-1000 cm-1. The theoretical Oxygen-Carbon stretching vibrations were calculated at1050, 1030, 1015 and 739 cm-1.
Experimental bands observed at 1789, 1608 and 1037 cm-1 in FT-IR and at 1728, 1629 and 1014 cm-1 in FT Raman.
Molecular Electrostatic Potential (MEP)
The force acting on a proton located at a point through the electrical charge cloud generated through the molecules electrons and nuclei provides the Molecular Electrostatic Potential (MEP) at a given point p(x,y,z) in the vicinity of a molecule. Although the molecular charge distribution remains unperturbed through the external test charge as no polarization occurs, the electrostatic potential of a molecule is a good tool in evaluating the reactivity of a molecule towards positively or negatively charged reactants. The MEP is characteristically pictured through mapping its values onto the surface reflecting the molecules boundaries. Electrostatic potential correlates with dipole moment, electro negativity and partial charges. Molecular electrostatic potential maps elucidate information about the charge distribution of a molecule, relative polarity and electrostatic potential properties of the nucleus and nature of electrostatic potential energy.
MEP is associated to the electronic density and is an expedient descriptor in understanding sites for electrophilic and nucleophilic reactions as well as hydrogen bonding interactions. MEP was calculated at the B3LYP/6-311++G (d,p) optimized geometry. A portion of a molecule that has a negative electrostatic potential is vulnerable to an electrophilic attack greater the negativity, the better. In MEP, maximum negative region represents the site for electrophilic attack indicated by red color while the maximum positive region represents nucleophilic attack indicated in blue color. While regions with the negative potential are over the electronegative Oxygen atom, the regions with the positive potential are over the hydrogen atoms. Potential increases in the order red<orange<yellow<green<blue Figure 5 provides a visual method to understand the relative polarity of the title molecule.
HOMO and LUMO analysis
The concept of HOMO and LUMO are of fundamental importance as it forms the basis of understating the chemical stability and reactivity of a given molecule. On the basis of chemical hardness, molecules can be classified as hard and soft molecules. Large HOMO-LUMO gap indicates that the title molecule is a hard molecule and minor HOMO-LUMO gap indicates that it is a soft molecule. The molecular stability and hardness are related inversely, i.e. the molecule with the least HOMO-LUMO gap is more reactive. The Ionization Potential (IP) is determined from the energy difference between the energy of the compound derived from electron transfer (Ecation-energy of radical cation) and the respective neutral compound (En) (Figure 6 and Table 4).
|Energy gap (eV)||12.39324|
TABLE 4. Calculated energy values of the 3-Furan-2-yl-4-Phenyl-ButyricAcid (2F4PBA).
Figure 6: Atomic orbital HOMO-LUMO composition of the frontier molecular orbital of 3-Furan-2-yl-4-Phenyl-Butyric Acid (2F4PBA).
The Electron Affinity (EA) is computed from the energy difference between the neutral molecule (En) and the anion molecule (Eanion)
The minimum energy required to promote an electron is given by the energy difference between the orbitals (energy gap) and is therefore the most frequent and important energy transfer mechanism within a system. The orbitals provides information about the electron density which in turn is used in determining which part of the molecule is most actively participating in an energy transfer event.
The calculated quantum chemical parameters such as the Highest Occupied Molecular Orbital Energy (EHOMO), the Lowest Unoccupied Molecular Orbital Energy (ELUMO), energy gap (ΔE), Electronegativity (χ), chemical potential (μ), global hardness (η) and the softness (S) were calculated for the title molecule and tabulated in (Table 4). The concept of these parameters is related to each other, where
Chemical potential (μ) = ½ (ELUMO +EHOMO),
Electronegativity (χ) = −μ = - ½ (ELUMO +EHOMO),
Global hardness (η) = ½ (ELUMO- EHOMO),
Electrophilicity (ω) = μ2 / 2η.
