Vibrational spectroscopic studies, normal co-ordinate analysis, first order hyperpolarizability, HOMO–LUMO of midodrine by using density functional methods

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 134 (2015) 127–142

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Vibrational spectroscopic studies, normal co-ordinate analysis, first order hyperpolarizability, HOMO–LUMO of midodrine by using density functional methods R. Shahidha a, Abdulaziz A. Al-Saadi b, S. Muthu c,⇑ a b c

Research and Development Centre, Bharathiar University, Coimbatore 641 046, India Department of Chemistry, King Fahd University of Petroleum & Minerals, Dhahran 31261, Saudi Arabia Department of Physics, Sri Venkateswara College of Engineering, Sriperumbudur 602 105, India

h i g h l i g h t s

g r a p h i c a l a b s t r a c t

 FTIR, FT-Raman and UV–Vis

Midodrine is a prodrug acting as a-adrenergic agonist useful in the treatment of neurogenic orthostatic hypotension. An extensive work has been carried out on the title compound and its derivatives in recent year. At present, vibrational spectroscopy is used not only for functional group identification of organic compounds, but also to investigate the molecular conformation, reaction kinetics.

investigations of MIDODRINE were carried out.  Molecular structure was studied using DFT/6-311++G(d,p)method.  The PED calculation provides a strong support for the frequency assignment.  NBO analysis used to explain the interaction between electron donors and acceptors.

a r t i c l e

i n f o

Article history: Received 27 March 2014 Received in revised form 28 May 2014 Accepted 3 June 2014 Available online 19 June 2014 Keywords: FTIR FT-Raman DFT NCA NBO

a b s t r a c t The FTIR (4000–400 cm1), FT-Raman (4000–100 cm1) and UV–Visible (400–200 nm) spectra of midodrine were recorded in the condensed state. The complete vibrational frequencies, optimized geometry, intensity of vibrational bands and atomic charges were obtained by using Density Functional Theory (DFT) with the help of 6-311++G(d,p) basis set. The first order hyperpolarizability (b) and related properties (l, a and Da) of this molecular system were calculated by using DFT/6-311++G(d,p) method based on the finite-field approach. The assignments of the vibrational spectra have been carried out with the help of Normal Co-ordinate Analysis (NCA) following the scaled quantum mechanical force methodology. Stability of the molecule arising from hyper conjugative interactions, charge delocalization has been analyzed using NBO analysis. From the recorded UV–Visible spectrum, the electronic properties such as excitation energies, oscillator strength and wavelength are calculated by DFT in water and gas methods using 6-311++G(d,p) basis set. The calculated HOMO and LUMO energies confirm that charge transfer occurs within the molecule. Besides MEP, NLO and thermodynamic properties were also calculated and

⇑ Corresponding author. Tel.: +91 9443690138; fax: +91 4427162462. E-mail addresses: [email protected], [email protected] (S. Muthu). http://dx.doi.org/10.1016/j.saa.2014.06.033 1386-1425/Ó 2014 Elsevier B.V. All rights reserved.

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R. Shahidha et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 134 (2015) 127–142

interpreted. The electron density-based local reactivity descriptor such as Fukui functions was calculated to explain the chemical selectivity or reactivity site in midodrine. Ó 2014 Elsevier B.V. All rights reserved.

Introduction Midodrine is a prodrug acting as a-adrenergic agonist useful in the treatment of neurogenic orthostatic hypotension [1]. It is significantly increases standing systolic blood pressure compared with placebo. The drug also improves the standing time, energy level and clinical symptoms of orthostatic hypotension including dizziness, headaches and syncope. It is a odorless, white, crystalline powder, soluble in water [2]. In addition, hypertensive individuals report cognitive impairment, above all deficits in attention and memory. Nevertheless, it is generally the case that in research as well as in clinical portance is as practice, relatively little importance is ascribed to hypotension. It is a odorless, white, crystalline powder, soluble in water. It has been used successfully in the treatment of neurogenic orthostatic hypotension and more recently, in the treatment of dialysis hypotension. It acts through vasoconstriction of the arterioles and the venous capacitance vessels, thereby increasing peripheral vascular resistance and augmenting venous return, respectively. It is a unique agent in the armamentarium against orthostatic hypotension since it has minimal cardiac and CNS effects. The metabolic effects of midodrine patients have been not fully investigated but data to date suggest that midodrine does not affect blood sugar or urea levels. It appears to have no central nervous system activity and does not affect the renal function and bone marrow. It causes a significant reduction in plasma and blood volume respectively [3]. FTIR and FT-Raman spectroscopy combined with quantum chemical computations has been recently used as an effective tool in the vibrational analysis of drug molecules, biological compounds and natural products. FTIR and Raman spectroscopic methods are being extensively used to identify the structural groups present in a compound [4,5]. In the present work has been undertaken to give a complete description of the molecular geometry and molecular vibration of the midodrine. FTIR and Raman spectra of midodrine have been reported together with the assignments of the vibrational modes supported by PED. We have investigated dipole moment, polarizability, hyperpolarizability rotational constants, atomic charges and other thermodynamic parameters of the title molecule using B3LYP/6311++G(d,p) basis set. Specific scale factors were employed in the predicted frequencies for the accuracy. The change in electron density (ED) in the r(bonding) and r(anti-bonding) orbital and stabilization energies E(2) have been calculated by natural bond (NBO) analysis to give clear evidence of stabilization originating in the hyper conjugation of hydrogen bonded interactions. In addition HOMO, LUMO analysis has been used to elucidate the information regarding charge transfer within the molecule. Experimental details The compound under investigation namely midodrine is purchased from Sigma–Aldrich chemical, USA with a stated purity of 99%. The FT-IR spectrum was recorded in the region 4000– 400 cm1 in the KBr pellet, using Nicolet Magna 560 FTIR spectrometer. The resolution of the spectrum is 4 cm1. The spectrum is recorded at room temperature with a scanning speed of 30 cm1 min1 and the spectral resolution of 2 cm1. The FTRaman spectrum of midodrine is also recorded in the range of 4000–100 cm1 using Bruker RFS with FRA 106 Raman module equipped with Nd: YAG laser source operating at 1.064 lm line

widths with 200 mW powers. The frequencies of all sharp bands are accurate to 1 cm1. The ultraviolet absorption spectrum of midodrine solved in water is examined in the range 200–400 nm by using Cary 5E UV–Visible NIR recording spectrometer. All the spectral measurements are carried out at SAIF, IIT, and Chennai, India.

Computational details In order to obtain stable structures, the geometrical parameters of midodrine in the ground state was optimized at DFT/B3LYP level theory by using 6-31++G(d,p) basis set. The calculations were performed with the Gaussian 03W [6] program package, invoking gradient geometry optimization [7] using Pentium IV personal computer. The calculated vibrational frequencies are scaled by 0.967 for B3LYP/6-311++G(d,p) basis set [8], the optimized structural parameters were used in the vibrational frequency calculation at DFT levels to characterize all stationary minima. In the present work using GAUSSVIEW program with symmetry considerations along with available related molecules, optimized structure, vibrational frequency assignments were made with a high degree of accuracy. Normal co-ordinates analysis (NCA) has been performed to obtain full description of the molecular motion pertaining to the normal modes using the MOLVIB program version 7.0 written by Sundius [9]. The natural bonding orbital (NBO) calculations [10] were performed using NBO 3.1 program as implemented in the Gaussian 03W package at the above said level in order to understand various second order interactions between the filled orbital of one subsystem and vacant orbital of another subsystem, which is a measure of the intermolecular and intramolecular delocalization or hyper conjugation.

Conformer In theory, there are several possible stable forms of the midodrine molecule due to the fact that there are a number of internal rotation possibilities the molecule could undergo. The absence of X-ray structural data for midodrine has requested us to carry out detailed conformational study to locate the most stable form. Although we searched a couple of possible stable structures, we have reported a set of representative forms (mostly are amongst the most stable ones) in Table 1. Midodrine tends to form an intramolecular hydrogen bonding between one of the two methoxy groups on the benzene ring and the hydroxyl group. The calculated hydrogen CH3O  HO bond is predicted to be about 2.0 A. The conformers with that special intramolecular hydrogen bonding are about 2.5 kcal/mol more stable than the corresponding forms that do not exhibit such a weak, but significant type of bonding. The g1t-syn-anti forms Fig. 1 were found from DFT/6-311++G(d,p) calculations to be the most stable form using both containingand non-containing diffuse function basis set. These forms are not less 0.7 kcal/mol more stable than the next most stable forms, i.e. g2t-syn-anti forms. Another noteworthy intramolecular hydrogen bond is the H2N  HN interaction which is predicted to be about 2.2 A in the glycinamide end. This type of bonding clearly causes the t-syn-syn structures to be further stabilized compared to the other conformation.

