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ISSN: 2329-9053
Journal of Molecular Pharmaceutics & Organic Process Research
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Vibrational and NMR Investigation on Pharmaceutical Activity of 2,5- Dimethoxy-4-Ethylamphetamine by Theoretical and Experimental Support

A Madanagopal1, S Periandy2, P Gayathri1, S Ramalingam3* and S Xavier4

1Department of Physics, Periyar Maniammai University, Thanjavur, Tamilnadu, India

2Department of Physics, Kanchi Mamunivar Centre for PG studies, Puducherry, India

3PG and Research Department of Physics, A.V.C. College, Mayiladuthurai, Tamilnadu, India

4Department of Physics, St. Joseph College of Arts and Science, Cuddalore, Tamil Nadu, India

Corresponding Author:
S Ramalingam
PG and Research Department of Physics
A.V.C. College, Mayiladuthurai, Tamilnadu, India
Tel: 04364 222264
Fax: 04364 222264
E-mail: [email protected]

Received Date: January 31, 2017; Accepted Date: February 28, 2017; Published Date: March 07, 2017

Citation: Madanagopal A, Periandy S, Gayathri P, Ramalingam S, Xavier S (2017) Vibrational and NMR Investigation on Pharmaceutical Activity of 2,5-Dimethoxy-4-Ethylamphetamine by Theoretical and Experimental Support. J Mol Pharm Org Process Res 5:135. doi: 10.4172/2329-9053.1000135

Copyright: © 2017 Madanagopal A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

The Detailed physical, chemical, thermal and circular vibrational investigations have been made on FT-IR, FTRaman, NMR and UV-Visible spectra of 2,5-Dimethoxy-4-ethylamphetamine. The modification of the basic property (deficit hyperactivity disorder) of the base compound (Amphetamine) is favoured by the insertion of two methoxy and ethyl-methyl groups have been discussed in detail. The transitional pattern among NBO emphasized the inducement of the psychedelic activity in the compound. The strong interpretation made on the physical and chemical properties by intense observation using excitations between the electronic energy levels within the molecule have been carried out. The arrangement of the dipole moment of the bonds and the change of resultant magnetic moment were observed from the average Polarizability first order diagonal hyperpolarizability. The receptor and inhibition property of the molecule were interpreted by the identification of reactive sites from molecular electrostatic potential contour map. The chemical reaction continuity is keenly observed from thermodynamical analysis.

Keywords

2,5-Dimethoxy-4-Ethylamphetamine; Amphetamine; Transitional Pattern; Hyperactivity Disorder; Amphetamine; Chemical Reaction Continuity

Introduction

The 2,5-Dimethoxy-4-ethylamphetamine is commonly known as substituted amphetamines and is a psychedelic(also known as psychotogenic) drug [1,2]. It has an active stereocenter which is more active enantiomer and it is a potent and long-acting psychedelic [3,4].

The compound is composed systematically and heavily by methoxy, methyl, ethyl and amino substitutions. Two methoxy groups are loaded symmetrically at ortho and meta positions of left and right moiety respectively of the benzene ring. Similarly, the chain of ethyl and methyl groups substituted at ortho in right moiety whereas the chain of ethyl and methyl groups along with amino ligand present at meta position of left moiety.

The benzene ring with chain of CH, CH2, CH3, and NH2 groups forms alpha-methylphenethylamine called as Amphetamine. It is a potent drug which stimulant central nervous system (CNS) and is used for the treatment of attention deficit hyperactivity disorder, narcolepsy and obesity [5,6]. The compound; Amphetamine drug existed in two enantiomer forms, such as levoamphetamine and dextroamphetamine.

Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Hence, when the Amphetamine is substituted by symmetrical insertion of two methoxy and asymmetrical addition of ethyl-methyl groups, the composite compound is changed as psychotogenic drug.

In spite of its important pharmaceutical applications thereof; 2,5- Dimethoxy-4-ethylamphetamine has not been subjected to systematic investigation on the structure activity related to its pharmaceutical potential. Therefore, the present investigation is made for the strong interpretation on the structure activity associated with active drug property of the compound using FT-IR, FT-Raman, NMR and UVVisible spectroscopical data and computational results.

Experimental Profile

Physical state

The compound has been taken in solid form which is pure and spectroscopic grade.

Recording profile

The FT-IR and FT-Raman spectra of the compound were recorded using a Bruker IFS 66V spectrometer and the instrument adopted with an FRA 106 Raman module equipped with aNd:YAG laser source operating at 1.064 μm line widths with 200 mW power [7].

The high resolution 1HNMR and 13CNMR spectra were recorded using 300 MHz and 75 MHz FT-NMR spectrometer [8].

The UV-Vis spectrum was recorded in the range of 200 nm to 800 nm, with the scanning interval of 0.2 nm, using the UV-1700 series instrument [9].

Computational Profile

In order to design the structure precisely, calculate geometrical parameters, display the Mulliken charge levels, study the vibrational spectral properties, observe the molecular orbital interactions, examine the frontier molecular transitions on the electronic structure, the entire quantum chemical computations were performed using the Gaussian 09 D. 01. version software program in core i7 computer [10].

The computational calculations were performed over entire geometrical parameters, vibrational frequencies, simulation of molecular structure and spectra using B3LYP and B3PW91 methods adopted with 6-31++G(d, p) and 6-311++G(d,p) basis sets (Table 1). The energy absorbance by the present compound related with electronic spectra, the NBO and HOMO-LUMO energies were calculated using time-dependent SCF method with best fit basis set. In the same way, the 1H and 13C NMR chemical shifts with respect to TMS were calculated by GIAO method using I-PCM model in combination with B3LYP/6-311++G(2d,p). The Mullikan charge assignment on different parts of the compound was calculated and was purposely elucidated for the determination of key factor for pharmaceutical activity of the compound. The dipole moment, linear polarizability and the first order hyper polarizability in different coordinates of the compound were computed using B3LYP method with the 6-311++G(d,p) basis set. The ECD and VCD spectra were simulated from available frequencies and the optical chirality was studied and the mechanism for masking the toxicity was interpreted.