The inverse values of the global hardness are designated as the softness(S), it is given by s Softness (s) = 1/η
The calculated value of electrophilicity index=3.283 describes the biological activity of title compound. Also the bigger the dipole moment, the stronger will be the intermolecular interactions. Correlations have been deduced between electrophilicity of several chemical compounds and reaction rates in biochemical systems and such phenomena as allergic contact dermatitis. The energy of the HOMO and the ionization potential are related and describes the susceptibility of the molecule toward electrophilic attack. The energy of LUMO is directly linked to the electron affinity and illustrates the susceptibility of the molecule toward attack of nucleophiles. The energy gap between HOMO and LUMO indicates molecular chemical stability. The mesh diagrams of HOMO and LUMO are given in Figure 6. The positive and negative phase is represented in red and blue colour respectively.
Nonlinear Optical effects (NLO)
The electron correlation can change the value of hyperpolarisability which is very sensitive to the basis sets and level of theoretical approach employed. The polarizability α, the hyper polarizability β and the electric dipole moment μ of title compound are calculated by finite field method using B3LYP/6-311++G (d,p) polar=enonly basis set. In the presence of an applied electric field, the energy of a system is a function of the electric field. Polarizability and hyperpolarisability illustrate the response of a system in an applied electric field. This determines the Non Linear Optical properties (NLO) of the system. First hyper polarizability is a third rank tensor that can be defined by 3 x 3 x 3 matrix. The 27 components of the 3D matrix can be reduced to 10 components due to the Klein man symmetry. It can be given in the lower tetrahedral format. It is obvious that the lower part of the 3 x 3 x 3 matrixes is a tetrahedral (Table 5). The components of β 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, this expansion becomes:
|Title||Enter Values||Title||Enter Values||Title||Enter Values|
|βxzz||55.4714412||α (e.s.u)||2.421 x 10-23|
|βzzz||44.6223981||Δα (e.s.u)||4.8427 x 10-23|
|βtot (e.s.u)||1.8085 x 10-30|
TABLE 5. The values of calculated dipole moment μ (D), polarizability (α) and first order hyperpolarisability (β) of 3-Furan-2-yl-4-Phenyl-ButyricAcid (2F4PBA).
E0 is the energy of the unperturbed molecules
Fα is the field at the origin
μα is the component of dipole moment, is the component of polarizability
βαβγ is the component of first hyper polarizability.
The total static dipole moment μ, the mean polarizability α0, the anisotropy of the polarizability Δα and the mean first hyperpolarisability β0, using the x, y, z components are defined as:
The values of polarizability α, hyper polarizability β and the electric dipole moment μ are given in Table 5. Urea being one of the exemplary molecules used in the study of the NLO properties of the molecular systems. It is often used as a threshold value for comparative purposes. The computed values of μ, α and β for the title molecule are 0.876 D, 2.739 x 10-23 esu and 1.0579 x 10-30 esu respectively. The total molecular dipole moment of the title molecule from B3LYP/6-311++G (d,p) basis set is 0.886 D which is less than that of urea (μ(D)=1.373 D).The first order hyper polarizability of the title molecule is 5 times than that of urea (βo= 0.373 x 10-30 esu). The B3LYP/6-311++G (d,p) calculated energy gap is E=12.3932eV which is lower than urea (ΔE=6.706 eV). These results indicate that the title compound may be a good candidate of NLO material and can also be considered to be an important class of compound in medical chemistry because if its high electrophilicity index (0.50791).
Mulliken charge distribution and Fukui function
The Mulliken Population Analysis (MPA) is calculated using the Natural Population Analysis of the title molecule (NPA) with B3LYP 6-311++G (d,p) method. The charge and multiplicity are varied in order to compare the variation in the Mulliken charges in each case.
Distribution of positive and negative charges is the important to increasing or decreasing of bond length between the atoms. In the present study, the optimized molecular geometry was employed in single-point energy calculations. The DFT calculations for the anions and cations were done using the ground state with double multiplicity. The individual atomic charges, calculated by MPA have been used to calculate the Fukui functions in Table 6 shows the fk and (sf)k values for the compound, using which one can find the complexities associated with fk values due to the negative values being removed in the (sf)k values.