R. Shahidha et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 134 (2015) 127–142 Table 1 Total energies and relative energy for nine conformers of title compound calculated by B3LYP/6-311++G(d,p) method. Conformers

Total energy (Hartree)

Relative energy (kcal/mol)

C1 C2 C3 C4 C5 C6 C7 C8 C9 C10

878.76179 878.76166 878.76070 878.76016 878.75986 878.75975 878.75508 878.75464 878.75722 878.75658

0 0.081 0.681 1.023 1.21 1.282 4.257 4.487 2.868 3.268

Results and discussions Molecular geometry The optimized structural parameters of midodrine are determined at the DFT/6-311++G(d,p) basis set. The optimized parameters are presented in Table 2 in accordance with the atom numbering scheme of the molecule as shown in Fig. 2. From the theoretical values, it is found to 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 the

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solid state. By allowing the relaxation of all parameters, the calculations converge to optimized geometries, which correspond to true energy minima, as revealed by lack of imaginary frequencies in the vibrational mode calculation. This molecule has CAC bond lengths, sixteen CAH bond lengths, three NAH bond lengths, three CAN bond lengths, five CAO bond lengths and one CAO bond length. The calculated bond length values for CAC and CAH in the benzene ring vary from 1.334 to 1.533 Å and 1.081 to 1.12 Å by B3LYP/6-311++G(d,p) basis set, respectively and well agreed with the experimental values [11]. In this study the optimized bond length of CAC are high and for OAH is low (0.96 Å), with the electron donating and withdrawing substituent on the benzene ring, the symmetry of the ring is distorted, yielding variation in bond angles at the point of substitution. It is clearly shown that the angles at the point of substitution CACAC, CACAH, CACAO, CANAH are 120°, 109° and 110° respectively. The small difference between experimental and theoretical bond lengths and bond angles may be due to presence of intermolecular hydrogen bonding or the experimental results belong to solid phase and theoretical calculations belong to gaseous phase.

Vibrational assignments The vibrational spectral assignments of midodrine have been carried out with the help of PED analysis. The detailed description of vibrational modes can be given by Normal Co-ordinate Analysis

synOCH3g2t-syn-anti

antiOCH3g2t-syn-anti

synOCH3g1t-anti-syn

antiOCH3g1t-anti-syn

synOCH3g1c-syn-syn

antiOCH3g1c-syn-syn

synOCH3g2t-anti-syn

antiOCH3g2t-anti-syn Fig. 1. Eight possible conformer of midodrine molecule.

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Table 2 Optimized geometrical parameters bond length, bond angle of title compound by B3LYP/6-311++G(d,p) in comparison with Experimental data. Parameter Bond length N1AC2 N1AH19 N1AH20 C2AC3 C3AN4 C3A013 N4AC5 N4AH23 C5AC6 C6AC7 C6AO14 C6AH26 C7AC8 C7AC12 C8AC9 C9AC10 C9AO15 C10AC11 C11A C12 O14A H27 O15A C16 O17AC18 Bond angle C2AN1AH19 C2AN1AH20 H19AN1AH20 N1AC2AC3 N1AC2AH21 N1AC2AH22 H21AC2AH22 C2AC3AN4 C2AC3AO13 N4AC3AO13 C3AN4AC5 C3AN4AH23 C5AN4AH23

Experimental 1.438 1.012 1.012 1.523 1.369 1.208 1.438 1.012 1.523 1.523 1.355 1.112 1.337 1.497 1.337 1.337 1.355 1.337 1.337 0.942 1.402 1.402 110 110 109 119 109 120 109 120 120 120 120 120 120

B3LYP/6311++G(d,p) 1.4661 1.0138 1.0124 1.5342 1.3546 1.225 1.4504 1.013 1.5419 1.5203 1.4294 1.0926 1.3975 1.4023 1.397 1.3945 1.3673 1.3903 1.3958 0.9665 1.4212 1.4229 111.7351 111.7762 107.6762 113.9917 108.9733 114.4756 106.4986 114.9211 120.2532 124.823 123.1282 116.1813 119.8295

(NCA). The internal co-ordinates describe the position of the atoms in terms of distances, angles with respect to an origin atom. The symmetry co-ordinates are constructed using the set of internal co-ordinates. In this study, the full sets of 121 standard internal co-ordinates for midodrine were defined as given in Table 3 and are summarized in Table 4 according to Pulay’s recommendations

Parameter

Experimental

B3LYP/6-311++G(d,p)

Bond angle N4AC5AC6 N4AC5AH24 N4AC5AH25 H24AC5AH25 C5AC6AC7 C5AC6AO14 C7AC6AO14 C7AC6AH26 O14AC6AH26 C6AC7AC8 C6AC7AC12 C8AC7AC12 C7AC8AC9 C8AC9AC10 C8AC9AO15 C10AC9AO15 C9AC10AC11 C10AC11AC12 C7AC12AC11 C7AC12AO17 C11AC12AO17 C6AO14AH27 C9AO15AC16 O15AC16AH31 O15AC16AH32 O15AC16AH33 H31AC16AH32 H31AC16AH33 H32AC16AH33 C12AO17AC18 O17AC18AH34 O17AC18AH35 O17AC18AH36 H34AC18AH35 H34AC18AH36 H35AC18AH36

109 109 109 109 120 109 109 109 109 120 120 120 120 120 120 120 120 120 120 120 120 109 120 109 109 109 109 109 109 120 109 109 109 109 109 109

111.656 109.8413 107.4162 108.5127 111.4813 110.9225 113.5665 108.1563 104.7773 119.1398 122.1195 118.7194 121.3119 119.1823 124.6082 116.2086 120.2526 120.3243 120.206 116.2921 123.5002 106.91 118.4993 105.83 111.4544 111.4842 109.2388 109.2965 109.4441 118.7828 111.1696 105.9491 111.3669 109.3062 109.6244 109.3355

[12]. The observed and calculated frequencies using DFT/631++G(d,p) force field along with their relative intensities, assignments and potential energy distribution (PED) of midodrine are given in Table 5. For visual comparison, the observed and simulated of FTIR and FT-Raman spectra of midorine are shown in Figs. 3 and 4.

Fig. 2. Atom numbering scheme adopted in the optimized structure of midodrine.

R. Shahidha et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 134 (2015) 127–142

CAH vibrations The aromatic structure shows the presence of CAH stretching vibration in the region 3100–3000 cm1 which is the characteristic region for the identification of CAH stretching vibration [13]. In this region, the bands are not affected appreciably by the nature of the constituents. For our title molecule the band corresponding to CAH stretching vibration at 3101, 3089, 3083, 3030, 3029, 3011 cm1 (mode nos. 5–10) by DFT/6-31++G(d,p) method shows excellent agreement with the literature data and also with the bands observed in the recorded FTIR spectrum at 3105, 3084, 3045, 3033 and 3000 cm1 and with the FT-Raman bands at 3100, 3092, 3086, 3040, 3033 and 3001 cm1 [14,15]. The PED corresponding to this vibration is pure mode of contributing to 90% as shown in Table 5. CH2 vibrations The CAH stretching of the CH2 (Methylene) groups are at lower frequencies than those of the aromatic CAH ring stretching. The antisymmetric stretching vibrations are generally observed in the region 3000–2950 cm1, while the CH2 symmetric stretching will appear between 2950–2800 cm1 [16,17]. The CH2 symmetric stretching vibration observed as a strong band at 2990 cm1 in FTIR and very strong band at 2925 cm1 at FT-Raman spectrum respectively for the title compound. The recorded spectrum shows one medium strong band at 1483 cm1 and one weak band at 1411 cm1 in FT-IR and a weak band at 1487 cm1 in FT-Raman are assigned to CH2 scissoring vibrations and also show the

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maximum PED contribution of 60%. The CH2 wagging mode observed at 1367 (medium strong) and 1315 cm1 in FTIR and 1338 cm1 in FT-Raman spectrum. The CH2 rocking mode observed at 1212 cm1 in FTIR and 1190 cm1 in FT-Raman spectrum.

CH3 vibrations Methyl groups vibrations are generally referred to as electrondonating substituent in the aromatic ring system, the symmetric CAH stretching mode of CH3 is 2980–2900 expected around at 2974, 2913 cm1 in FT-IR and for FT-Raman around 2914, 2900 cm1 [18,19]. The recorded spectrum shows one medium strong band at 1457 cm1 in FTIR and one strong band at 1459 cm1 in FT-Raman are assigned to CH3 scissoring vibrations and it shows the maximum PED of 87%.