Geometrical Parameters Methods
HF/6-311++G(d,p) B3LYP/6-311++G(d,p) CAM-B3LYP/6-311++G(d,p) B3PW91/6-311++G(d,p)
Bond length(Å)
C1-C2 1.391 1.404 1.402 1.4
C1-C6 1.386 1.397 1.396 1.394
C1-O12 1.381 1.403 1.374 1.367
C2-C3 1.39 1.401 1.397 1.395
C2-C13 1.511 1.511 1.51 1.505
C3-C4 1.386 1.397 1.396 1.394
C3-H7 1.071 1.08 1.082 1.083
C4-C5 1.39 1.404 1.402 1.4
C4-O10 1.381 1.403 1.375 1.368
C5C-6 1.389 1.4 1.396 1.394
C5-C9 1.511 1.513 1.511 1.506
C6-H8 1.071 1.08 1.082 1.084
H7-H26 3.229 3.24 1.093 1.094
C9-H14 1.082 1.091 1.094 1.095
C9-H15 1.085 1.093 1.539 1.532
C9-C34 1.536 1.543 1.418 1.41
O10-C11 1.426 1.449 1.096 1.097
C11-H16 1.082 1.092 1.096 1.096
C11-H17 1.082 1.092 1.089 1.09
C11-H18 1.076 1.085 1.418 1.41
O12-C30 1.426 1.449 1.092 1.093
C13-H19 1.08 1.089 1.097 1.097
C13-H20 1.087 1.096 1.544 1.538
C13-C21 1.541 1.549 1.093 1.095
C21-H22 1.081 1.091 1.535 1.53
C21-C23 1.535 1.54 1.473 1.466
C21-N27 1.461 1.475 1.094 1.094
C23-H24 1.085 1.092 1.096 1.097
C23-H25 1.087 1.095 1.093 1.094
C23-H26 1.083 1.091 1.015 1.014
N27H28 0.995 1.012 1.017 1.016
N27H-29 0.997 1.014 1.096 1.097
C30-H31 1.082 1.092 1.095 1.096
C30-H32 1.082 1.092 1.089 1.09
C30-H33 1.076 1.085 1.092 1.092
C34-H35 1.082 1.089 1.094 1.094
C34-H36 1.085 1.092 1.093 1.094
C34-H37 1.084 1.092 1.093 1.089
Bond angle(?)
C2-C1-C6 120.784 120.931 120.213 120.137
C2-C1-O12 116.171 115.552 116.033 116.079
C6-C1-O12 123.044 123.515 123.752 123.781
C1-C2-C3 117.628 117.577 117.892 117.935
C1-C2-C13 121.133 120.971 120.945 120.851
C3-C2-C13 121.23 121.448 121.159 121.211
C2-C3-C4 121.599 121.493 121.888 121.917
C2-C3-H7 118.212 118.041 117.895 117.846
C4-C3-H7 120.187 120.464 120.215 120.234
C3-C4-C5 120.706 120.874 120.181 120.107
C3-C4-O10 123.173 123.619 123.791 123.808
C5-C4-O10 116.119 115.505 116.026 116.083
C4-C5-C6 117.77 117.697 117.981 118.026
C4-C5-C9 121.15 120.971 121.092 120.994
C6-C5-C9 121.076 121.325 120.92 120.972
C1-C6-C5 121.509 121.423 121.841 121.872
C1-C6-H8 120.213 120.461 120.226 120.232
C5-C6-H8 118.277 118.114 117.931 117.894
C3-H7-H26 73.274 72.766 109.291 109.233
C5-C9-H14 109.292 109.165 108.782 108.799
C5-C9-H15 108.884 108.96 113.286 113.092
C5-C9-C34 112.966 113.257 106.967 106.921
H14-C9-H15 107.182 107.132 108.959 109.087
H14-C9-C34 109.046 108.777 109.359 109.519
H15-C9-C34 109.303 109.365 109.78 118.315
C4-O10-C11 121.649 119.028 118.681 111.675
O10-C11-H16 111.196 111.416 111.595 111.657
O10-C11-H17 111.179 111.386 111.582 106.057
O10-C11-H18 105.645 105.184 105.919 109.207
H16-C11-H17 109.613 109.63 109.27 109.051
H16-C11-H18 109.538 109.535 109.169 109.095
H17-C11-H18 109.585 109.586 109.21 118.4
C1-O12-C30 121.75 119.091 118.753 109.896
C2-C13-H19 109.812 110.1 109.821 108.935
C2-C13-H20 108.896 109.047 108.884 115.006
C2-C13-C21 115.273 115.216 115.268 107.143
H19-C13-H20 107.267 107.323 107.149 107.027
H19-C13-C21 106.86 106.443 106.958 108.54
H20-C13-C21 108.433 108.408 108.453 107.237
C13-C21-H22 107.515 107.157 107.377 112.35
C13-C21-C23 112.788 112.6 112.532 107.752
C13-C21-N27 107.909 107.887 107.719 108.774
H22-C21-C23 108.943 108.989 108.756 106.51
H22-C21-N27 106.788 106.619 106.375 113.86
C23-C21-N27 112.604 113.247 113.723 110.672
C21-C23-H24 110.247 110.3 110.576 110.654
C21-C23-H25 110.619 110.442 110.679 111.737
C21-C23-H26 111.933 111.948 111.753 107.726
H24-C23-H25 107.745 107.806 107.751 107.949
H24-C23-H26 108.063 108.153 107.948 107.952
H25-C23-H26 108.091 108.054 107.984 110.432
H7-H26-C23 97.0435 98.176 110.619 110.191
C21-N27-H28 115.959 113.805 110.455 106.554
C21-N27-H29 115.758 113.459 106.733 111.696
H28-N27-H29 112.717 110.925 111.613 111.605
H12-C30-H31 111.215 111.432 111.525 106.019
O12-C30-H32 111.147 111.33 105.885 109.222
O12-C30-H33 105.607 105.154 109.285 109.071
H31-C30H-32 109.617 109.639 109.189 109.129
H31-C30-H33 109.542 109.56 109.25 110.75
H32-C30-H33 109.627 109.623 110.766 110.851
C9-C34-H35 110.532 110.424 110.743 111.029
C9-C34-H36 110.638 110.714 111.009 108.042
C9-C34-H37 110.987 111.017 108.082 108.021
H35-C34-H36 108.195 108.201 108.091 108.024
C35-C34H-37 108.339 108.303 108.032 108.068
H36-C34-H37 108.048 108.08 108.11 108.126
Dihedral angle(º)
C6-C1-C2-C3 0.2271 0.2242 -0.324 -0.3673
C6-C1-C2-C13 179.2725 179.7039 -179.731 -179.94
O12-C1-C2-C3 179.6798 79.6527 179.2584 179.155
O12-C1-C2-C13 0.6344 0.173 -0.1483 -0.4175
C2-C1-C6-C5 -0.0646 0.0888 -0.0672 -0.0459
C2-C1-C6-H8 79.6903 79.6153 179.5592 179.6015
O12-C1-C6-C5 179.9649 179.9555 -179.616 -179.53
O12-C1-C6-H8 -0.21 -0.2515 0.0105 0.1171
C2-C1-O12-C30 -174.47 176.1274 -176.683 -176.968
C6-C1-O12-C30 5.4349 3.7459 2.8833 2.5358
C1-C2-C3-C4 0.4012 0.4049 0.4779 0.5127
C1-C2-C3-H7 179.3774 179.394 -179.226 -179.193
C13-C2-C3-C4 179.4455 179.882 179.8833 -179.916
C13-C2-C3-H7 -0.333 0.0831 0.1797 0.379
C1-C2-C13-H19 46.169 46.8291 46.0494 45.665
C1-C2-C13-H20 163.3504 164.332 163.0863 162.7675
C1-C2-C13-C21 -74.5629 -73.5367 -74.8138 -75.1622
C3-C2-C13-H19 -132.842 -132.63 -133.338 -133.894
C3-C2-C13-O20 -15.6605 -15.1274 -16.3009 -16.7915
C3-C2-C13-C21 106.4263 107.0039 105.7989 105.2788
C2-C3-C4-C5 -0.2852 -0.2765 -0.2377 -0.2405
C2-C3-C4-O10 179.8851 179.9045 -179.927 -179.901
H7-C3-C4-C5 179.489 79.5175 179.4591 179.4578
H7-C3-C4-O10 -0.3407 -0.3014 -0.2304 -0.2022
C2-C3-H7-H26 -59.4852 -59.615 -0.1607 -0.1807
C4-C3-H7-H26 120.733 120.584 178.9917 178.8832
C3-C4-C5-C6 -0.0153 -0.0438 179.5522 179.5047
C3-C4-C5-C9 179.3232 79.1222 -1.2955 -1.4314
O10-C4-C5-C6 179.8259 179.7891 1.6901 1.638
O10-C4-C5-C9 -0.8355 -1.0448 -178.011 -178.035
C3-C4-O10-C11 2.3475 2.2294 0.3115 0.3225
C5-C4-O10-C11 -177.489 -177.598 -179.323 -179.333
C4-C5-C6-C1 0.1873 0.2234 -178.842 -178.742
C4-C5-C6-H8 179.5722 179.4874 1.5231 1.6031
C9-C5-C6-C1 179.1517 178.9396 42.3411 41.8907
C9-C5-C6-H8 1.0887 1.3497 158.8045 158.2769
C4-C5-C9-H4 42.0464 43.2342 -79.3545 -79.7956
C4-C5-C9-H15 158.8247 159.9241 -138.532 -139.073
C4-C5-C9-C34 -79.5454 -78.1186 -22.0681 -22.6869
C6-C5-C9-H14 -138.637 137.6302 99.7729 99.2406
C6-C5-C9-H15 -21.8586 -20.9403 60.2666 60.2085
C6-C5-C9-C34 99.7713 101.017 -179.827 -179.875
C3-H7-C6-C23 125.5512 125.2534 -59.8252 -59.7981
C5-C9-C34-H35 60.7348 60.6445 -61.615 -61.5602
C5-C9-C34-H36 -179.438 -179.543 58.2913 58.3561
C5-C9-C34-H37 -59.4996 -59.4932 178.2932 178.4331
H14-C9-C34-H35 -60.9959 -60.9262 -178.216 -178.268
H14-C9-C34-H36 58.8312 58.8861 -58.3095 -58.3518
H14-C9-C34-H37 178.7697 178.9361 61.6924 61.7253
H15-C9-C34-H35 -177.872 -177.625 -62.1885 -62.2328
H15-C9-C34-H36 -58.045 -57.8131 60.3786 60.3644
H15-C9-C34-H37 61.8935 62.237 179.1162 179.088
C4-O10-C11-H16 -62.5093 -62.4929 -63.0582 -63.0069
C4-O10-C11-H17 59.927 60.2695 59.4997 59.5879
C4-O10-C11-H18 178.7322 178.9106 178.2336 178.3013
C1-O12-C30-H31 -64.418 -63.4613 59.2628 59.2119
C1-O12-C30-H32 58.015 59.2837 -60.3804 -60.2541
C1-O12-C30-H33 176.8317 177.9217 173.4756 173.5269
C2-C13-C21-H22 61.3757 60.8094 -63.1458 -63.1723
C2-C13-C21-C23 -58.7462 -59.019 177.211 177.3617
C2-C13-C21-N27 176.2293 175.2768 51.067 51.1427
H19-C13-C21-H22 -60.951 -61.5383 -178.406 -178.505
H19-C13-C21-C23 178.927 178.6333 61.9505 62.029
H19-C13-C21-N27 53.9026 52.9291 -64.1935 -64.19
H20-C13-C21-H22 -176.289 -176.717 179.7739 179.4964
H20-C13-C21-C23 63.5891 63.4547 -60.8983 -61.1621
H20-C13-C21-N27 -61.4353 -62.2495 59.4959 59.1624
C13-C21-C23-H24 -179.219 179.7443 60.9338 60.9309
C13-C21-C23-H25 -60.1479 -61.1871 -179.738 -179.728
C13-C21-C23-H26 60.4624 59.2642 -59.3443 -59.4031
H22-C21-C23-H24 61.4838 60.9816 -57.39 -57.6603
H22-C21-C23-H25 -179.446 -179.95 61.9378 61.6812
H22-C21-C23-H26 -58.8352 -59.4985 -177.668 -177.994
N27-C21-C23-H24 -56.791 -57.5096 -175.142 -175.66
N27-C21-C23-C5 62.2798 61.559 66.9091 66.8902
N27-C21-C23-H26 -177.11 -177.99 -60.2637 -60.8623
C13-C21-N27-H28 -158.498 -165.162 -178.212 -178.312
C13-C21-N27-H29 66.1179 66.742 59.4193 59.0155
H22-C21-N27-H28 -43.1647 -50.3384 -58.5294 -58.4343
H22-C21-N27-H29 -178.549 -178.434 -178.9 -178.879
C23-C21-N27-H28 76.3685 69.5166 68.974 68.982
C23-C21-N27-H29 -59.0159 -58.5792 58.398 58.391
C21-C23-H26-H7 -71.0767 -70.3717 70.692 70.684
24H-C23-H26-H7 167.3395 167.9067 167.256 167.281
H25-C23-H26-H7 50.9918 51.46 51.745 51.698