The calculated Mulliken charge values of the title molecule are listed in Table 6. It can be observed graphically in Figure 7 that the carbon atom C-9 has most positive charge of 0.3910, 0.3870 where the charge and multiplicity are (0,1), (-1,2) and (1,2) respectively. The least positive value is that of H-26 is 0.1120. Similarly the maximum negative charge is that of the carbon atom C-17 with a value of -0.0600, -0.0700 and 0.0230. The least negative value is that of C-7 which is -0.6860.Three oxygen atoms have negative charges and all the hydrogen atoms have positive charges. The result suggests that the oxygen atoms acts as lone pair donor and the charge transfer takes place from O to C due to electron accepting substitutions at that position in the title molecule.
|Atom||Mulliken atomic charges||Fukui functions||Local softness|
|0,1 (N)||N +1 (-1, 2)||N-1 (1,2)||fr+||fr-||fr0||sr+ƒr+||sr-ƒr-||sr0 ƒr0|
TABLE 6. Mulliken charge distribution, Fukui function and local softness corresponding to (0,1), (-1,2) and (1,2) charge and multiplicity of- 3-furan-2-yl-4-phenyl-butyric acid (2F4PBA).
The electron density based local reactivity descriptors such as Fukui functions are proposed to clarify the chemical selectivity or reactivity at a particular site of a chemical system. Electron density is a property that contains all the evidence about the molecular system and plays an important role in calculating nearly all the chemical quantities proposed a finite difference approach to compute Fukui function indices i.e. nucleophilic, electrophilic and radical attacks (Table 6).
Fukui indices are reactivity indices that provide information about which atoms in a molecule have a greater tendency to either loose or accept an electron. This information plays a vital role in helping the chemists to interpret which atoms are more prone to undergoing a nucleophilic or an electrophilic attack. The functions are defined as
ρ(r)is the electronic density
N is the number of electrons and r is the external potential exerted by the nucleus.
The Fukui function is a local reactivity descriptor that indicates the ideal regions where a chemical species will change its density with the modification in the number of electrons. Therefore, it indicates the tendency of the electronic density to deform at a given position upon accepting or donating electrons also, it is possible to define the corresponding condensed or aromatic Fukui functions on the kth atom site as,
Where +, -, 0 signs show nucleophilic, electrophilic and radical attack respectively.
In these equations, qk is the atomic charge at kth atomic site for the Neutral (N), anionic (N+1) and cationic (N-1) chemical species. The Fukui function allows analyzing the distribution of the active sites in a molecule for which the value of the function is totally dependent on the type of charges used. To solve the negative Fukui function problem, different attempts have been made by various groups introduced the atomic descriptor to determine the local reactive sites of the molecular system.
The partition function is one of important parameters of thermodynamics (Figure 8). The partition function associates thermodynamics, spectroscopy and quantum theory. The partition functions are further classified as (i) translational partition function, (ii) rotational partition function, (iii) vibrational partition function and (iv) electronic partition function. The standard statistical thermodynamic functions such as standard heat capacity (CP), standard entropy (S) and standard enthalpy changes (H) were obtained from the theoretical harmonic frequencies on the basis of vibrational analysis at B3LYP/6-311++G (d,p) level using thermo.pl software and listed in Table 7. From the observations in the above Table 6, all the values of Cp, S and H increase with the increase in temperature from 100 K to 1000 K. This is accredited to the enhancement of the molecular vibration. The temperature increases because at a constant pressure, the values of Cp, S and H are equal to the quantity of temperature. The relations between these thermodynamic properties and temperatures are fitted by quadratic equations and the corresponding fitting factor (R2). It was found to be 0.99999, 0.9997 and 0.9994 for entropy, heat capacity, and enthalpy, respectively. The temperature dependence correlation graph is represented in Figure 8 and the corresponding fitting equations are shown below:
|T (K)||S (J/mol.K)||Cp (J/mol.K)||ddH (kJ/mol)|
TABLE 7. Thermodynamics functions of - 3-furan-2-yl-4-phenyl-butyric acid with different temperature.
Figure 8: Graphs representing dependence of entropy, specific heat capacity and enthalpy on temperature of -3-furan-2-yl-4-phenyl-butyric acid (2F4PBA).
