Quantum chemical calculation was correlated with geometrical structure and total energy of fluoxetine and its five derivatives. Theoretical vibrational frequencies and geometric parameters (bond lengths and bond angles) have been calculated using ab initio (HF), density functional theory (B3LYP), semi-empirical (AM1, PM3) methods with different basis sets to design the fluoxetine drugs and its derivatives by a Gaussian 09 W program. Theoretical optimized geometric parameters and vibrational frequencies of fluoxetine have been compared with the corresponding five derivatives data. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies have been determined. The theoretical study includes the calculation of the thermodynamic properties of the drugs and its derivatives like zero-point energy, enthalpy, entropy, ionization energy, electron affinity to make a correlation between the gained results. The results of the four methods were not very clear, but an correlation between the dipole moment (potential character), static distribution (an active site character) and HOMO-LUMO energies (energy for electron transfer) shows that the patent 1.5 was important derivatives as a recommended drug relative to fluoxetine drug.
Fluoxetine hydrochloride (C17H18F3NO) (
Fluoxetine is a racemic mixture of the R- and S-enantiomers and are of equivalent pharmacologic activity. Despite distinct structural differences between compounds in this class, SSRIs possess similar pharmacological activity, as with other antidepressant agents [
The molecular structures of fluoxetine and its derivatives are presented in
IUPAC Name | Molecular Weight | Formula | Name |
---|---|---|---|
N-methyl-3-phenyl-3-(4-(trifluoromethyl)phenoxy)propan | 309.332 g/mol | C17H18F3NO | Fluoxetine |
2-[4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]ethanamine | 295.305 g/mol | C16H16F3NO | Patent 1 |
2-[4-[(IS)-3-(methylamino)-1-phenylpropoxy]phenyl]ethanol | 285.387 g/mol | C18H23NO | Patent 2 |
2-[4-[(1S)-3-(methylamino)-1-thiophen-2-ylpropoxyl]phenyl]ethanol | 291.409 g/mol | C16H21NO2S | Patent 3 |
3.3-bis(4-chlorophenyl)propan-1-amine | 280.192 g/mol | C15H15Cl2N | Patent 4 |
3-(2-fluorophenoxy)-N,N-dimethyl-3-phenylpropan-1-amine | 273.351 g/mol | C17H20FNO | Patent 5 |
The program that used in the search.
Gaussian 09W (G09) is a computational chemistry program that runs on any modern windows 32 bit PC, or on a 64 bit PC [
- Molecular energies;
- Structure;
- Vibrational frequencies;
- Utilizing an initio, density functional theory, semi-empirical.
* semi-empirical methods (AM1, PM3, PM6, MNDO);
* ab initio methods (HF, MP2, CCSD, QCISD);
* density functional theory (B3LYP, MO6, Custom).
- Graphical interface for Gaussian 09 [
- Sketch molecules;
- Setup Gaussian 09 input files;
- Graphically examine results.
In the first step of the calculation, geometrical parameters of these structures were further optimized by using density functional theory DFT (B3LYP)/6-31G, HF, AM1, PM3 methods. On the basis of the lowest energy conformer, the bond length and bond angles were obtained using the four methods.
The electronic properties: HOMO-LUMO energies are calculated by four methods, based on the optimized structure for soluble in water solvent [
Thermodynamic properties of the title compound at 310 k temperature have been calculated using four methods. Moreover, the dipole moment and Mulliken atomic charge have also been studied using Gaussian 09 W program package.