NAH vibrations It is stated that in amines, the NAH stretching vibrations occur in the region 3500–3300 cm1. The asymmetric ANH2 stretching vibration appears from 3500 to 3420 cm1 and the symmetric ANH2 stretching is observed in the range 3420 to 3340 cm1 [20]. With the above reference, the NAH stretching band identified at 3448 cm1 in FTIR spectrum and for FT-Raman at 3440 cm with contribution of PED (100%). One weak band observed at 3513 cm1 in FT-IR and one weak band identified at 3500 cm1 in FT-Raman spectrum is assigned to the NH2 asymmetric stretching mode.

Table 3 Definition of internal coordinates of midodrine. No.

Symbol

Type

Definition

Stretching 1–6 7–9 10–13 14–19 20–22 23–24 25 26–30 31–33 34–36

Ri Ri Ri Ri Ri Ri Ri Ri Ri Ri

CAC(Ring) CAH(Ring) CAO CAH(Methyl) CAC CAO OAH CAH NAH NAC

C12AC11, C11AC10, C10AC9, C9AC8, C8AC7, C7AC12 C11AH30, C10AH29, C8AH28 C12AO17, C9AO15, C18AO17, C16AO15 C16AH31, C16AH32, C16AH33, C18AH34, C18AH35, C16AH36 C7AC6, C6AC5, C3AC2 C6AO14, C3AO13 O14AH27 C6AH26, C5AH25, C5AH24, C2AH21, C2AH22 N4AH23, N1AH19, N1AH20 N1AC5, N4AC3, N4AC5

In-plane-bending 37–42 43–54

bi bi

cAcAc(Ring) CACAH(Ring)

55–62

bi

CACAO

63–68

bi

CACAH(Methyl)

C12AC11AC10, C11AC10AC9, C10AC9AC8, C9AC8AC7, C8AC7AC12, C7AC12AC11 C12AC11AH30, C10AC11AH30, C11AC10AH29, C9AC10AH29, C9AC8AH28 C7AC8AH28, C7AC6AH26, C6AC5AH26, C6AC5AH24, C6AC5AH25, C2AC3AH21, C2AC3AH22 C5AC6AO14, C12AC18AO17, C12AC11AO17, C7AC12AO17, C8AC9AO15, C10AC9AO15, C6AC7AO14, C2AC3AO13 C18AH35AH36, C18AH36AH34, C16AH31AH32, C16AH32AH33, C2AH21AH22, C5AH24AH25 C6AH26AO14 C6AC5AN4, C3AC5AN4, C2AC3AN4, C2AC3AN1 N1AH19AH20 C2AN1AH19, C2AN1AH20, C2AN1AH21, C2AN1AH22, C3AN4AH23, C5AN4AH23, C5AN4AH24, C5AN4AH25

69 bi 70–73 bi 74 bi 75–82 bi Out-of-plane bending 83–89 ci

CAHAO CACAN NAHAH CANAH CACACAO(Ring)

90–91 92–95 96–98 99–108

ci ci ci ci

CACAOAH CACACAH CACACAN CACANAH

109–112

ci

CACANAO

Torsion 113–118

ti

CACACAC

119–122 123–130

ti ti

CACACAH CACA0AH

C8AC9AC16AO15, C10AC9AC16AO15, C11AC12AC18AO17, C7AC12AC18AO17 C8AC7AC6AO14, C12AC7AC6AO14, C5AC6AC7AO14 C7AC6AO14AH27, C7AC6AO14AH26 C5AC6AC7AH26, C5AC6AC7AH24, C5AC6AC7AH25, C12AC7AC6AH26 C2AC3AC5AN4, C6AC5AC3AN4, C5AC6AC7AN4 C3AC5AN4AH23, C6AC5AN4AH23, C6AC5AN4AH24, C5AC6AN4AH25, C2AC3ANM0 AH21, C2AC3AN4AH22 C2AC3AN1AH19, C2AC3AN1AH20, C2AC3AN1AH21, C2AC3AN1AH22 C2AC3AN4AO13, C2AC3AN1AO13, C3AC5AN4AO13, C6AC5AN4AO14 C12AC11AC10AC9, C11AC10AC9AC8, C10AC9AC8AC7, C9AC8AC7AC12, C8AC7AC12AC11, C7AC12AC11AC10 C12AC11-C10AH30, C11AC10AC9AH29, C7AC8AC9AH28, C8AC7AC6AH26 C9AC16AO15AH31, C9AC16AO15AH32, C9AC16AO15AH33, C12AC18AO17AH34, C12AC18AO17AH35, C8AC9AO15AH28, C12AC11AO17AH30, C12AC18AO17AH36

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Table 4 Definition of local symmetry coordinates of midodrine. No.

Symbol

Definition

1–6 7–9 10–11 12–13 14–15 16–21 22–24 25 26–30 31 32 33 34–36 37 38 39 40–45 46–49 50 51 52–53 54–55 56 57–58 59 60–63 64–70 71–72 73–76 77–79 80–89 90–93 94 95 96 97–98 99–102

CAC(Ring) CAH(Ring) CH3ss CH3ips CH3ops CA0 CAC OAH CAH NH2ss NH2ips NH2ops NAC bCC(Ring) bCCasym bCCsym bCH bCO bCH3sb bCH3ipb bCH3ipr bCH3opr bCHO bccn bNHH bNCH cCCCO cCCOH cCCCH cCCCN cCCNH cCCNO sCCC(ring) sCCC asym sCCC sym sCCCH sCCOH

R1, R2, R3, R4, R5, R6 R7, R8, R9 p p (R10 + R11 + R12)/ 3, (R13 + R14 + R15) 3 p p (2R12  R11  R10)/ 8, (2R15  R14  R13)/ 8 p p (R11  R10)/ 2, (R14  R13)/ 2 R16, R17, R18, R19, R20, R21 R22, R23, R24 R25 R26, R27, R28, R29, R30 p (R31  R32 + R33)/ 3 p (2R31  R32  R33)/ 3 p (R32  R33)/ 2 R34, R35, R36 p (b37  b38 + b39  b40 + b41  b42)/ 6 p (b37  b38 + 2b39  b40  b41 + 2b42)/ 12 p (b37  b38 + b40  b41)/ 2 p p p p p p (b43  b44)/ 2, (b45  b46)/ 2, (b47  b48)/ 2, (b49  b50)/ 2, (b51  b52)/ 2, (b53  b54)/ 2 p p p p (b55  b56)/ 2, (b57  b58)/ 2, (b59  b60)/ 2, (b61  b62)/ 2 p (b63  b64  b65  b66  b67  b68)/ 6 p (b66  b67  b68)/ 6 p p (2b65  b64  b63)/ 6, (2b68  b67  b66)/ 6, p p (b63  b64)/ 2, (b66  b67)/ 2 b69 p p (b70  b71)/ 2, (b72  b73)/ 2 b74 p p p p (b75  b76)/ 2, (b77  b78)/ 2, (b79  b80)/ 2, (b81  b82)/ 2, c83, c84, c85, c86, c87, c88, c89 c90, c91 c92, c93, c94, c95 c96, c97, c98 c99, c100, c101, c102, c103, c104, c105, c106, c107, c108 c109, c110, c111, c112 p (s113  s114 + s115  s116 + s117  s118/ 6 p (s112  s113 + 2s114  s115  s116 + 2s117)/ 12 p (s112  s113 + s115  s116)/ 2 p p (s119  s120)/ 2, (s121  s122)/ 2 p p p p (s123  s124)/ 2, (s125  s126)/ 2, (s127  s128)/ 2, (s129  s130)/ 2

Similarly one band is identified in FT-Raman at 3410 cm and one band observed at FT-IR spectrum is 3402 cm assigned to the NH2 symmetric stretching modes with maximum contribution of PED. For amino group the NH2 scissoring identified at 1692 cm1 in FT-IR and at1654 cm1 in FT-Raman spectrum. The bands at 1382, 1324, 1171 cm1 are attributed to the rocking modes of amino group, respectively. The computed wave numbers identified at 1092, 1074, 823, 372 cm1 are assigned for CANH and CANH2 wagging modes respectively. These amino vibrations are also in good agreement with literature values [21]. Ring vibrations Many ring modes are affected by the substitutions in the ring of midodrine. The actual position of these modes determined not so much by the natural of the substituent’s but by the form of substitution around the ring system [22]. In our present study the wave number computed 1648, 1628, 1551, 1532, 1437, 1382, 1372, 1346, 1329, 1291, 1270, 1253, 1239, 1184, 1092, 1074, 777 cm1 by DFT/6-311++G(d,p) method (modes 21, 22, 23, 24, 34, 36, 37, 39, 41–44, 48, 54, 55, 67) are assigned to CAC and CAN stretching vibration for title molecule shows good agreement with recorded spectra. The in-plane deformation vibrations are at higher wave number than the out-of-plane vibrations are presented in table Shimanouchi et al. [23] gave the wave number data for these vibrations for five different benzene derivatives as a result of normal coordinate analysis. The in-plane and out-of-plane bending vibration are computed by DFT/6311++G(d,p) method shows good agreement with literature [24,25] and recorded spectral data.