The thermodynamic data provides the required data for the further study on the title molecule. Thermodynamic energies according to the relationships of thermodynamic functions and estimate directions of chemical reactions in accordance to the second law of thermodynamics in thermochemical field.
Molecular docking study
Auto Dock suite 1.5.6 (ADT) is graphical front end for running auto dock automated docking software designed to predict how small molecules (substrates or drug candidates) bind to a receptor of known 3D structure. The title compound was selected to be docked into the active site of the protein 4Y95 which belongs to the class of proteins exhibiting the property as a (BTK) Bruton's Tyrosine Kinase expression inhibitor Ibrutinib (PCI-32765) in B-Cell Acute Lymphoblastic Leukemia (B-ALL). Bruton's Tyrosine Kinase (BTK) Bruton’s Tyrosine Kinase (BTK) is a cytoplasmic, non-receptor tyrosine kinase which is expressed in most of the hematopoietic cells and plays an important role in many cellular signaling pathways. B cell malignancies are dependent on BCR signaling, thus making BTK an efficient therapeutic target. The transcription factor BTK plays a significant role in cellular response to systemic oxygen levels in mammals (Figure 9). BTK activity is controlled by a host of post translational modifications: hydroxylation, acetylation and phosphorylation. When a body suffers with hypoxia a region of the body is deprived of adequate oxygen supply at the tissue level leading to stiffness. The ligand was docked into the functional sites of the selected protein and minimum docking energy value was examined. Auto dock results designate the binding position and bound conformation of the peptide, together with an approximation of its interaction. Docked conformation which had the lowest binding energy was chosen to study the mode of binding. The molecular docking binding energies (kcal/mol) and inhibition constants (mm) were also obtained and listed in Table 8. The 3-Furan-2-yl-4-Phenyl-Butyric Acid (2F4PBA) ligand interactions with protein 4Y95 is shown in Figure 9. A minimum binding energy of -4.79 kcal/mol was seen in the interaction.
|Bonded residues||Bond distance
TABLE 8. Hydrogen bonding and molecular docking with 4Y95, BTC expression inhibitor protein targets.
Figure 9: (a). Docking and Hydrogen bond interactions of - 3-furan-2-yl-4-phenyl-butyric acid (2F4PBA) with 4Y9Z protein; (b). Docking and Hydrogen bond interactions of - 3-furan-2-yl-4-phenyl-butyric acid (2F4PBA) with 4Y9Z protein.
The complete vibrational spectral analysis and DFT theoretical calculation were performed for title molecule. The optimized geometric parameters (bond lengths and bond angles) are theoretically determined and compared with the structurally similar molecules. The interaction energy, related to resonance in the molecule, is electron withdrawing from the ring through π*(C7-C8) of the NBO conjugated with π*(C9-C16) resulting with large stabilization energy of 263.92 kJ/mol. The large difference in HOMO and LUMO energy supports the charge transfer model of interaction within the molecule. Finally, the theoretical results showed an acceptable general agreement with the experimental record. The predicted MEP figure revealed the negative and positive regions of the molecule. The computed values of μ, α and β for the title molecule are 0.876 D, 2.739 x 10-23 esu and 1.0579 x 10-30 esu respectively. The first order hyper polarizability of the title molecule is 3 times than that of urea (βo= 0.3728 x 10-30 esu) and the calculated energy gap is E= 12.3932eV which is lower than urea (ΔE= 6.7063 eV). These results indicate that the title compound is a good candidate of NLO material and can also be considered to be an important class of compound in medical chemistry because if its high electrophilicity index (0.5079). The FT-IR and FT-Raman spectra of the title molecule are observed with the experimental and calculated vibrational wavenumbers and their PED is noted. Thermodynamic properties in the range from 100 to 1000 K are obtained. The gradients of Cp, S and H increases, as the temperature increases which is attributed to the enhancement of the molecular vibration. The charge and multiplicity are varied in order to compare the variation in the Mullikan charges in each case. The electron density based local reactivity descriptors such as Fukui functions are proposed. The title compound was selected to be docked into the active site of the protein 4Y95 which belongs to the class of proteins exhibiting the property as a Bruton's Tyrosine Kinase (BTK) expression inhibitor.
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