The initial atomic coordinates for geometry optimization was taken from Gauss View software database [
The schematic depiction of fluoxetine and optimized structure are shown in
To evaluate the energetic behavior of the title compound in water solvent media theoretical calculations were carried out at 310 k. Total energies and dipole
Bond Length (G09) | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Bond | Fluoxetine | Patent 1 | Patent 2 | Patent 3 | Patent 4 | Patent 5 | ||||||
AM1 | PM3 | AM1 | PM3 | AM1 | PM3 | AM1 | PM3 | AM1 | PM3 | AM1 | PM3 | |
C1-N | 1.44 | 1.47 | 1.45 | 1.48 | 1.44 | 1.47 | 1.44 | 1.47 | 1.44 | 1.48 | 1.45 | 1.48 |
N-C7 | 1.45 | 1.48 | ….. | ….. | 1.45 | 1.48 | 1.45 | 1.48 | …… | 1.46 | 1.49 | |
C12-O14 | 1.44 | 1.44 | 1.43 | 1.41 | 1.44 | 1.48 | 1.45 | 1.44 | ….. | … | 1.44 | 1.43 |
O14-C26 | 1.37 | 1.37 | 1.38 | 1.38 | 1.38 | 1.38 | 1.39 | 1.39 | ….. | … | 1.38 | 1.37 |
C10-C12 | 1.53 | 1.53 | 1.53 | 1.50 | 1.52 | 1.52 | 1.53 | 1.52 | 1.53 | 1.52 | 1.52 | 1.52 |
C7-C10 | 1.52 | 1.52 | 1.52 | 1.52 | 1.53 | 1.53 | 1.53 | 1.54 | 1.52 | 1.53 | 1.53 | 1.53 |
C-F | 1.37 | 1.36 | 1.37 | 1.35 | ….. | ….. | ...... | …... | ...... | … | 1.35 | 1.34 |
C-S | ….. | ….. | …. | ….. | ….. | …... | 1.68 | 1.74 | ….. | ….. | ….. | ….. |
C-Cl | ….. | ….. | ….. | ….. | ….. | ….. | ….. | ….. | 1.70 | 1.68 | ….. | ….. |
Bond Length (G09) | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Bond | Fluoxetine | Patent 1 | Patent 2 | Patent 3 | Patent 4 | Patent 5 | ||||||
HF | DFT | HF | DFT | HF | DFT | HF | DFT | HF | DFT | HF | DFT | |
C1-N | 1.45 | 1.47 | 1.45 | 1.47 | 1.45 | 1.46 | 1.45 | 1.47 | 1.46 | 1.47 | 1.46 | 1.46 |
N-C7 | 1.45 | 1.46 | ….. | …… | 1.46 | 1.47 | 1.46 | 1.47 | ….. | ….. | 1.46 | 1.47 |
C12-O14 | 1.45 | 1.48 | 1.45 | 1.45 | 1.48 | 1.46 | 1.46 | 1.50 | ….. | …… | 1.46 | 1.48 |
O14-C26 | 1.36 | 1.38 | 1.39 | 1.39 | 1.39 | 1.38 | 1.39 | 1.40 | ….. | …… | 1.38 | 1.38 |
C10-C12 | 1.52 | 1.53 | 1.50 | 1.51 | 1.53 | 1.53 | 1.53 | 1.53 | 1.53 | 1.53 | 1.52 | 1.53 |
C7-C10 | 1.52 | 1.53 | 1.52 | 1.48 | 1.53 | 1.53 | 1.53 | 1.53 | 1.54 | 1.55 | 1.53 | 1.53 |
C-F | 1.35 | 1.36 | 1.37 | 1.41 | ….. | ….. | ….. | ….. | ….. | ….. | 1.37 | 1.39 |
C-S | …… | ….. | …… | ….. | ….. | …. | 1.80 | 1.82 | …… | …… | ….. | …. |
C-Cl | ….. | ….. | ….. | ….. | ….. | …. | …… | ….. | 1.82 | 1.84 | ….. | ….. |
Bond Angles (˚) (G09) | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Bond | Fluoxetine | Patent 1 | Patent 2 | Patent 3 | Patent 4 | Patent 5 | |||||||
AM1 | PM3 | AM1 | PM3 | AM1 | PM3 | AM1 | PM3 | AM1 | PM3 | AM1 | PM3 | ||
C7-N5-C10 | 112.9 | 110.6 | 109.4 | 110.6 | 113.6 | 110.7 | 113.5 | 110.5 | 113.4 | 110.8 | 113.7 | 110.6 | |
C7-C10-C12 | 109.5 | 110.4 | 120.4 | 117.3 | 109.9 | 110.7 | 110.2 | 111.0 | 110.2 | 111.0 | 1109.5 | 110.4 | |
C12-O14-C26 | 117.3 | 117.6 | 115.6 | 1.45 | 113.9 | 113.5 | 114.2 | 114.6 | ….. | …… | 115.5 | 116.8 | |
C33-C36-F37 | 114.6 | 114.1 | 114.8 | 114.9 | ….. | ….. | …… | …… | ….. | …… | ….. | …… | |
C29-C33-C31 | 120.5 | 120.6 | 119.5 | 121.0 | 120.9 | 120.2 | 120.4 | 120.0 | ….. | ….. | …… | ….. | |
Bond Angles (˚) (G09) | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Bond | Fluoxetine | Patent 1 | Patents 2 | Patent 3 | Patent 4 | Patent 5 | ||||||
HF | DFT | HF | DFT | HF | DFT | HF | DFT | HF | DFT | HF | DFT | |
C7-N5-C10 | 110.4 | 110.4 | 110.5 | 110.6 | 111.6 | 111.7 | 111.4 | 111.5 | 110.1 | 110.3 | 112.1 | 112.6 |
C7-C10-C12 | 113.7 | 113.3 | 112.6 | 112.7 | 113.4 | 113.0 | 113.6 | 113.6 | 113.1 | 113.0 | 113.0 | 112.8 |
C12-O14-C26 | 124.2 | 121.2 | 117.6 | 118.9 | 120.1 | 120.8 | 119.9 | 117.9 | ….. | …… | 120.7 | 120.3 |
C33-C36-F37 | 113.3 | 113.3 | 112.9 | 113.0 | ….. | ….. | ….. | …… | ….. | …… | …… | ….. |
C29-C33-C31 | 119.8 | 119.3 | 119.7 | 120.1 | 120.9 | 121.0 | 120.9 | 120.9 | ….. | …… | …… | ….. |
moments have been calculated in solvent media with (AM1, PM3) and (HF, DFT/B3LYP/6-31G) level for fluoxetine drug and its derivatives.