Table 1: Optimized geometrical parameters for 2,5-Dimethoxy-4-ethylamphetamine computed at HF and DFT [B3LYP] methods with 6-311+ +G(d,p) basis sets.

Results and Discussion

Structural deformation analysis

The Molecular Weight of the compound and the Monoisotopic Mass are found to be 223.31 g/mol and 223.15 g/mol respectively. The present compound acting as good inhibitor since the Hydrogen Bond Acceptor Count was 3 and Hydrogen Bond donor was 1. Due to 2 Rotatable Bond Count of the present compound, the molecule possesses five stable conformers with mirror symmetry. Since the Defined and undefined Atom Stereocenter count of the compound were found to be zero and one, the resultant dipole moment was so high. Since the covalently-bonded unit count was unity, the entire bonds were saturated. The rough Complexity of 4-Methoxy-3- methylbenzaldehyde was observed to be 198 which are very high enough to make multi dynamic functions.

The bond and tube type of present compound was displayed in the Figure 1 and the corresponding (111) plane crystal view of thereof shown in same. The compound under study was basically the derivative of Amphetamine which was composed with couple of methoxy group and ethyl-methyl groups. According to the previous work [11], the bond length between CC of the benzene ring was ranging from 1.392-1.397 Å. In this case, the substituted benzene ring was found to be multi dimensionally broken by the ligand and was evident by the stretching bond length of CC in the range of 1.397-1.404 Å. The entire CC bond length of the ring stretched out and the hexagonal pattern of the ring expanded. The bond length C2-C13 (bond between ring C and amino with ethyl-methyl group chain) was 0.002 Å lesser than C5-C9 (bond between ring C and ethyl-methyl group chain). The bond length limitation was mainly due to the placement of different groups in different dimensions. The ethylmethyl chain was moved apart from the chain due to the electrochemical polar forces. The symmetrical substitutions of methoxy groups proved their symmetry by the constant bond length; C1-O12=C4=O10=1.403Å.

molecular-pharmaceutics-organic-process-research-tube-type

Figure 1: The bond and tube type of 2,5-Dimethoxy-4-Ethylamphetamine.

The bond lengths of C-H of the methyl groups were 1.092, 1.092 and 1.085 respectively which are same for that entire methyl group’s present compound. This view showed the consistency of methyl groups. The bond angles C1-O12-C30 and C4-O10-C11 were found to same and were equal to 119? and making the R enantiomer which has four times potency in terms of psychedelic activity. The multiple injections of substitutional groups in the base ring showed the resultant molecule in mighty form and renovate the important pharmaceutical phase.

Mulliken charge analysis

The Mulliken charge level values of 4-Methoxy-3- methylbezaldehyde were displayed in the Table 2 and its diagram was shown in Figure 2. Generally, the charge levels are oriented in carbons (negatively charged) and hydrogen’s (positively charged) of the benzene ring without substitutions. When it is substituted, the charges are depleted with respect to the production of the polar and non-polar bonds among the atoms. Thus the charges are reoriented and dynamic chemical potential are generated for inducing the meticulous property. Here, the carbons C2 and C5 in the ring were found to be neutral where the important substitutions were injected whereas at the point of methoxy substitutions, the carbons C1 and C4 are appeared as positive due the sucking of negative charges by O in order to make polar dipoles in methyl group. Rest of two carbons were happened to be negative since there was no ligand. The benzene ring was stretched parallel to the long chain of methyl-ethyl groups.

Atom Position Charge level
C1 0.25
C2 0.021
C3 -0.144
C4 0.247
C5 0.033
C6 -0.149
C9 0.413
C11 -0.288
C13 -0.375
C21 -0.073
C23 -0.485
C34 -0.504
C30 -0.289
H7 0.168
H8 0.166
H14 0.195
H16 0.18
H17 0.181
H18 0.196
H19 0.205
H20 0.149
H22 0.2
H24 0.157
H25 0.146
H26 0.185
N27 -0.684
H28 0.28
H29 0.272
H31 0.178
H32 0.181
H33 0.198
H35 0.195
H36 0.167
H37 0.167
O12 -0.538
O10 -0.541

Table 2: Mulliken Charges of 2,5-Dimethoxy-4-ethylamphetamine

molecular-pharmaceutics-organic-process-research-tube-type

Figure 2: The Mulliken charge level values of 4-Methoxy-3-methylbezaldehyde

Dynamic state of charges generate strong dipole moments between the atoms and the substitutions in ortho and meta positions of the universal hexagonal pattern induced special pharmaceutical properties particularly antifungal and anti-biotic properties [12].

Here, two same substituent (methoxy group) were penetrated in ortho and meta positions and made strong dipole moments in the ring which was the main cause of the inducement of the psychedelic activity. There was neutral atom found at midpoint of the CH2-CH3- NH2 chain on meta position of left moiety of ring.

Usually, when the charges are abruptly depleted at a point of atom, a neutral region is formed due to asymmetrical suction of electron cloud. Here, C of CH group was changed as neutral for the creation of strong dipole moment which was also the reason of the incentive of the drug property.

Vibrational analysis

The distinct vibrational fundamental pattern of 2,5-Dimethoxy-4- ethylamphetamine was presented in Table. 3. The scanned FT-IR and FT-Raman vibrational frequencies of observed and simulated spectra by HF and DFT were matched and exhibited in the Figures 3 and 4 respectively. The present novel composite was assembled by two methoxy, two ethyl-methyl group and amino groups with benzene ring. The resultant compound consists of 37 atoms and the structure belongs to CS point group. The 105 fundamental modes of vibrations were dispersed as Γvib = 71A′ + 34 A″.