NLO properties The dipole moment (l), polarizability (a) and first order hyperpolarizability (b) are calculated using DFT/6-311++G(d,p). The complete equations for calculating their magnitudes using the x, y, z components obtained from Gaussian 03 are taken from [26]. It is well known that the higher values of dipole moment, molecular polarizability and first order hyperpolarizability are important for more active NLO properties. The values of the polarizabilities (a) and hyperpolarizability (b) of Gaussian 03 output are reported in atomic units (a.u.), the calculated values have been converted into electrostatic units (e.s.u) (a: 1 a.u. = 0.1482  1012 esu, b: 1 a.u. = 8.6393  1033 esu). The calculated dipole moment and hyperpolarizability values obtained from DFT/6-311++G(d,p) method are collected in Table 6. The total molecular dipole moment of midodrine from DFT with 6-311++G(d,p) basis set is 1.20695 D, which are nearer to the value of urea (l = 1.3732 D). Similarly the first order hyperpolarizability of midodrine with DFT/6-311++G(d,p) basis set is 8.8536  1030 twenty-three times greater than the value (b = 0.372  1030 esu). Thermodynamic properties On the basis of vibrational analysis at B3LYP/6-311++G(d,p) level, the standard statistical thermodynamic functions; heat capacity (Cop,m), entropy (Som) and enthalpy changes (Hom) for the title compound were obtained from the theoretical harmonic frequencies are listed in Table 7. From Table 7 it can be observed that these thermodynamic functions are increasing with temperature ranges from

Table 5 Vibrational wave numbers obtained for MIDODRINE at DFT/6-311++G(d,p) [(harmonic frequency cm1, IR intensities (K mmol1, Raman intensities (units)]. S. No.

Calculated frequencies (cm1) DFT/6-311++G(d,p)

FT-IR

FT-Raman

Unscaled

Scaleda

IRb

Ramanc

3671(w) 3513(w) 3448(w) 3410(w) 3105(s) – 3084(ms) 3045(ms) 3033(w) 3000(w) – – – – 2990(s) 2980(w) 2974(w) 2913(w) 1712(w) 1692(ms) 1611(ms) 1523(s) 1500(s) 1483(ms) 1457(ms) – – – – – 1423(w) 1411(w) 1400(ms) 1387(w) 1367(ms) 1315(w) – – – – – – 1212(w) – – – – 1149(s) – – – – –

3600(vw) 3500(w) 3440(w) 3402(w) 3100(s) 3092(s) 3086(s) 3040(s) 3033(s) 3001(s) – – – – 2925(vs) 2915(w0 2914(w) 2900(w) 1699(w) 1654(w) 1600(w) 1555(w) 1500(w) 1487(w) 1459(s) – – – – – – – 1400(w) 1379(s) – 1338(s) – – – 1265(ms) – – – – 1190(w) – – 11459ms) – – 1122(s) 1095(s) 1078(ms)

3764 3602 3565 3523 3207 3194 3189 3133 3132 3114 3075 3071 3068 3062 3042 3024 3010 3003 1732 1663 1648 1628 1550 1532 1507 1505 1493 1492 1484 1479 1476 1473 1454 1437 1395 1382 1346 1340 1329 1324 1291 1270 1253 1239 1237 1209 1199 1184 1171 1168 1168 1137 1113

3640 3483 3447 3406 3101 3089 3083 3030 3029 3011 2974 2970 2967 2961 2942 2924 2911 2904 1675 1608 1594 1574 1499 1481 1457 1455 1443 1442 1435 1430 1427 1424 1406 1389 1348 1336 1301 1296 1285 1280 1248 1228 1211 1198 1196 1169 1159 1144 1132 1130 1129 1099 1076

103.1 7.03 90 1.94 1.94 3.96 6 20.46 20.89 5.95 10.12 31.46 31.25 35.26 15.77 32.24 58.76 54.54 303.09 42.75 18.75 0.65 331.76 331.761 23.61 96.25 10.52 8.56 12.95 5.35 16.4 16.82 81.82 12.64 1.65 12.87 52.51 10.71 13.34 18.22 23.26 31.46 73.35 393.5 5.33 1.23 34.91 7.23 1.62 0.6 0.91 12.53 7.61

39.55 85.75 89.63 186.4 152.74 44.27 77.81 167.34 78.68 23.79 69.48 65.86 16.18 49.32 118.74 156.47 192.58 145.39 5.67 5.57 49.05 23.27 8 1.17 8.52 2.07 12.37 12.24 11.17 3.6 2.51 8.63 3.05 4.14 23.43 2.8 2.7 11.32 14.6 5.19 32.06 4.66 9.02 1.4 4.89 11.3 5.62 1.34 1.43 3.03 1.45 3.33 1.86

Vibrational modes (>10% PED)

masOH(100) masNH2(96) msymNH(100) msymNH2(87) mCH(100) mCH(98) mCH(92) masCH(100) msymCH(100) masCH(97) masCH2(100) masCH2(98) vasymCH2(88), mCH(10) maymCH2(99) msymCH2(56), mCH(40) msymCH2(74) msymCH3(98) msymCH3(87) mC@O(100) bNH2scs(78) mCC(87) mCC(64) mCC(16), bNCH(56) bCC(17), bCH2scs(49), mCH(6) bCH3scs(87) bCH3scs(98) bCH3scs(79) bCH3scs(63) bCH2scs(33), mCN(41), mOH(26) bCH3wag(98) bCH3wag(30) bCH2scs(60) mCC(23), mCH(34), bCH3wag(20), bCH(13) mCH(34), mOH(20), bCH2scs(30), mCC(10) bCH2wag(26), mCC(28), mNC(19) bNH2rock(49), bCH2scs(12), mCC(12) bCCC(35), mCH(12), mCC(24), bCCO(33) bCH2tws(66), mCH(13), mOH(19) mCH(26), cCCH(24), mNC(11) bCH2tws(23), bNH2rock(20), mNC(11), mCC(14) bCH3(22), mNC(17), mCH(14), mCC(14), bCCH(10) mNC(15), bCH2rock(17), bCH3(15) bNCH(10), cNCC(24), bCH2rock(50), mCH(6), mCC(8) mCC(14), bCCH(19), bCCC(14), bCOC(31) mCH(10), bNCH(43), bCH2rock(33), bCCH (10) bCH2rock(37), mCC(21), bCCH(11) bCH2rock(30), mCH(24), cCCH(11), bCH3(20) mCC(25), bCCH(29), mCO(21) bCH2(22), bNH2rock(48), mNC(30) bCH2tws(60), mCH(14) bCH2scs(98) mCC(32), bCHO(23), mCO(10) mCN(9), mCC(25), mCO(12), bNCH(23), bCH2wag(22)

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53

Observed frequencies (cm1)

134

Table 5 (continued) S. No.

Calculated frequencies (cm1) DFT/6-311++G(d,p)

FT-IR

FT-Raman

Unscaled

Scaleda

IRb

Ramanc

– – – – 1000(vs) – – – 850(ms) 832(w) 800(w) 757(w) 730(w) – – 665(s) – – – – – – – – – – – – – – – – – – – – – – – – – – – – – –

– – 1030(w) – 1014(vw) 939(ms) – 900(w) – 866(w) 840(w) – 784(w) 755(w) 724(w) 700(w) 670(w) 645(ms) 630(ms) 594(ms) 575(ms) – 518(ms) 500(ms) 478(s) – 437(w) 407(w) 378(w) 350(w) 337(w) 276(w) 245(w) – 234(vw) 219(vw) 200(vw) 190(vw) 187(vw) 163(vw) 137(vw) 110(vw) – – 71(vs) – – – –

1092 1074 1067 1060 1048 963 943 937 920 875 848 823 820 777 747 742 696 676 653 617 580 570 521 509 503 488 457 428 395 372 344 294 272 273 251 231 212 205 192 165 148 110 98 85 59 55 43 29 11

1056 1039 1032 1025 1013 931 911 906 889 846 820 795 782 751 722 717 673 653 631 596 560 551 503 492 486 471 441 413 381 359 332 284 262 263 242 223 205 198 185 159 143 106 94 82 57 53 41 28 10

62.33 33.97 140.12 16.45 16.15 3.94 29.14 0.5 23.23 19.85 41.01 52.74 54.79 9.34 18.47 40.92 74.27 2.29 10.02 10.11 28.97 8.33 97.85 0.74 16.83 14.99 2.76 0.37 8.82 25.77 1.49 1.11 5.46 4.76 1.96 1.88 10.28 8.56 3.14 6.69 3.02 4.89 2.44 0.8 1.69 4.22 3.43 2.43 3.84