Thermodynamic Parameter | Fluoxetine | Patent 1 | Patent 2 | Patent 3 | Patent 4 | Patent 5 | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
AM1 | PM3 | AM1 | PM3 | AM1 | PM3 | AM1 | PM3 | AM1 | PM3 | AM1 | PM3 | |
Zero-Point Vibrational Energy (Kcal∙mole−1) | 205.91 | 199.49 | 186.97 | 182.83 | 240.85 | 232.46 | 219.26 | 211.55 | 170.11 | 164.02 | 214.63 | 207.43 |
Thermal Correction to Energy (Kcal∙mole−1) | 219.57 | 213.34 | 196.49 | 195.81 | 254.82 | 246.67 | 233.07 | 225.64 | 181.26 | 175.48 | 227.26 | 220.37 |
Thermal Correction to Enthalpy (Kcal∙mole−1) | 220.19 | 213.96 | 197.11 | 196.43 | 255.43 | 247.28 | 233.68 | 226.25 | 181.88 | 176.09 | 227.87 | 220.99 |
Thermal Correction to Gibbs Free Energy (Kcal∙mole−1) | 170.15 | 163.32 | 159.97 | 146.79 | 203.89 | 195.88 | 182.39 | 175.03 | 138.56 | 132.18 | 181.05 | 226.01 |
CV (Cal/mole-Kelvin) | ||||||||||||
Total | 77.14 | 79.43 | 62.09 | 74.45 | 78.52 | 82.06 | 76.38 | 79.93 | 63.40 | 66.06 | 72.33 | 75.52 |
Translation | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 |
Rotational | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 |
Vibrational | 71.15 | 73.474 | 56.14 | 68.49 | 72.55 | 76.10 | 70.42 | 73..96 | 57.45 | 60.10 | 66.37 | 69.55 |
S (Entropy) (Cal/mole-Kelvin) | ||||||||||||
Total | 161.42 | 163.34 | 119.79 | 160.11 | 166.27 | 165.79 | 165.45 | 165.28 | 139.72 | 141.66 | 151.01 | 153.48 |
Translation | 43.28 | 43.27 | 43.14 | 43.14 | 43.04 | 43.03 | 43.09 | 43.09 | 42.97 | 42.97 | 42.91 | 42.90 |
Rotational | 35.43 | 35.59 | 35.06 | 35.37 | 35.21 | 35.18 | 35.19 | 35.18 | 34.75 | 34.76 | 34.39 | 34.51 |
Vibrational | 82.72 | 84.47 | 41.59 | 81.59 | 88.03 | 87.58 | 87.16 | 87.01 | 62.005 | 63.94 | 73.70 | 76.06 |
EHomo (eV) | −9.653 | −9.5 | −9.635 | −9.290 | −9.375 | −9.495 | −9.358 | −9.511 | − 9.584 | −9.457 | − 9.518 | − 9.380 |
ELumo (eV) | −0.329 | −0.448 | −0.447 | −0.645 | −0.042 | −0.143 | −0.265 | −0.587 | − 0.191 | − 0.261 | − 0.118 | − 0.128 |
Eg = E Lumo − E Homo (eV) | 9.323 | 9.065 | 9.188 | 8.644 | 9.334 | 9.352 | 9.093 | 8.924 | 9.3926 | 9.196 | 9.399 | 9.252 |
Ionization Potential (IE = −EHOMO) | 0.329 | 0.448 | 9.635 | 9.290 | 9.375 | 9.495 | 9.358 | 9.511 | 9.584 | 9.457 | 9.518 | 9.380 |
Electron Affinity (EA = −ELUMO) | 9.653 | 9.513 | 0.447 | 0.645 | 0.042 | 0.143 | 0.265 | 0.587 | 0.192 | 0.261 | 0.118 | 0.128 |
Dipole Moment (Debye) | 4.416 | 4.029 | 3.811 | 2.087 | 2.655 | 2.400 | 2.511 | 2.019 | 1.434 | 1.685 | 4.287 | 4.506 |
Mulliken atomic charge calculation plays an important role in the application of quantum chemical calculation to molecule system [