S. No. Symmetry Species CS Observed frequency(cm-1) Calculated frequency Vibrational Assignments
HF B3LYP B3PW91
FT-IR FT-Raman 6-311++G(d,p) 6-311++G(d,p) 6-311++G(d,p)
1 A′ 3250s - 3279 3298 3298 (N-H) υ
2 A′ 3220s - 3226 3230 3232 (N-H) υ
3 A′ - 3080s 3064 3098 3089 (C-H) υ
4 A′ - 3050s 3042 3035 3032 (C-H) υ
5 A′ - 3030s 3028 3018 3024 (C-H) υ
6 A′ - 3010s 3008 3010 3019 (C-H) υ
7 A′ 2970s - 2984 2988 2992 (C-H) υ
8 A′ 2950m 2950s 2948 2987 2995 (C-H) υ
9 A′ 2940w 2940s 2938 2962 2942 (C-H) υ
10 A′ 2930w - 2938 2946 2912 (C-H) υ
11 A′ 2910m - 2901 2906 2896 (C-H) υ
12 A′ 2900m - 2892 2894 2888 (C-H) υ
13 A′ - 2890m 2858 2865 2873 (C-H) υ
14 A′ 2870w 2870w 2835 2842 2838 (C-H) υ
15 A′ 2850w - 2824 2836 2816 (C-H) υ
16 A′ - 2840s 2818 2812 2807 (C-H) υ
17 A′ - 2835s 2808 2798 2791 (C-H) υ
18 A′ 2830m - 2802 2788 2789 (C-H) υ
19 A′ 2790w - 2789 2776 2765 (C-H) υ
20 A′ 2770w 2770vw 2735 2729 2754 (C-H) υ
21 A′ 2740w 2740w 2728 2713 2731 (C-H) υ
22 A′ - 1620s 1632 1625 1618 (N-H) δ
23 A′ - 1600s 1627 1614 1610 ( N-H) δ
24 A′ 1590s - 1608 1603 1598 (C=C) υ
25 A′ 1560s - 1580 1569 1562 (C=C) υ
26 A′ 1510m - 1528 1526 1511 (C=C) υ
27 A′ 1460m - 1475 1471 1460 (C-C)υ
28 A′ - 1440s 1466 1498 1482 (C-C)υ
29 A′ 1410s 1410s 1421 1426 1421 (C-C)υ
30 A′ 1380m - 1397 1375 1392 (N-H)γ
31 A′ 1370m 1370w 1387 1362 1374 (N-H)γ
32 A′ - 1345s 1361 1328 1321 (C-O) υ
33 A′ - 1340s 1338 1315 1312 (C-O) υ
34 A′ - 1305s 1325 1305 1309 ( C-H) δ
35 A′ - 1300s 1312 1298 1291 ( C-H) δ
36 A′ 1250m 1250s 1268 1251 1243 ( C-H) δ
37 A′ 1240m - 1269 1243 1221 ( C-H) δ
38 A′ 1225m 1225s 1236 1212 1209 ( C-H) δ
39 A′ - 1220s 1225 1208 1203 ( C-H) δ
40 A′ - 1185s 1198 1191 1172 ( C-H) δ
41 A′ - 1180s 1187 1174 1158 ( C-H) δ
42 A′ 1170s 1170vs 1168 1151 1146 ( C-H) δ
43 A′ - 1150s 1154 1138 1131 ( C-H) δ
44 A′ - 1140s 1135 1123 1118 ( C-H) δ
45 A′   1070m 1089 1079 1074 ( C-H) δ
46 A′ 1040s - 1069 1059 1035 ( C-H) δ
47 A′ 990m - 1003 996 988 ( C-H) δ
48 A′ - 980w 993 974 966 ( C-H) δ
49 A′ - 970m 987 961 947 ( C-H) δ
50 A′ - 960m 978 949 928 ( C-H) δ
51 A′ - 940w 958 922 916 ( C-H) δ
52 A′ - 920w 933 906 902 ( C-H) δ
53 A′ 880m - 901 892 867 ( C-N)υ
54 A′ 870m 870w 897 872 848 ( C-H)υ
55 A′ 850m - 872 848 824 ( O-C) υ
56 A′ 840m 840w 864 814 807 ( O-C) υ
57 A′ - 835s 842 803 799 ( C-C) υ
58 A′ 830w 830s 838 801 797 ( C-C) υ
59 A′ - 825s 832 821 781 ( C-C) υ
60 A′ - 820s 825 805 778 ( C-C)υ
61 A′ 810w - 822 792 773 ( C-C) υ
62 A′ 800w - 787 787 768 ( C-H) γ
63 A′ 795w - 781 781 760 ( C-H) γ
64 A″ 790w - 753 763 758 ( C-H) γ
65 A″ 780m - 824 824 746 ( C-H) γ
66 A″ - 760m 726 726 724 ( C-H) γ
67 A″ 750w - 780 780 718 ( C-H) γ
68 A″ 740w - 766 766 710 ( C-H) γ
69 A″ - 730m 755 755 705 ( C-H) γ
70 A″ - 720m 711 711 698 ( C-H) γ
71 A″ 688s - 702 702 694 ( C-H) γ
72 A″ 680s - 686 686 671 ( C-H) γ
73 A″ - 645s 646 646 639 ( C-H) γ
74 A″ - 640s 634 634 618 ( C-H) γ
75 A″ 600m - 605 605 606 ( C-H) γ
76 A″ 595w - 578 578 568 ( C-H) γ
77 A″ 590w - 567 567 566 ( C-H) γ
78 A″ 580w - 582 582 657 ( C-H) γ
79 A″ 570m 570w 566 556 592 ( C-H) γ
80 A″ 530w - 546 586 556 ( C-H) γ
81 A″ 560w - 537 577 536 ( C-O) δ
82 A″ 555w - 528 519 521 ( C-O) δ
83 A′ 530w 530w 517 507 513 ( C-C-C) δ
84 A′ - 500m 525 498 506 ( C-C-C) δ
85 A′ - 460w 470 470 472 ( C-C-C) δ
86 A′ - 450w 411 411 443 ( C-C-C) γ
87 A′ - 370m 388 388 378 ( C-C-C) γ
88 A″ - 360m 376 376 365 ( C-C-C) γ
89 A″ 340w 340m 351 351 348 ( C-O) γ
90 A″ 310 - 323 323 314 ( C-O) γ
91 A′ 300 300m 234 302 302 ( O-C)δ
92 A′ - 290m 219 288 288 ( O-C)δ
93 A″ - 250w 213 276 276 ( C-N) δ
94 A′ 240w 240vw 202 258 258 ( C-C) δ
95 A′ 230w - 188 238 238 ( C-C) δ
96 A′ 210w - 179 229 229 ( C-C) δ
97 A′ 170w 170vw 166 170 170 ( C-C) δ
98 A′ 160w 160vw 149 148 148 ( C-C) γ
99 A″ 150w - 123 134 124 ( C-C) γ
100 A″ 110w - 73 117 110 ( C-C) γ
101 A″ 100w 100w 68 101 91 ( C-C) γ
102 A″ 90w - 56 58 68 ( C-C) γ
103 A″ 80w - 51 54 48 ( O-C) τ
104 A″ 70w - 42 44 41 ( O-C) τ
105 A″ 50w - 38 37 37 (C-N) τ

Table 3: Observed and HF and DFT (B3LYP & B3PW91) with 6-31++G(d,p) & 6-311++G(d,p) level Calculated vibrational frequencies of 2,5- Dimethoxy-4-ethylamphetamine.

molecular-pharmaceutics-organic-process-research-Experimental

Figure 3: Experimental [A], Calculated [B], [C] and [D] FT-IR Spectra of 2,5-Dimethoxy-4-ethylamphetamine.

molecular-pharmaceutics-organic-process-research-Calculated

Figure 4: Experimental [A], Calculated [B], [C] and [D] FT-Raman Spectra of 2,5-Dimethoxy-4-ethylamphetamine.

To get a good correlation with the experimental vibrational modes, it is essential to correct the calculated fundamental frequencies. For this reason, one possible approach involves the rescaling of the force constant matrix, as proposed by Meyer and Pulay [13,14]. The improved procedure has been adopted certainly to improve the agreement between computed and experimental frequencies. However, it was preferable to introduce necessary scaling factors for the fundamental modes was the circuitous approach of scaling the force constants [15]. The HF calculated wave numbers were scaled by the factor 0.910, 0.857 and 0.808, 0.903. The method of B3LYP calculated wavenumbers were scaled by 0.874, 0.933, 0.910 and 0.852 and in the same way B3PW91were scaled by the factors 0.908, 0.914, 0.852 and 0.879 respectively.

Base ring C–H vibrations: Regularly, the ring and chain complex compound is linked with sustainable ligand tailored fascinated compound for the desired chemical properties. By injecting ligand groups with the base molecule, the vibrational fundamentals might be affected. The impression of interference of ligand group over the base can be measured from the rate of appearance of fundamental pattern of the frequencies and consequently pioneer property of the base compound is altered accordingly. Here, three dissimilar ligand groups were linked with the base compound and by studying the suppression of vibrational pattern of thereof, it can be concluded that, whether the property of the base is changed or not. Accordingly, in general, the CH stretching vibrations are observed in the region 3000-3100 cm1 for benzene derivatives [16-18]. In this case, the C-H stretching bands have been found with medium intensity at 3080 and 3050 cm1 in Raman spectrum only. Two vibrations were found within the expected region. This native attitude showed the less influence of ligand on the ring. Here, the C-H in plane and out of plane bending modes were found at 1305 and 1300 cm1 and 800 and 790 cm1 respectively. Usually, those vibrational two different bending bands identified in the region 1300-1000 cm1 and 1000-750 cm1 respectively [19-21]. The in plane bending were pushed well above the expected region whereas out of plane vibrations were pulled down to the lower end of the expected region. Unlike stretching, the bending modes have rather influenced since their strong dipole character of C-H. The entire ring C-H vibrations have not suffered much. This view cleared that, the ring C-H bonds took part in the inducement of new property of the compound.