4.72 2.46 7.51 7.06 5.03 33.56 0.57 0.24 4.41 1.14 4.37 3.13 0.49 9.92 1.01 8.63 0.25 4.25 1.71 0.63 1.31 3.59 1.47 3.28 0.88 0.32 0.31 3.98 1.29 1.28 2.14 3.65 1.25 1.09 0.63 1.06 0.54 0.19 0.64 1.07 0.6 1.55 0.73 0.42 0.68 0.19 0.91 0.84 1.08

Vibrational modes (>10% PED)

bNH2wag(23), bCH2(11), mCC(35), mNC(18) bCH2wag(10), bNH2wag(12), bCOC(27), mCC(27) mCC(62), bCCH(8), bCHO(11) bCH2scs(86) bCOC(43), mCC(19), bCCH(10), cCHO (20) mCC(15), mNC(12), bCH2tws(45), cCCH (14) bNH2tws(65), bCH2tws(34) cCH(21), bNCH(28), mCC(19) bCH2rock(34), bNH2rock(35), cCH(11), bCCC (8) cCH(71) cCH2tws(36), bNH2tws(45) bNH2wag(27), cCH2tws(57) cCH(78) bCHO(12), bCCO(13), cCCC(36), cCH(21) sHCCC(12), sCCOH(62) cCH(42), d CH2(23), mCC(10) bNH(100) bCCHH(25), cCCCC(40), cCCOC(16) bCCC(56), sCCCH(44) sCCOH(41), bCC(12), bCCC(7) cCH2tws(37), bCH3wag(16), bCCC(23), bCCO(10) bCH2tws(28), bNH2scs(24), bNCH(17), mCH(7), cCOH(13) bOH(84) bNH2wag(45), sCCOH(16), cCCNH(14) bCH2tws(32), bNH2wag(21), mCH(19), mNH(4), mCO(10), bCOH(9) sCCC(27), sCCH(14), sCCOH(16) bCH3wag(76) bCH2rock(7), bCH3wag(45), sCCOH(9), bCCC(13), cCCCH(10) sCHO(11), bCCO(26), bCCC(12), mCC(25) bNH2wag(12), cCH2roc(24), bCH3wag(10), cNCCH(34), sCOH(12) bCCC(30), sCCCH(10), sCCOH(12) sCCC(41), bCCN(29), bCC(11), mCH(14) sCH3(54) sCH2(36) Ring breathing (64) bCH3tws(35), cCH2rock(28), mCC(34) tNH2(23), bCCC(44), mCH(5) bNH2tws(13), sCCCC(21) sNH2(23), sCCOH(20), mOH(31), CH3 rock(27) bNH2rock(43), bCH3rock(34), bCCO(14) bCH(45), bCH3(27) bNH2roc(40), bCH2rock(34) bCH2rock(56), bNH2rock(20), mCH(12) cCCNH(34), sCCCH(37), sCCOH(28) sCCO(41), cCCC(22) cCH3rock(87) bCCC(20), cCCNH(42), sCCCH(10), sCCOH(14) bCCC(88), mCC(10) sCCOH(67)

Notes: s: strong, vs: very strong, m: medium, ms: medium strong, w: weak, v:stretching, ops: out of plane stretching, ips: in plane stretching, s: torsion, b: in plane bending, c: out of plane bending, sym: symmetric stretching, asym: asymmetric stretching, scs: scissoring, wag: wagging, rock: rocking, tws: twisting. a Scaling factor: 0.961 for DFT(B3LYP)/6-311++G(d,p). b Relative absorption intensities normalized with highest peak absorption equal to 100. c Relative Raman intensities normalized to 100.

R. Shahidha et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 134 (2015) 127–142

54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102

Observed frequencies (cm1)

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Table 6 The electric dipole moments (Debye), polarizability (in esu), b components and btot (10–30 esu) value of title compound calculated by B3LYP/6-311++G(d,p) method.

Fig. 3. FT-IR spectra of midodrine: (A) experimental and (B) DFT/6-311++G(d,p).

Parameters

B3LYP/6-311++G(d,p)

Parameters

B3LYP/6-311++G(d,p)

lx ly lz l(D) axx axy ayy axz ayz azz a0 (a.u.) a (esu) Da0 (au) Da (esu)

0.04006 1.176365 0.267002 1.20695 212.697 3.19475 199.311 10.233 1.95826 126.544 179.5207 2.6605  1022 377.05 5.5879  1023

bxxx bxxy bxyy byyy bxxz bxyz byyz bxzz byzz bzzz btot (a.u.) btot (esu)

130.287 20.9321 77.5262 51.68175 15.8881 17.2365 18.6222 7.72896 3.75974 11.3341 102.4896 8.8536  1030

[27,28]. The Mulliken atomic charges of midodrine molecule calculated by B3LYP/6-311++G(d,p) basis set. Calculation of effective atomic charges plays an important role in the application of quantum chemical calculations to molecular systems. The results of the calculated charges at B3LYP/6-311++G(d,p) is listed in Table 8. The charges depending on basis set are changed due to polarizability. The H23 and H27 atoms have more positive charges than any other atoms. This is due to the presence of electro negativity of oxygen atoms and nitrogen atoms; the hydrogen atoms attract the positive charge from the oxygen and nitrogen atoms. The N1 and O13 atoms are more negative charges than the other atoms due to electron accepting substitutions at that position in midodrine. The result suggests that the atoms to O. N atoms and all H atoms are electron acceptor and charge transfer takes place from O and N to H in midodrine respectively. Global and local reactivity descriptors The energy gap between HOMO and LUMO is a critical parameter to determine molecular electrical transport properties. By using HOMO and LUMO energy values for a molecule, the global chemical reactivity descriptor of molecules such as hardness, chemical potential, softness, electronegativity and electrophilicity index as well as local reactivity have been defined [29–33]. Pauling introduced the concept to attract electrons to it. Using Koopman’s theorem for closed shell compounds can be defined as

l ¼ ðI  AÞ=2 and v ¼ ðI þ AÞ=2 Fig. 4. FT-Raman spectra of midodrine: (A) experimental and (B) DFT/6311++G(d,p).

100 to 1000 K due to the fact that the molecular thermodynamic the calculation of enthalpy change. The corresponding fitting equations are as follows and the correlation graphs are shown in Fig. 5.

C 0p;m S0m

4

¼ 34:74495 þ 1:03145 T  4:06897  10

4

¼ 278:92676 þ 1:21276 T  2:96024  10

2

2

T ðR ¼ 0:9996Þ 2

2

T ðR ¼ 0:9999Þ

H0m ¼ 11:81791 þ 0:13746 T  2:93495  104 T 2 ðR2 ¼ 0:9995Þ:

Mulliken atomic charges The Mulliken atomic charges are calculated by determining the electron population of each atom as defined by the basis function

where A and I are ionization potential and electron affinity of the molecules respectively. The ionization energy and electron affinity can be expressed through HOMO and LUMO orbital energies as

Table 7 Thermodynamic properties at different temperatures of the B3LYP/6-311++G(d,p) level. T (K)

Cop,m (cal mol1 K1)

Som (cal mol1 K1)

DHom (kcal mol1)

100 200 298.15 300 400 500 600 700 800 900 1000

139.17 221.72 301.79 303.31 382.92 452.71 510.66 558.37 598.04 631.44 659.84

391.36 513.66 617.04 618.91 717.23 810.39 898.22 980.64 1057.87 1130.29 1198.33

8.89 27.01 52.68 53.24 87.61 129.49 177.75 231.28 289.16 350.68 415.28

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R. Shahidha et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 134 (2015) 127–142

Fig. 5. Correlation graphs of thermodynamic properties at different temperature of the midodrine.