Calculated atomic charges are a different matter. Atomic charges can be defined in various ways. Mulliken atomic charges are commonly used in molecular orbital theory and are used in and G09. They have varying values according to the basis set and the method of calculation [
Thermodynamic Parameter | Fluoxetine | Patent 1 | Patent 2 | Patent 3 | Patent 4 | Patent 5 | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
HF | DFT | HF | DFT | HF | DFT | HF | DFT | HF | DFT | HF | DFT | |
Zero-Point Vibrational Energy (Kcal mole−1) | 217.78 | 202.77 | 198.47 | 184.63 | 255.59 | 238.74 | 232.84 | 216.89 | 180.01 | 167.59 | 227.68 | 212.55 |
Thermal Correction to Energy (Kcal/mole−1) | 230.67 | 216.51 | 209.90 | 197.70 | 268.83 | 252.73 | 245.99 | 230.83 | 190.63 | 178.97 | 239.61 | 225.26 |
Thermal Correction to Enthalpy (Kcal/mole−1) | 231.28 | 217.12 | 210.49 | 198.32 | 269.44 | 253.34 | 246.60 | 231.45 | 191.25 | 179.58 | 240.22 | 225.87 |
Thermal Correction to Gibbs Free Energy (Kcal/mole−1) | 183.28 | 167.58 | 165.69 | 212.17 | 220.39 | 203.03 | 197.53 | 180.83 | 149.29 | 135.76 | 195.03 | 179.08 |
CV (Cal/mole-Kelvin) | ||||||||||||
Total | 73.11 | 79.23 | 66.66 | 74.98 | 74.63 | 80.67 | 73.14 | 79.02 | 60.54 | 65.63 | 68.43 | 74.20 |
Translation | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 |
Rotational | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 | 2.981 |
Vibrational | 69.14 | 73.27 | 60.70 | 69.03 | 68.66 | 74.70 | 67.17 | 73.05 | 54.58 | 59.67 | 62.47 | 68.24 |
S (Entropy) (Cal/mole-Kelvin) | ||||||||||||
Total | 154.83 | 159.79 | 150.27 | 157.75 | 158.20 | 162.31 | 158.28 | 163.30 | 135.32 | 141.36 | 145.76 | 150.49 |
Translation | 43.28 | 43.27 | 42.95 | 43.14 | 43.03 | 43.03 | 43.09 | 43.09 | 42.97 | 42.97 | 42.90 | 42.90 |
Rotational | 35.40 | 35.44 | 35.01 | 35.16 | 35.29 | 35.35 | 35.31 | 35.34 | 34.82 | 34.85 | 34.37 | 34.55 |
Vibrational | 76.15 | 81.07 | 72.32 | 79.45 | 79.87 | 83.93 | 79.88 | 84.34 | 57.53 | 63.54 | 68.49 | 73.48 |
EHomo (eV) | −9.215 | −5.754 | −8.822 | −5.945 | −8.716 | −5.699 | −8.790 | −5.723 | −9.061 | −5.989 | −9.176 | −5.582 |
ELumo (eV) | 3.107 | −0.777 | 2.598 | −1.024 | 3.573 | −0.295 | 3.175 | −0.859 | 3.110 | −0.643 | 3.326 | −0.402 |
Eg=ELumo − EHomo (eV) | 12.321 | 4.977 | 11.419 | 4.920 | 12.289 | 5.403 | 11.965 | 4.864 | 12.171 | 5.3466 | 12.502 | 5.1804 |
Ionization Potential (E = −EHOMO) | −3.107 | 0.777 | 8.822 | 5.945 | 8.716 | 5.699 | 8.790 | 5.723 | 9.061 | 5.989 | 9.176 | 5.582 |