CC vibrations: Generally, the CC (C=C and C-C) stretching vibrations for phenyl ring are observed in the region 1600 - 1400 cm1 [22-24], in which the wavenumbers in the region 1600 - 1500 cm1 are fundamentally assigned to C=C stretching and the rest to C-C stretching conventionally. In such a case, since C=C and C-C bonds are uncertainty in the ring, three bonds of each to be appeared. Accordingly, the C=C and C-C stretching bands were found at 1590, 1560 & 1510 cm1 and 1460, 1440 & 1410 cm-1 respectively. Though the substitutions strongly bonded with the ring and stretched diagonally, the bands related to C=C and C-C stretching were substantially found with strong and medium intensity within the expected region of the spectrum. This appearance depicted the ring enhancement for the compound being with spectacular property. The ring CCC in plane and out of plane breathing have been found at 460, 450 and 370 cm1 and 360, 340 and 310 cm1 respectively. Even a single ring breathing mode was not been identified within the limit of the observed region. From this condition, it was well known that, due to the loading of different ligand group with huge mass, the ring could not be breathed well.

Methyl groups vibrations: The substitution of methyl group with the aromatic ring expressed their vibrational frequencies for three; stretching, in plane and out of plane bending vibrations normally taking place in the region of 3000- 2750 cm1, 1250-950 cm1 and 950- 720 cm1[23,24] respectively. Accordingly, the stretching vibrational peaks have been identified at 3030, 3010, 2970, 2950, 2940 and 2930 cm-1, in plane bending vibrational peaks were found at 1250, 1240, 1225, 1220, 1185 and1180 cm-1 and out of plane bending signals were found at 780, 760, 750, 740, 730 and 720 cm-1.

All the CH3 stretching vibrations were located in asymmetric region of methyl group vibrations which represent the enhancement of CH3 group in the present molecule. Similarly, the bending group of bands; in plane vibrations was observed within the expected region whereas some of out of plane bending modes have appeared below the expected level. Hopefully, such the vibrational impression in the spectrum, explored the certainty that, the methyl group actively participate in the pharmaceutical reactivity.

The methyl group deformation vibrations are very rare to observe and if they are present, the methyl group will be making strong impact on the base structure [25]. Usually, the CH3 deformation vibrations are expected in the region 1460-1430 cm1 for methyl derivative compounds. But unfortunately, there was no deformation found in the vibrational sequence which was due to the existence of strong dipole moment between C and H.

OCH3 vibrations: The methoxy group is compiled with base ring at para position with respect to ethyl-methyl groups which plays the important role in the property of the product. In this case, the electron clouds on O are significantly high and created very weak interaction with C of methyl group. But it forms strong dipole moment with C of ring. Usually, in this condition, strong absorption taking place in IR spectrum. Here, the C-H stretching vibrations appeared with weak intensity at 2910, 2900, 2890, 2870, 2850 and 2840 cm1. Actually these vibrational region for C-H asymmetric and symmetric stretching is sectioned in the region 2860-2935 cm1 and 2825-2870 cm1 respectively [26,27]. But, here, most of the stretching belongs to asymmetric and rest of some located in symmetric. Therefore such consistent hike observed in the stretching limit and the above said effect was observed in this case. The in plane and out of plane bending modes were found at 1170, 1150, 1140, 1040, 990 and 980 cm1 and 688, 680, 645, 640, 600 and 595 cm1 respectively. The methoxy derivative compounds have multiple peaks by the absorptions related to C-H in plane and out of plane bending vibrations in the region 1250- 875 cm1 and 850-710 cm1 respectively. In this observation, the considerable impact was found in the out of plane bending absorption bands and this was surely by the asymmetric charge orientation on O.

The C-O and O-CH3 stretching mode is normally assigned in the region 1350-1300 [28] cm-1 and 1100-1000 cm1 respectively for anisole compounds. In this case, the C-O and O-CH3 stretching vibrations were happened at 1345 & 1340 cm1 and 850 & 840 cm1 respectively. Obviously, the C-O vibrational bands occupied at the top position of well above the expected region whereas the O-CH3 stretching moved down well below the expected region. This explicit that, the first part have participated in the product property which was found being active. The C-O in plane and out of plane deformations observed at 560 & 555 cm1 and 340 & 310 cm1 respectively. Similarly, the O-C in and out of plane bending modes was found at 300 & 290 cm1 and 80 & 70 cm1. These bending modes were found at far infrared region and such that the frequencies were also downward due to the rotational effect.

Ethyl group vibrations: The aliphatic C-H stretching bands are expected in the region 3000 - 2900 cm-1 [29,30]. In the present compound the vibrations of the ethyl group are observed at 2830, 2790, 2770 and 2740 cm-1. Similarly, the in-plane and out of-plane deformations of such C-H bond are expected in the regions 1200–1100 cm-1 and 900–700 cm-1 respectively. Four bands due to in-plane and out-of-plane bending are observed at 970, 960, 940 cm1 and 920 cm-1 and 590, 580, 570 and 530 cm1 respectively. These observations indicate that, the energy of stretching modes was consumed for the inducement of the new property. Similarly, the in-plane and out-ofplane bending vibrations are moved down from the expected region, because ethylene group acts as bridge between methyl and phenyl ring and it is always affected by either sides of the groups vibrations.

Amino group and C-N vibrations: Generally, the NH group vibrations are very dominative and no way have their vibrational bands not affected. Here the mono amine group was substituted along with the chain of ethyl-methyl group. When the NH group placed between chain and aromatic ring, the secondary N-H stretching vibrational frequencies are observed in the region 3360-3310 cm1 [31,32]. In this case, the N-H stretching bands were observed at 3250 and 3220 cm-1. The in plane and out of plane bending signals have appeared at 1620 & 1600 cm1 and 1380 & 1370 cm1 respectively. The N-H in plane and out of plane bending are expected in the range 1490-1580 cm-1 and 900-700 cm1 [33,34] respectively. In this case, the stretching vibrations were moved down well below the expected region where as in plane and out of plane bending bands moved up extremely well above the expected region. Due to the favouring of charge levels in amino group, the bending mode only were active. The C-N stretching vibrations, in plane bending and out of plane bending vibrations are generally observed in the region 1155-1130 cm1, 550-400 cm1 and 400-360 cm1 respectively [35,36]. In this title compound, the C-N stretching, in plane and out of plane bending bands were observed at 880, 250 and 50 cm1 respectively. These vibrations were affected much due to the lees energy availability and moved in far infrared region.

NMR Analysis

The paramagnetic shield of group of atoms is broken by the attainment of bonding. The chemical properties are alternatively changed with respected to the dynamic character of the electron cloud. Thus the chemical property is exchanged and modified according to the electronic charge transformation. Similarly, the molecule is formed by making bonds with substitutional groups. Therefore corresponding chemical property of the product-compound is complicated and which depends upon their asymmetrical displacement of electron clouds [11]. The change of chemical property is scaled by the chemical shift of associated atoms.

The computed values in gas and solvent phase, along with the experimental values are presented in the Table 4 and the experimental spectra are presented in Figure 5. The aromatic carbon atoms generally [37] have shifts in the range of 120-130 ppm. In the present compound the chemical shifts of the aliphatic carbon atoms C9, C11, C13, C21, C23, C30 and C34 were ranging from 11-55 ppm. But, the carbons of the aromatic ring; C1-C6 were lie in the range of 115-159 ppm experimentally and between 121-161 ppm theoretically. In the case of C3 and C6, there was no substitutional group found, the chemical shift was found to be 115 and 128 ppm respectively. But, the rest of others have large shift which was purely due to the asymmetrical breaking of the paramagnetic shield of the particular carbon. The chemical shift of C1 and C4 was so high which was mainly due to the energy transformation from methoxy group via ring. The transferred energy was exchanged between ring and ethyl-methyl groups. Due to this transformation, the particular carbon in the ring appeared to be neutral. Such a condition shows that, the inherent change of property of the benzene ring in this compound. This trend is in accordance with the charge predicted by Mullikan analysis.