Table 8 Mulliken atomic charges of title compound obtained by B3LYP/6-311++G(d,p) method. Atom with numbering

B3LYP/6-311++G(d,p)

Atom with numbering

B3LYP/6-311++G(d,p)

N1 C2 C3 N4 C5 C6 C7 C8 C9 C10 C11 C12 O13 O14 O15 C16 O17 C18

0.44604 0.41434 0.065813 0.03775 0.60972 0.56447 1.245358 0.234308 0.63642 0.54992 0.07204 0.48344 0.3621 0.18397 0.16599 0.34099 0.19314 0.27302

H19 H20 H21 H22 H23 H24 H25 H26 H27 H28 H29 H30 H31 H32 H33 H34 H35 H36

0.231647 0.240032 0.197108 0.181502 0.338121 0.196543 0.210659 0.278158 0.300038 0.14626 0.186506 0.161622 0.180339 0.155771 0.161203 0.15854 0.164683 0.155049

I = EHOMO and A = ELUMO, electron affinity refers to the capability of a ligand to accept precisely one electron from a donor. The ionization potential calculated by B3LYP/6-311++G(d,p) is 5.1716 eV. Considering, the chemical hardness, large HOMO–LUMO gap means a hard molecule and small HOMO–LUMO gap means a small molecule. One can also relate the stability of the molecule hardness, which means that the molecule with least HOMO–LUMO gap means it, is more reactive. Recently Parr et al. have defined a new descriptor to quantity the global index which defines as quantitative classification of global electrophilic nature of the compound. Parr et al. have proposed electrophilicity index as a measure of energy lowering due to maximal electron flow between donor and acceptor. Fukui functions DFT is one of the important tools of quantum chemistry to understand popular chemical potential and ionization potential [34]. The electron density-based local reactivity descriptors such as Fukui functions are proposed to explain the chemical selectivity or reactivity at a particular site of a chemical system [35]. Electron density is a property that contains all the information about the molecular system and plays an important role in calculating almost all these chemical quantities. Parr and Yang [36] proposed a finite difference approach to calculate Fukui function indices.

i.e. nucleophilic, electrophilic and radical attacks. Fukui indices are, in short, reactivity indices; they give us information about which atoms in a molecule have a larger tendency to either loose or accept an electron, which are chemist interpret as which are more prone to undergo a nucleophilic or an electrophilic attack, respectively. The Fukui function is defined as [37].

 f ðrÞ ¼

 dqðrÞ r @N

where q(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 preferred regions where a chemical species will change its density when the number of electrons is modified. Therefore. It indicates the propensity of the electronic density to deform at a given position upon accepting or donating electrons [38,39]. Also, it is possible to define the corresponding condensed or atomic Fukui functions on the kth atom site as,

fkþ ¼ qk ðN þ 1Þ  qk ðNÞ for nucleophilic attack fk ¼ qk ðNÞ  qk ðN  1Þ for electrophilic attack fk0 ¼ 1=2½qk ðN þ 1Þ  qk ðN  1Þ for radical attack

R. Shahidha et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 134 (2015) 127–142

where +, , 0 signs show nucleophilic, electrophilic and radical attack respectively. In these equations, qk is the atomic charge at the kth atomic site is the neutral (N), anionic (N + 1) and cationic (N  1) chemical species. The Fukui functions allows determining the pin point distribution of the active sites on a molecule, the value of this function is completely dependent of the kind of charges used. In order to solve the negative Fukui function problem, different attempts have been made by various groups [40–42]. Kolandaivel et al. [43] introduced the atomic descriptor to determine the local reactive sites of the molecular system. In the present study, the optimized molecular geometry was utilized in single-point energy calculations, which have been performed at the DFT for the anions and cations of the title compound using the ground state with doublet multiplicity. The individual atomic charges calculated by Mulliken population analysis (MPA) have been used to calculate the Fukui function is in Table 9 shows the fk and (sf)k values for the compound midodrine, using which one can find the complexities associated with fk values due to the negative values being removed in the (sf)k values. It has been found that MPA schemes predict C16 has higher f k value indicates the possible site for electrophilic attack. From the values reported in Table 9, MPA scheme predict the reactivity order for the electrophilic case as C16 > C12 > C18 > C5 > C6. The observation of the reactive sites by (sf) k is found almost identical to f k . Even though the (sf)k values are numerically less it should be worth nothing that the values are positive and the ordering of the reactivity has not changed in any case. The calculated f+k values predicts that the possible sites for nucleophilic attack is C18 > C2 > C11 > C16 > C8 > C10 > C5 > C6 > H28. From the tabulated values it is compare that the two kinds of attacks and it is possible to observe that, nucleophilic attack is bigger reactivity comparison than electrophilic attack. Table 9 Condensed Fukui table fk and descriptors (sf)k for midodrine. Atoms

f+k

f k

s+k f+k

 s k fk

N1‘ C2 C3 N4 C5 C6 C7 C8 C9 C10 C11 C12 O13 O14 O15 C16 O17 C18 H19 H20 H21 H22 H23 H24 H25 H26 H27 H28 H29 H30 H31 H32 H33 H34 H35 H36

0.004174 1.195469 0.420642 0.047844 0.178146 0.162951 0.056712 0.244808 0.010822 0.222292 0.519214 0.536179 0.026289 0.014059 0.016505 0.354823 0.056602 1.291423 0.348395 0.447504 0.256755 0.209381 0.095664 0.063299 0.062774 0.177346 0.009941 0.143495 0.251075 0.432613 0.300267 0.106675 0.089308 0.435479 0.759869 0.399942

0.016438 0.008306 0.008885 0.022786 0.005028 0.003663 0.024263 0.069248 0.035192 0.015912 0.043075 0.01547 0.080433 0.035274 0.088021 0.025639 0.056246 0.012895 0.022096 0.024595 0.02789 0.028465 0.000521 0.01962 0.007122 0.029785 0.0062 0.043672 0.064651 0.055475 0.045192 0.038416 0.033215 0.031036 0.038365 0.032297

0.000045 3.754938 0.464891 0.006014 0.083383 0.069765 0.00845 0.157462 0.000307 0.129829 0.708302 0.755345 0.001815 0.000519 0.000715 0.330787 0.008417 4.381907 0.318911 0.526162 0.173206 0.115186 0.024044 0.010527 0.010353 0.082635 0.000259 0.0541 0.165627 0.491794 0.236887 0.029898 0.020955 0.498265 1.517063 0.420262

0.000709 0.000181 0.000207 0.001364 0.000066 0.000035 0.001546 0.012599 0.003254 0.000665 0.004875 0.000628 0.016997 0.003269 0.020356 0.001727 0.008312 0.000436 0.001282 0.001589 0.002043 0.002128 0.000071 0.001011 0.000133 0.002331 0.0001 0.050111 0.010981 0.008086 0.005365 0.003877 0.002898 0.002528 0.003867 0.002741

137

NBO analysis Natural bond analysis provides a possible ‘natural Lewis structure’ picture of /, 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 inter-molecular interactions. The second-order Fock matrix was carried out to evaluate the donor–acceptor interactions in the NBO analysis [44]. The interactions result is 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 ¼ DEij ¼

qi ðF ij Þ2 ej  ei

where qi is the donor orbital occupancy, ej and ei are diagonal elements and Fij is the off diagonal NBO Fock matrix element. Natural bond orbital analysis provides an efficient method for studying intra and intermolecular bonding and interaction among bonds, and also provides a convenient basis for investigating in molecular systems. Some electron donor orbital, acceptor orbital and the interacting stabilization energy resulted from the second order micro-disturbance theory are reported [45,46]. 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 orbitals and formally unoccupied (antibond or Rydgberg) nonLewis NBO orbitals correspond to a stabilizing donor–acceptor interaction. NBO analysis has been performed on the molecule at the DFT/B3LYP/6-311++G(d,p) level in order to elucidate the intra molecular, rehybridization and delocalization of electron density within the molecule. The strong intramolecular hyper conjugative interaction of the r and p electrons of CAC to the antibond CAC bond in the ring leads to stabilization of some part of the ring as evident from Table 10. The intramolecular hyperconjugative interactions of p (C7AC12) orbital to p(C8AC9) and p(C10AC11) leads to strong stabilization energy of 19.01 kJ/mol and 21.27 kJ/mol, respectively. For p(C8AC9) orbital to p(C7AC12) and p (C10AC11) shows the strong stabilization energy of 29.74 kJ/mol and 19.31 kJ/mol. Similarly, the case of p(C10AC11) bonding orbital to antibonding orbital p(C7AC12) and p(C8AC9) shows the highest energy of 19.42 kJ/mol and 19.25 kJ/mol. The most important interaction energy in this molecule is electron donating from O15 LP(2) to the antibonding acceptor p(C8AC9) resulting high stabilization energy of 28.67 kJ/mol whereas for O17 LP(2) to the antibonding acceptor p(C7AC12) gives strong stabilization energy of 22.08 kJ/mol. Therefore, the maximum energy delocalization takes place in the p–p transition. The E(2) values and types of the transition are shown in table. Analysis of molecular electrostatic potential The total electron density and MEP surface of the molecules under investigation are constructed by using DFT/6-311++G(d,p) method. Molecular electrostatic potential (MEP) mapping is useful in the investigation of the molecular structure with its physiochemical property relationships [47–49]. The total electron density mapped with electrostatic potential surface and the contour map of electrostatic potential are shown in Figs. 6 and 7. The MEP which is a plot of electrostatic potential mapped onto the constant

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Table 10 Second order perturbation theory analysis of Fock matrix in NBO basis. Donor