Atom position Chemical Shift - TMS-B3LYP/6-311G(2d,p) (ppm) Experimental shift (ppm)
Gas Solvent phase
DMSO Chloroform
C1 158.9 157.99 158.28 159.5
C2 131.742 132.49 132.31 128.5
C3 127.77 129.28 128.75 129
C4 161.67 161.67 161.69 159.5
C5 136.46 136.11 136.2 130
C6 122.33 121.73 121.91 115
C9 20.77 20.46 20.55 15
C11 49.67 50.42 50.18 40
C13 25.3 24.81 24.96 15
C21 45.21 44.77 44.89 54.5
C23 34.69 34.01 53.67 38
C30 53.32 53.81 53.67 55
C34 8.35 8.2 8.24 11
H7 12.6 12.98 12.87 9.6
H8 5.8 5.92 5.88 7.2
H14 1.59 1.46 1.51 1.5
H15 0.57 0.65 0.61 -
H16 2.5 2.75 2.68 -
H17 1.7 1.93 1.89 1.2
H18 2.42 2.59 2.56 2.7
H19 1.74 1.53 1.61 -
H20 0.26 0.36 0.33 -
H22 1.27 1.34 1.32 -
H24 0 0.21 0.14 -
H25 0.64 0.4 0.48 -
H26 7.8 7.5 7.61 7.2
H28 0.84 0.55 0.64 -
H29 0.74 1 1.08 -
H31 2 2.21 2.18 -
H32 2 2.16 2.11 -
H33 2.4 2.54 2.56 -
H35 0.25 0.39 0.3 -
H36 0.25 0.27 0.487 -
H37 0.63 0.53 0.57 -

Table 4: Experimental and calculated 1H and 13C NMR chemical shift in 2,5-Dimethoxy-4-ethylamphetamine.

molecular-pharmaceutics-organic-process-research-ethylamphetamine

Figure 5: Experimental Spectra of 2,5-Dimethoxy-4-ethylamphetamine.

The chemical shift of carbon atoms C13 and C34 in the ethyl and methyl groups has of 15 and 11 ppm experimentally and 24 and 8 ppm theoretically, these were lower than the expected values. When the negative charge domain is dislocated towards the CH and NH2 groups, the negative charges were exchanged via C13 and made as virtually shielded and neutral.

So, the chemical shift of such carbon becomes very low and below 50 ppm. In the case of C34, the charges were moved asymmetrically to the ethyl group and making strong dipole. The chemical shift of C21 was found to be 54.5 ppm and made as neutral which was due to the absorption of charges by the amino group.

In this case, the chemical shift value was rather increased which was clearly due to the presence of four σ bond character.

The chemical shifts of the hydrogen atoms in benzene ring as well as methyl group are expected between 7-8 ppm. In this case, ring related hydrogen’s H7 and H8, the chemical shift was found to be within the limit at both experimentally and theoretically.

The entire H of alkyl, ethyl and methyl groups were found to be very low and some of the chemical shift was not observed. This view showed the charge prediction by Mullikan analysis for hydrogen atoms are correct. Except H7 and H8, the entire theoretical shift was found to be 0.5 - 2.0 ppm and this trend is in tune with the above literature.

There was no appreciable difference observed in the chemical shifts in different solvents phases. Hence the impact of the solvents on the chemical shifts of the compound for various atoms is negligibly small.

Frontier molecular interaction profile

After the assembly of molecular orbitals in the compound, the charge depletion region is formed generally between two elevated orbitals with different characteristics called HOMO and LUMO.

Such these orbitals are arranged with respect to the energy of bonded molecules and some the orbitals with same energy are usually overlapped with one another and intersected. The overlapped orbitals are shared by the electrons and they spent most of the time on blended orbitals separately in HOMO and LUMO.

The transitions taking place between those orbitals strongly set the chemical character of the compound and thus, the new physicochemical property was induced in the compound. The energy of Frontier molecular structure was depicted in the Table 5 and the diagram was displayed in Figure 6.

Energy levels IR region UV-Visible region
B3LYP/ 6311G Energy (eV) B3LYP/ 6311G Energy (eV)
H+10 -9.8918 -9.599
H+9 -9.6056 -9.469
H+8 -9.4709 -9.469
H+7 -9.1615 -9.1503
H+6 -9.0983 -9.0298
H+5 -9.0586 -8.2932
H+4 -8.799 -7.9593
H+3 -8.43 -7.3073
H+2 -7.731 -6.7925
H+1 -6.6733 -6.2474
H -5.8675 -6.0597
L -0.117 -0.3333
L-1 0.4764 0.0712
L-2 1.203 0.9455
L-3 1.3344 1.3698
L-4 1.6593 1.4645
L-5 1.9243 1.7567
L-6 2.2389 1.8569
L-7 2.382 1.9763
L-8 2.2389 2.415
L-9 2.382 2.5959
L-10 2.4558 2.6332

Table 5: Frontier molecular orbitals with energy levels.

molecular-pharmaceutics-organic-process-research-Frontier-molecular

Figure 6: Frontier molecular orbitals with energy levels.

Here, in HOMO, the right and left moiety (CCC semi-circle) of the ring system occupied by π- bond overlapping whereas methoxy group making δ-bond overlapping with O. There was no electron occupied orbitals found on ethyl and methyl groups’ and also there was no orbital interaction lobes were found on same system. In the case of LUMO, σ-bonding overlapping was appeared on the C-C and C-H of the ring and another σ-bond overlapping lobes were occupied over ring ethyl and methyl group whereas the methoxy groups were abandoned. From this view, it was clear that, the electron density were reoriented asymmetrically and they were prepared to provide the charges to the LUMO to induce chemical energy for generating psychotogenic character. In addition to that, HOMO+1, σ-bond lobes in cascade form were found at amino-ethyl-methyl chain group and some of the orbital interaction residue was observed over the ring carbons and methoxy groups. From this view, the chemical energy was started from this group and transferred via C of the ring. In the case of HOMO+2, there were strong π and δ-bond overlapping lobes identified over the ring carbons and two ethyl-methyl chains. From this view, it was observed that, the energy was exchanged between two chains via ring. There were no other lobes over rest of the atoms. In LUMO-1, two π-bond and three σ-bond overlapping of orbitals were to be appeared in ring and methoxy group while in the case of LUMO-2, only σ-bonded lobes were found in the ring. Form this display of orbital lobes; it was obvious that, in HOMO spatial quantization, the aggressive δ-bonding donor orbitals were available for supplying the chemical energy over the empty orbitals whereas in LUMO sequence, σ and π bonding lobes appeared on ring and ligand groups. This arrangement was suitable for creating the drug for treating hyperactivity disorder. For forming potential drug, the chemical energy transition was restricted among the orbitals by 5.325 eV which was very high and enough to sustain the property. The energy values of frontier molecular levels were presented in the Table 5.

UV-visible absorption analysis

The confinement of vibrational energy states depends on the impact of the ligand groups on the base molecule. The energy was supposed to be within the transition among the energy states which shift the vibrational pattern (wavenumber region) of the resultant compound from lower to higher or vice versa. Thus the electronic shift also is observed in the electronic energy states pattern. A charge transfer complex or electron donor-acceptor complex is associated with different energy domain of the molecule, in which electronic charges are transferred between the two entities of molecule. The resulting electrostatic attraction provides a stabilizing force for the molecular complex. The charge transfer is taking place anywhere in the molecular complex and usually, the electronic transition is occur into an excited electronic states of the substitutional group to base, among electronic states of the substitutional group and among different parts of the base molecule. These electronic transitions into the coordinated excited electronic states of different entities of the compound frequently occur in UV-Visible region which characterize the physical and chemical property.

In this case, the electronic excitation absorption CT band was found at 250 nm of oscillator strength 0.05 on the energy gap of 4.95 eV and was assigned to n→ π* in gas phase. The energy of CT complex was found to be 4.95 eV is enough to make sure the transition between acceptor (ethyl-methyl-amino group) and donor (phenyl ring) whereas the observed UV-Visible band was identified at 260 nm. The experimental CT band was shifted to higher wavelength region since the source material was in solid phase. In solvent phase, the CT band is identified at 249 nm with oscillator strength of 0.07 at the same energy gap. The attained result of CT complex in gas as well as solvent phase showed the strong interaction between donor (methoxy) and acceptor (phenyl). The absorption band of present compound was transparently occurring in the UV spectrum in R-band (German, radikalartig) and consistently being with anti-depression activity. In this case, the identification of absorption band in quartz-UV region predicted that, the symmetrical placement of methoxy entities in opposite sides of the ring was playing the important role of such pharmaceutical action. The electronic excitation parameters are presented in the Table 6 and the absorption band was displayed in the Figure 7.