Type

ED/e

Acceptor

Type

C3AO13 C2AH21 C2AC3 C2AH21 N1AH20 C3AO13 N4AC5 N1AH19 C3AN4 C3AO13 C3AN4 C3AO13 C3AO13 N4AC5 N4AH23 N1AC2 C2AC3 C3AN4 N4AH23 C2AH21 C3AO13 C2AC3 C3AN4 C6AC7 C3AO13 C5AH25 C3AN4 C6AC7 C7AC8 C7AC12 C3AN4 C6AH26 N4AH23 C6AO14 N4AC5 C5AC6 C7AC8 C7AC12 C8AC9 C11AC12 C12AO17 C5AH25 C7AC8 C7AC12 C5AH24 C7AC12 O14AH27 C6AC7 C6AO14 C7AC12 C8AC9 C8AH28 C9AO15 C12AO17 C6AC7 C6AH26 C7AC8 C8AH28 C11AC12 C11AH30 C12AO17 O17AC18 C8AC9 C10AC11 C6AC7 C7AC8 C8AH28 C9AC10 C10AH29 C7AC12 C10AC11 C7AC8 C7AC12 C8AC9



N1AC2 N1AH19 N1AH20

r r r

1.99381 1.9913 1.99081

C2AC3

r

1.97722

C2AH21

r

1.96791

C2AH22

r

2

C3AN4

r

1.9893

C3AO13

r

1.9414

N4AC5

p r

1.99296 1.98692

N4AH23

r

1.98276

C5AC6

r

1.97397

C5AH24

r

1.97844

C5AH25

r

1.97561

C6AC7

r

1.97309

C6AO14

r

1.9905

C6AH26

r

1.97256

C7AC8

r

1.96538

C7AC12

r

1.96674

p

1.64279

r

1.97604

p

1.65652

r

1.9748

C8AC9

C8AH28

r r r r r r r r r p r p r r r r r r r r p r r⁄ r r r r r r p r r r r r r r r r r r r r p r r r r r r r r r r r r r r r r r⁄ r p p r r r r r p p r r r

ED/e

E2

E(j)  E(I)

F(I,j)

0.01402 0.01183 0.07394 0.01183 0.00659 0.01402 0.0217 0.00728 0.07328 0.3117 0.07328 0.3117 0.01402 0.0217 0.02719 0.00872 0.07394 0.07328 0.02719 0.01183 0.3117 0.07394 0.07328 0.0349 0.01402 0.0145 0.07328 0.0349 0.01888 0.40736 0.07328 0.02567 0.02719 0.02872 0.0217 0.03991 0.01888 0.0304 0.02946 0.02651 0.03232 0.0145 0.01888 0.40736 0.02162 0.0304 0.01879 0.0349 0.02872 0.0304 0.02946 0.01538 0.02988 0.03232 0.0349 0.02567 0.01888 0.01538 0.02651 0.01343 0.03232 0.0103 0.40168 0.3704 0.0349 0.01888 0.01538 0.02243 0.01255 0.40736 0.3704 0.01888 0.0304 0.02946

2.15 1.8 1.91 0.98 I.52 0.67 4.67 2.71 0.7 5.36 2.46 2.14 1.16 1.14 0.56 0.52 0.89 1.31 1.3 1.07 1.37 2.11 1.23 1.35 5.22 1.22 1.35 0.84 0.96 2.25 1.65 2.41 4.04 4.03 1.76 0.62 2.66 1.98 2.25 2.88 0.51 0.92 1.19 0.54 2.6 4.11 2.35 1.9 0.84 3.59 4.16 1.44 4.11 3.68 1.81 0.56 3.31 2.42 4.57 2.23 0.66 3.06 19.01 21.27 2.96 4.33 1.25 4.17 2.14 21.74 19.31 1.46 4.56 0.91

1.35 1.02 1 1.02 I.05 1.23 0.99 0.93 1.01 0.54 1.01 0.54 1.44 1.19 1.25 1.38 1.41 1.54 1.47 0.74 0.39 1.11 1.24 1.15 1.26 1.06 1.1 1.01 1.16 0.63 1.1 0.89 0.93 0.79 1 1 1.18 1.19 1.17 1.19 0.95 1.23 1.37 0.24 0.9 1.06 0.94 1.11 0.99 1.26 1.24 1.13 1.06 1.03 1.11 1.1 1.26 1.14 1.26 1.14 1.03 0.98 0.28 0.28 1.12 1.26 1.14 1.28 1.15 0.29 0.29 1.08 1.09 1.07

0.048 0.038 0.04 0.028 0.036 0.026 0.061 0.045 0.024 0.052 0.045 0.033 0.037 0.033 0.024 0.024 0.032 0.041 0.039 0.025 0.023 0.044 0.025 0.035 0.072 0.032 0.035 0.026 0.03 0.037 0.037 0.041 0.055 0.04 0.038 0.022 0.05 0.043 0.046 0.052 0.02 0.03 0.036 0.021 0.043 0.059 0.042 0.041 0.026 0.06 0.064 0.036 0.059 0.055 0.04 0.022 0.058 0.047 0.068 0.045 0.046 0.049 0.066 0.07 0.051 0.066 0.034 0.065 0.044 0.072 0.067 0.036 0.063 0.028

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R. Shahidha et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 134 (2015) 127–142 Table 10 (continued) Donor

Type

ED/e

C9AC10

r

1.97247

C9AO15

r

1.9916

C10AC11

r

1.97174

p

1.71517

C10AH29

r

1.97713

C11AC12

r

1.97762

C11AH30

r

1.97587

C12AO17

r

1.99079

O14AH27 O15AC16 C16AH31 O17AC18 C18AH35 N1

r r r r r LP(1)

1.98767 1.99325 1.99103 1.99348 1.9906 1.94925

N4

LP(1)

1.68343

O13

LP(1)

1.979

O14

LP(1)

1.97656

O15

LP(1)

1.96314

O17

LP(2) LP(1)

1.84972 1.95728

LP(2)

1.86729

Acceptor

Type

C9AC10 C9AO15 C8AC9 C8AH28 C9AO15 C10AC11 C10AH29 C11AH30 O15AC16 C7AC8 C8AC9 C9AC10 C10AC11 C9AC10 C9AO15 C10AH29 C11AC12 C11AH30 C12AO17 C7AC12 C8AC9 C8AC9 C9AC10 C9AO15 C10AC11 C11AC12 C6AC7 C7AC12 C10AC11 C10AH29 C11AH30 C7AC12 C9AC10 C10AC11 C11AC12 C12AO17 C7AC8 C7AC12 C10AC11 C11AC12 C6AH26 C9AC10 C9AO15 C7AC12 C12AO17 C2AC3 C2AH22 N4AH23 C5AC6 C5AH24 C6AC7 C2AC3 C3AN4 C5AC6 C6AC7 C6AH26 C8AC9 C9AC10 C16AH31 C16AH32 C16AH33 C8AC9 C7AC12 C11AC12 O14AH27 C18AH34 C18AH35 C18AH36 C7AC12



r r r r r r r r r r r⁄ r r r r r r r r p p r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r r p r r r r r r p

ED/e

E2

E(j)  E(I)

F(I,j)

0.02243 0.02988 0.02946 0.01538 0.02988 0.01206 0.01255 0.01343 0.0088 0.01888 0.02946 0.02243 0.01206 0.02243 0.02988 0.01255 0.02651 0.01343 0.03232 0.40736 0.40168 0.02946 0.02243 0.02988 0.01206 0.02651 0.0349 0.0304 0.01206 0.01255 0.01343 0.0304 0.02243 0.01206 0.02651 0.03232 0.01888 0.0304 0.01206 0.02651 0.02567 0.02243 0.02988 0.0304 0.03232 0.07394 0.02448 0.02719 0.03991 0.02162 0.0349 0.07394 0.07328 0.03991 0.0349 0.02567 0.02946 0.02243 0.00905 0.01942 0.01916 0.40168 0.0304 0.02651 0.01879 0.01851 0.00871 0.01871 0.40736

3.66 0.68 4.09 2.68 0.65 2.67 1.01 2.37 3.07 0.96 0.93 0.65 1.35 2.7 3.41 1.16 3.29 1.23 4.77 19.42 19.25 4.13 0.61 1.22 0.87 3.7 2.93 5.13 3.05 2.26 1.09 4.07 3.41 0.92 0.67 0.8 1.71 0.66 0.99 0.73 1.93 2.6 3.46 2.24 3.63 3.84 5.92 2.84 4.5 5.72 0.65 1.67 1.74 0.94 1.63 2.58 6.98 0.69 2.87 0.76 0.78 28.67 0.67 6.05 3.18 0.61 2.75 0.81 22.08

1.09 0.88 1.25 1.14 1.06 1.29 1.14 1.14 0.99 1.45 1.44 1.47 1.48 1.27 1.06 1.14 1.26 1.14 1.03 0.28 0.29 1.06 1.09 0.88 1.1 1.08 1.13 1.28 1.3 1.15 1.15 1.09 1.1 1.12 1.09 0.86 1.45 1.46 1.48 1.45 1.11 1.39 0.89 1.4 0.87 0.7 0.72 0.76 0.61 0.64 0.65 1.04 1.17 0.97 1.01 0.99 1.09 1.11 0.94 0.92 0.92 0.34 1.13 1.13 1.02 0.93 0.95 0.93 0.36

0.056 0.022 0.064 0.049 0.023 0.053 0.03 0.046 0.049 0.033 0.033 0.028 0.04 0.052 0.054 0.033 0.058 0.033 0.063 0.069 0.068 0.059 0.023 0.029 0.028 0.056 0.051 0.072 0.056 0.046 0.032 0.06 0.055 0.029 0.024 0.023 0.045 0.028 0.034 0.029 0.041 0.054 0.05 0.05 0.05 0.047 0.049 0.052 0.05 0.059 0.02 0.038 0.041 0.027 0.036 0.045 0.078 0.025 0.047 0.024 0.024 0.094 0.025 0.074 0.051 0.021 0.046 0.025 0.086

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R. Shahidha et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 134 (2015) 127–142

Fig. 8. UV–Visible spectrum of the midodrine compound.