λ (nm) E (eV) ( f ) Major contribution Assignment Region Bands
Gas
250.38 4.9519 0.0562 H®L (92%) n→π* Quartz-UV R-band (German, radikalartig)
235.5 5.2647 0.0003 H®L (89%) n→π*
219.55 5.6472 0.0201 H®L (86%) n→π*
DMSO
249.61 4.9671 0.0704 H®L (90%) n→π* Quartz-UV R-band (German, radikalartig)
236.95 5.2326 0.0002 H®L (90%) n→π*
221.64 5.5939 0.015 H®L (87%) n→π*
Chloroform
250.13 4.9568 0.074 H®L (86%) n→π* Quartz-UV R-band (German, radikalartig)
236.38 5.2452 0.0003 H®L (85%) n→π*
220.84 5.6142 0.0207 H®L (78%) n→π*

Table 6: Theoretical electronic absorption spectra of 2,5-Dimethoxy-4-ethylamphetamine (absorption wavelength λ (nm), excitation energies E (eV) and oscillator strengths (f)) using TD-DFT/B3LYP/6-311Gmethod.

molecular-pharmaceutics-organic-process-research-Excitation-Parameters

Figure 7: The Electronic Excitation Parameters of 2,5-Dimethoxy-4-ethylamphetamine.

The rearrangement of electronic orbitals on par with the equilibrium force of attraction existing between the dipoles of the compound induced the local electric field which making instantaneous polarization causing ECD.

The interaction of chromophores and auxochrome with base compound providing smaller energy increments for transition to excited states modify the chemical activity of the compound which can be identified in the ECD spectra. As in the Figure 7, the ECD absorption band was identified at 220 nm which was nearly equal energy absorption as UV-visible energy transition. This effect explored the unique chemical reactivity.

Molecular Electrostatic Potential (MEP) maps

The asymmetrical charge reorientation of the molecule has been organized by the restoring chemical equilibrium forces from the arrangement of different dipoles in various part of the compound.

Such an elevated charge orientation over the molecule was produced by homo and hetero nuclear bonds of the ring and ligand groups.

Here, the main frame of molecule was substituted by three dissimilar atomic groups and thereby the asymmetric charge orientation causing strong electrostatic potential between two extreme charge levels. The electrostatic appearance among various parts of the molecule was shown in the Figure 8.

molecular-pharmaceutics-organic-process-research-appearance-among

Figure 8: The electrostatic appearance among various parts of the molecule.

The faded electron rich and electron deficient zones were distinguished by the red to blue colour region on the molecule. The electron rich showed intensive red and proton wealthy part identified by concentrated blue.

In the Figure 8, the electron bustle zone was captured over the O of methoxy group and N of amino group. The moderate negative region was concealed over the ring carbons and further decayed when moved towards chain.

The protonic content was incarcerated on the hydrogen zones over the methyl group. It was copious in around the edge of the molecule and deficient in carbon bonded side. This faze situation was induced by the hydrogen bond chaos on methoxy and methyl groups.

Due to the electron pulling away from the ring, the electrostatic energy was found to be uniform at the centre part of the ring and acted as defect free energy grid. In each and every molecule has strong ligand which is the root cause of the major property of the compound.

In this case, the strong electrophilic-nucleophilic dipole was found between ring C-H and N of amino group and o of methoxy group. The out of plane ligand usually making strong receptor activity when docking is made.

Here, methoxy and ethyl-methyl chain appeared as out of plane ligand which was indicated in the Figure 7.

Polarizability and hyperpolarizability analysis

The chemical force of attraction stabilized the polarized orbitals in different coordinates of the molecule which facilitate the strong physico-chemical property and can be measured by computing Polarizability and first order hyperpolarizability as in the Table 7.

Parameter a.u. Parameter a.u.
αxx -102.4282 βxxx -15.8134
αxy 0.2259 βxxy -20.5931
αyy -79.5913 βxyy -2.9661
αxz -5.8184 βyyy 8.6568
αyz 2.4708 βxxz 26.1358
αzz -102.6729 βxyz 2.1077
αtot 198.432 βyyz -11.5149
Δα 268.436 βxzz -4.7675
μx 0.1763 βyzz -0.9354
μy -0.4912 βzzz -1.493
μz 0.7768 βtot 187.7
Δμ 0.9358    

Table 7: The dipole moments μ (D), the polarizability α(a.u.), the average polarizability αo (esu), the anisotropy of the polarizability Δα (esu), and the first hyperpolarizability β(esu) of 2,5-Dimethoxy-4-ethylamphetamine.

The calculated value of the dipole moment was found to be very less (0.935 Debye) since the multi pole moments were found to be dispersed in different dimensions. The ligand in the compound oriented in different sides and the resultant dipole moment was very low. The calculated showed that, the major entities were found to be on x and y coordinates of the compound which point out the direction of the chain and methoxy group.

The calculated average polarizability and anisotropy of the polarizability is 198 x10−30esu and 268 x 10−30esu, respectively. The hyperpolarizability? is one of the important key factors of stabilization of frontier molecular orbital interaction system. The B3LYP/6-311+ +G(d,p) calculated first hyperpolarizability value (?) is 187.7 x10−33esu. From this observation, it was clear that, the hyper asymmetrical polarization was taking place abruptly to empower the frontier molecular orbitals for the stimulation of pharmaceutical property.

Thermodynamical functions analysis

Normally, the thermo dynamical analysis on aromatic compound is very important since they provide the necessary information regarding the chemical reactivity [12]. The thermodynamic functional parameters were depicted in the Table 8. The variation of thermodynamic functional parameters with temperature was shown in Table 8. The calculated entropy, specific heat capacity and enthalpy were found to be varied with positive temperature coefficient. When the temperature increased from 100K to absolute temperature 298.15, the functional parameters were varied unhurriedly whereas from 350 to 1000K, the thermodynamical functions established to swing as linear pattern and rather constant at maximum temperature. This view of variation showed the consistent chemical reactivity and considerable chemical hardness of the present compound. The Gibbs free energy is always negative temperature coefficient and here, since it was found to be true, the present compound has strong and unique chemical property and endless chemical reaction.

T(K) (cal mol-1 K-1) (calmol-1K-1) (kcalmol-1) Gibbs free energy ΔG=ΔH-TΔS KJmol1
100 359.47 132.87 8.09 -35938.9
200 477.67 214.28 25.61 -95508.4
298.15 577.18 289.86 50.32 -172036
300 578.98 291.32 50.85 -173643
400 673.54 369.21 83.91 -269332
500 763.7 439.82 124.44 -381726
600 849.36 500.04 171.52 -509444
700 930.36 550.72 224.13 -651028
800 1006.78 593.58 281.41 -805143
900 1078.86 630.1 342.64 -970631
1000 1146.91 661.42 407.25 -1146503

Table 8: Thermodynamic parameters at different Temperatures for 2,5-Dimethoxy-4-ethylamphetamine.

NBO transition analysis

The NBO data of the compound was derived from perturbed and non-perturbed frontier molecular orbitals in which the electronic energy was exchanged. The energy was transferred among various energy domains for standardize the significant orbitals for obtaining desired physical and chemical characteristics [38]. In this venture, the donor and acceptors of electronic orbitals were identified and their energy transitions were tabulated in Table 9.

Donor[i] Type of bond Occupancy Acceptor[j] Type of bond E2[kcal/mol] Ej – Ei [au] F(I j) [au]
C1-C2 σ 1.97172 C2-C3 σ* 3.39 1.28 0.059
C1-C2 σ 1.97172 C3-C4 σ* 19.39 0.28 0.066
C1-C2 σ 1.97172 C5-C6 σ* 19.43 0.29 0.067
C1-C6 π 1.976 C1-C2 π* 4.57 1.28 0.068
C1-C6 π 1.976 C2-C13 π* 3.4 1.1 0.055
C1-C6 π 1.976 C5-C6 π* 3.52 1.28 0.06
C2-C3 π 1.96654 C1-C2 π* 3.61 1.27 0.061
C2-C3 π 1.96654 C1-O12 π* 4.19 0.98 0.057
C2-C3 π 1.96654 C3-C4 π* 3.59 1.25 0.06
C2-C3 π 1.96654 C4-O10 π* 4.04 0.98 0.056
C2-C13 σ 1.97109 C1-C6 σ* 3.26 1.15 0.055
C3-C4 σ 1.67521 C2-C3 σ* 3.65 1.28 0.061
C3-C4 σ 1.67521 C2-C13 σ* 3.27 1.1 0.054
C3-C4 σ 1.67521 C4-C5 σ* 4.6 1.28 0.069
C3-C4 σ 1.67521 C5-C9 σ* 3.22 1.1 1.1
C3-C4 σ 1.67521 C1-C2 σ* 20.49 0.29 0.07
C3-C4 σ 1.67521 C5-C6 σ* 20.92 0.29 0.071
C3-H7 σ 1.97462 C1-C2 σ* 4.27 1.11 0.061
C3-H7 σ 1.97462 C4-C5 σ* 3.76 1.11 0.058
C4-C5 π 1.97208 C3-C4 π* 4.32 1.26 0.066
C4-C5 π 1.97208 C5-C6 σ* 3.2 1.29 0.057
C5-C6 σ 1.96709 C1-C6 σ* 3.44 1.25 0.059
C5-C6 σ 1.96709 C1-O12 σ* 4.06 0.98 0.056
C5-C6 σ 1.96709 C1-C2 σ* 20.34 0.29 0.069
C5-C6 σ 1.96709 C3-C4 σ* 19.38 0.28 0.067
C5-C9 σ 1.97355 C3-C4 σ* 3.31 1.15 0.055
C6-H8 σ 1.97461 C1-C2 σ* 3.78 1.11 0.058
C6-H8 σ 1.97461 C4-C5 σ* 4.24 1.11 0.061
C9-H14 σ 1.97872 C5-C6 σ* 3.27 1.08 0.053
C9-H15 σ 1.98004 C4-C5 σ* 3.01 1.07 0.051
C13-H19 σ 1.97768 C21-C23 σ* 3.32 1.07 0.053
C23-H26 σ 1.98554 C21-N27 σ* 3.48 0.86 0.049
O10 n 1.9678 C3-C4 σ* 4.67 1.14 0.065
O10 n 1.9678 C3-C4 σ* 17.03 0.34 0.073
O10 n 1.9678 C11-H16 σ* 4.52 0.72 0.052
O10 n 1.9678 C11-H17 σ* 5.67 0.72 0.058
O12 n 1.96751 C1-C6 π* 4.65 1.14 0.065
O12 n 1.96751 C1-C12 π* 16.37 0.35 0.073
O12 n 1.96751 C30-H31 σ* 4.5 0.72 0.052
O12 n 1.96751 C30-H32 σ* 5.67 0.72 0.058
N27 n 1.96142 C23-H26 σ* 6.81 0.68 0.061
C3-C4 σ 0.02637 C1-C2 σ* 316.66 0.01 0.082

Table 9: The calculated NBO of 2,5-Dimethoxy-4-ethylamphetamine by second order Perturbation theory.

Usually, the electron density delocalized among occupied Lewis type (bond or lone pair) orbitals and unoccupied (anti-bonding and Rydberg) non-Lewis orbital in order to stabilize donor acceptor interaction [39]. Here, in ring system, the transition from C1-C2 to C3-C4 and C5-C6 and they assigned to σ-σ* in which 19.39 kcal/mol energy was transferred from first chain to second chain in order to connect the major ligand groups. In same system, another transitions from C3-C4 to C1-C2 and C5-C6 which were assigned to σ-σ* with energy of 20.50 kcal/mol respectively. In these transitions, the received energy was exchanged from methoxy group to chain and another methoxy group on another side. Similarly, the transitions were taking place from C5-C6 to C1-C2 and C3-C4 by σ-σ* interaction with the energy of 20.3 and 19.3 kcal/mol respectively. In this case, the energy was transferred in order to blend the Lewis of chain and methoxy group. It was very rare to take place the transitions from lone pair to other system. Here it was happened from C5-C6 to C1-C2 and C3-C4 with the exchanged energies of 20.3 and 19.3 kcal/mol respectively for the back donation of interaction energy (from chain to methoxy group). The huge amount of energy of 316.6 kcal/mol was transferred from C3-C4 to C1-C2 for the two symmetrical chain and methoxy groups. In these transitions, the electronic energies exchanged between ligand to ligand via the ring and also the residue energy was transferred from the chain to the ring system. Thus the energy was exchanged back and forth among the orbitals to make desirable physical and chemical property of the study compound.

Physico-chemical properties

The chemical properties and molecular reactivity descriptors of the present compound were computed from Frontier molecular energy levels. The entire parameters were presented in the Table 10. The resultant dipole moment is the measuring scale of asymmetric charge orientation of compound and the Total determined dipole moment was found to be 0.93 and 2.34 dyne in IR and UV-visible region respectively. In this case, the base compound is benzene; its dipole moment is almost zero. Here, the total compound composed by multiple ligands with benzene ring. Due to the symmetrical substitutions in ortho and meta positions in the ring, the total computed dipole moment was found to be very low and it ensured that symmetric charge orientation for the desired pharmaceutical property. The energy gap of the frontier molecular orbitals measured usually, the chemical stability of the compound; the same was determined to be 2.66 and 2.86 eV in IR and UV-Visible region respectively. Both the values showed moderate chemical stability and also it was appeared in non-reactive Quartz UV region.

Parameter B3LYP 6311G UV-Visible Electrophilicity charge transfer (ECT) (ΔNmax)A-(ΔNmax)B
Etotal (Hartree) 7.13 -7.13 1.321
EHOMO (eV) 5.442 6.059
ELUMO (eV) 0.117 0.333
DEHOMO-LUMO gap (eV) 5.325 5.726
EHOMO-1 (eV) 6.343 6.13
ELUMO+1 (eV) 6.556 6.58
DEHOMO-1-LUMO+1 gap (eV) 12.9 0.449
Chemical hardness (h) 2.662 2.863
Electronegativity (χ) 2.662 2.863
Chemical potential (μ) 2.662 2.863
Chemical softness(S) 10.65 11.452
Electrophilicity index (ω) 1.331 1.431
Dipole moment 0.935 2.34

Table 10: Calculated energies, chemical hardness, electro negativity, Chemical potential, Electrophilicity index of 2,5-Dimethoxy-4-ethylamphetamine.

The electron affinity of the molecule is very important for the determination of the reaction ability of receptor protein and was found to be 5.44 which were elevated to the extreme and the reaction capability of the present compound is energetic. The ionization potential of the compound is significant to evaluate chemical-bond reorganization. The ionization potential was found to be 0.11 which is very small and was main reason for the low dipole moment and it was enough to maintain the chemical bond stability. Generally, the chemical hardness is a scale of obstacle for transformation of charge whereas the electronegativity is measure of the tendency to attract electrons by inter-chemical bond [39]. Here, both parameters were found to be 2.66 which was moderate and illustrated the good reactive character and it was not possible to add further additive drug properties.

The electrophilicity index is an indicator of energy flow via frontier molecular orbitals. In this case, the electrophilicity index was recognized to be 1.331 eV, but the same was 2.09 eV for benzene ring. The derived energy was very low due to the symmetrical existence of the ligand groups. From this point of view, it was clear that, the maximum energy exchanged between ligand via ring for creating the prosperous pharmaceutical application. Here, the benzene acted as base compound and it was substituted with ethyl-methyl-amino groups and methoxy groups in balanced form and the electrophilicity charge transfer of the compound was found to be + 1.321 which emphasized the maximum charge flow from ligand to ligand via benzene. This also major reason for the present compound is an antidepression agent.

VCD verification

The good Chirality of the compound can have good biological and pharmaceutical property with hiding of toxicity. The architecture of the chirality reflects masking of side effect. The regular peak sequence on both sides was created by circularly polarized infrared radiation during a vibrational transition. Generally, the peaks are found to be in unique sequential pattern. In addition to that, there were few small opaque parts identified in different region of the spectrum which reflect the unwanted properties. This is mainly due to the flaw in optimization which can be removed by re optimizing the structure. The unique pattern of VCD spectrum of the conformational structure of title compound was displayed in the Figure 9. The VCD of present compound showed the R- enantiomer and emphasized the optical and chemical purity of the present substance.

molecular-pharmaceutics-organic-process-research-VCD-spectrum

Figure 9: The unique pattern of VCD spectrum of the conformational structure of title compound.

Conclusion

The present compound; 2,5-Dimethoxy-4-ethylamphetamine was the primary derivative of Amphetamine. In order to evaluate and determining unknown properties, the basic Amphetamine was substituted by suitable ligand and different analyses have been made on the chemical structure. The molecular deformation analysis gave the complete information regarding the structure activity on par with the ligand. The charge reorientation among bonded entities revealed the asymmetric movement of the charges which was favoured for inducement of peculiar drug property. The vibrational assignments of the compound explicit the fundamental IR and Raman frequencies which were consistently emphasized the correct compositional bonds which composed the compound. The chemical reaction path arrangement of different carbons was ensured from the discrete chemical shift and the background reason was extracted. The orbital interaction lobe formation favoured for the chemical process to produce desirable drug property was predicted from the cascade arrangement of HOMO-LUMO. The chromophores reactivity on the base compound causing the electronic shift in UV-Visible spectra was discussed in detail. The electronic energy transition from donor and acceptor orbitals was studied. The consumption of energy between ligand and base compound was measured and maximum energy flow among the orbitals for the completion of the drug property was determined.

Conflict of Interest

As a corresponding Author, I hereby declare that there is no conflict with other fields and other persons belong to field.

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