Fig. 6. MEP map of the midodrine compound.

electron density surface. The MEP is a useful property to study reactivity given that an approaching electrophile will be attracted to negative regions (where the electron distribution effect is dominant). In the majority of the MEP, while the maximum negative

region which preferred site for electrophilic attack indications as red color, the maximum positive region which preferred site for nucleophilic attack symptoms as blue color. The importance of MEP lies in the fact that it simultaneously displays molecular size, shape as well as positive, negative and neutral electrostatic potential regions in terms of color grading. The resulting surface simultaneously displays molecular size and shape and electrostatic potential value. The different values of the electrostatic potential are represented by different colors. Potential increases in the order red < orange < yellow < green < blue. As can be seen from the MEP

Fig. 7. The contour map of molecular electrostatic potential surface of midodrine.

Table 11 The UV–Vis excitation energy DE and oscillator strength (f) for midodrine calculated by DFT/6-311++G(d,p) method. States

S1 S2 S3

kobs (nm)

275 224 210

kcal (nm)

Excitation energy (eV)

Oscillator strength (f)

Water

Gas

Water

Gas

Water

Gas

259 225 218

271 254 242

4.7783 5.4901 5.6682

4.5745 4.8800 5.1162

0.1168 0.0022 0.1231

0.0875 0.0007 0.0029

R. Shahidha et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 134 (2015) 127–142

141

map of the title molecule, while regions having the negative potential are over the electronegative atoms (CC group and nitrogen atom), the regions having the positive potential are over hydrogen atoms. From these results, we can say that the N (Nitrogen) atoms indicate the strongest attraction and O (Oxygen) atoms indicate the strongest repulsion. UV–Visible spectra analysis The UV–Visible spectral analysis of midodrine have been calculated by B3LYP/6-311++G(d,p) method along with measured UV–Visible data are summarized in Table 11 and the UV–Visible spectrum is shown in Fig. 8. The calculated visible absorption maxima of kmax which are function of the electron availability have been reported in Table 11. The Calculations of molecular orbital geometry show that the visible absorption maxima of this molecule correspond to the electron transition between frontier orbitals, such as translation from HOMO to LUMO as can be seen from the UV–Vis spectrum absorption maxima values have been found to be 275, 224 and 210 nm. The kmax is a function of substitution, stronger than donor character of the substitution, the more electrons pushed into the ring, the larger kmax values may be slightly shifted by solvent effects. The role of substituent’s and solvent are influence on the UV spectrum. This band may be due to electron transition of the ring to amine through bridge [transition of p] and the calculated results involving the vertical excitation energies, oscillator strength (f) and wave length. TD-DFT (B3LYP) with 6-311++G(d,p) predict one intense electronic transition at eV (218 nm) with an oscillator strength f = (0.1231) is good agreement for water with the measured experimental data (kmax = 210 nm) and (271 nm) with an oscillator strength f = (0.0875) is good agreement for gas phase with the measured experimental data (kmax = 275 nm) as shown in Fig. 8. The highest Occupied Molecular Orbital’s (HOMOs) and Lowest Unoccupied Molecular Orbitals (LUMOs) are named as Frontier molecular orbital’s (FMOs). The energy gap between the HOMOs and LUMOs is the critical parameters in determining molecular electrical transport properties helps in the measure of electron conductivity. To understanding the bonding feature of the title molecule, plot of the Frontier orbital’s, the highest occupied molecular orbital’s HOMO and lowest unoccupied molecular orbital’s LUMO as shown in Fig. 9. The HOMO shows that the charge density localized mainly on carbon and amine group where as LUMO is localized on ring system. HOMO–LUMO analysis

Fig. 9. The atomic orbital composition of the frontier molecular orbital of midodrine.

Table 12 Calculated energy values of midodrine by DFT/6-311++G(d,p) basis set. HOMO–LUMO

DFT/6-311++G(d,p)

EHOMO (eV) ELUMO (eV) EHOMO–LUMO gap (eV) EHOMO1 (eV) ELUMO+1 (eV) EHOMO1–LUMO+1 gap (eV)

5.8826 0.711 5.1716 6.5866 0.4493 6.1373

Molecular orbitals (MO’s) both the Highest Occupied Molecular Orbital (HOMO) energy value and Lowest Unoccupied Molecular Orbital (LUMO) and their properties such as energy are very useful for physicists and chemists are the main orbital taking part in chemical reaction. While the energy of the HOMO is directly related to the ionization potential, LUMO energy is directly related to the electron affinity [50,51]. This is also used by the frontier electron density for predicting the most reactive position in p-electron systems and also explains several types of reaction in conjugated system [52]. The conjugated molecules are characterized by a small Highest Occupied Molecular Orbital–Lower Unoccupied Molecular Orbital (HOMO–LUMO) separation, which is the result of a significant degree of intramolecular charge transfer from the end-gapping electron-donor groups to the efficient electronacceptor group through p-conjugated path [53]. Surfaces for the frontier orbitals are drawn to understand the bonding scheme of present compound. The energy difference between HOMO and LUMO orbital which is called as energy gap is a critical parameter in determining molecular electrical transport properties because it

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is a measure of electron conductivity, calculated 5.1716 eV for title molecule. The plots of MO’s (HOMO and LUMO) are shown in Fig. 9 and its energy values are given in Table 12. All the HOMO and LUMO have nodes. The nodes in each HOMO and LUMO are placed symmetrically. The positive phase is red and the negative is green. Conclusion FT-IR, FT-Raman, UV spectra and DFT quantum chemical calculations studies were performed on midodrine, in order to identify its structural and spectroscopic features. Several properties were carried out using experimental techniques and tools derived from DFT using 6-311++G(d,p) basis set. On the basis of experimental results and PED calculations, assignments of all the fundamental vibrational frequencies were done. NLO properties of midodrine are much greater than those of urea. The Mulliken atomic charges of the title molecule have been studied by DFT method, it suggests that the atoms to O, N atoms and all H atoms are electron acceptor and charge transfer takes place from O and N to H in midodrine respectively. The calculated HOMO, LUMO energies and NBO show that charge transfer occurs within molecule. The MEP map shows that the negative potential sites are on oxygen atoms as well as the positive potential sites are around the nitrogen atoms. These sites may provide information about the possible reaction regions for the title structure. Furthermore, theoretical calculations give the thermodynamic properties (heat capacity, entropy and enthalpy) for the compound. It can be observed that these thermodynamic functions are increasing with temperature ranging from 100 to 1000 K due to the fact that the molecular vibrational intensities increase with temperature. And also Fukui functions; local softness and electrophilicity indices for the selected atomic sites in midodrine have been calculated. Therefore, we hope the results of this present study will help researchers to analyze and synthesize new materials. Acknowledgement A. A. Al-Saadi thanks King Fahd University for Petroleum & Minerals (KFUPM) for providing the computing facility to support this work. References [1] R.A. Wright, H.C. Kaufmann, R. Perera, T.L. Opfer-Gehrking, M.A. McElligott, K.N. Sheng, P.A. Low, A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension, Neurology 51 (1998) 120–124. [2] C.T. Supuran, A. Scozzafava, A. Casini, Med. Res. Rev. 23 (2003) 146–189. [3] Donna McTavish, Karen L. Goa, Midodrine – a review of its pharmacological properties and therapeutic use in orthostatic hypotension and secondary hypotensive disorders, Drugs 38 (5) (1989) 757–777. [4] G. Ramachandran, S. Muthu, J. Uma Maheswari, Solid State Sci. 16 (2013) 45– 52. [5] N.R. Sheela, S. Sampathkrishnan, M. Thirumalai Kumar, S. Muthu, Spectrochim. Acta A 112 (2013) 62–77. [6] Gaussian 03 Program, Gaussian Inc., Wallingford, CT, 2004.

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