Electron Affinity (EA = −ELUMO) | 9.215 | 5.754 | −2.598 | 1.024 | −3.573 | 0.295 | −3.175 | 0.859 | −3.110 | 0.643 | −3.326 | 0.402 |
Dipole Moment (Debye) | 6.121 | 5.869 | 5.880 | 6.320 | 3.394 | 3.094 | 3.047 | 2.983 | 4.438 | 4.152 | 5.445 | 4.787 |
methods. The results in the (AM1, PM3, HF, and DFT) were in
In principle, there are several ways to calculate the excitation energies. The simplest one involves the difference between the highest occupied molecular orbital (HOMO) of a neutral system, which is a key parameter in determining molecular properties [
Patent 5 | Patent4 | Patent 3 | Patent 2 | Patent 1 | Fluoxetine | Atoms | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
PM3 | AM1 | PM3 | AM1 | PM3 | AM1 | PM3 | AM1 | PM3 | AM1 | PM3 | AM1 | |
−0.093 | −0.129 | ……. | ……. | −0.116 | −0.137 | −0.116 | −0.136 | ……. | .…… | −0.101 | −0.132 | 1C |
0.048 | 0.087 | ……. | ……. | 0.045 | 0.086 | 0.053 | 0.086 | ……. | .…… | 0.046 | 0.083 | 2H |
0.035 | 0.058 | ……. | ……. | 0.032 | 0.052 | 0.032 | 0.053 | …… | ..…. | 0.032 | 0.056 | 3H |
0.048 | 0.086 | ……. | ……. | 0.053 | 0.083 | 0.048 | 0.083 | ..…. | ..…. | 0.046 | 0.087 | 4H |
−0.096 | −0.278 | −0.065 | −0.365 | −0.084 | −0.323 | −0.085 | −0.323 | −0.065 | −0.370 | −0.087 | −0.323 | 5N |
…… | .…… | 0.037 | 0.150 | 0.053 | 0.167 | 0.057 | 0.166 | 0.037 | 0.156 | 0.056 | 0.162 | 6H |
…… | ……. | 0.034 | 0.157 | …… | ……. | ……. | …… | 0.034 | 0.150 | ……. | ……. | 8H |
−0.082 | −0.076 | −0.065 | −0.087 | −0.087 | −0.076 | −0.091 | −0.078 | −0.101 | −0.080 | −0.091 | −0.081 | 8C |
0.049 | 0.095 | 0.104 | 0.090 | 0.062 | 0.094 | 0.048 | 0.065 | 0.056 | 0.089 | 0.060 | 0.093 | 9H |
0.045 | 0.068 | 0.057 | 0.059 | 0.045 | 0.062 | 0.059 | 0.092 | 0.041 | 0.056 | 0.048 | 0.065 | 10H |
−0.128 | −0.161 | −0.116 | −0.160 | −0.151 | −0.180 | −0.153 | −0.184 | −0.055 | −0.126 | −0.143 | −0.165 | 11C |
0.077 | 0.103 | 0.067 | 0.098 | 0.077 | 0.099 | 0.070 | 0.098 | 0.061 | 0.097 | 0.076 | 0.104 | 12H |
0.071 | 0.102 | 0.068 | 0.093 | 0.073 | 0.100 | 0.076 | 0.099 | 0.062 | 0.094 | 0.077 | 0.106 | 13H |
0.111 | 0.070 | −0.011 | −0.035 | 0.152 | 0.102 | 0.119 | 0.068 | …… | ……. | 0.106 | 0.068 | 14C |
0.082 | 0.108 | 0.084 | 0.116 | 0.079 | 0.109 | 0.072 | 0.107 | ……. | …….. | 0.085 | 0.113 | 15H |
−0.192 | −0.231 | .….. | ….. | −0.220 | −0.245 | −0.222 | −0.244 | −0.200 | −0.228 | −0.193 | −0.217 | 16O |
……. | ……. | ……. | …… | ……. | …… | …….. | ...... | 0.083 | 0.005 | ….. | …… | 17C |
……. | ……. | ….. | …… | ….. | ….. | ……. | ……. | 0.076 | 0.110 | …… | …… | 18H |
……. | ……. | …… | ….. | …… | ….. | …….. | ……. | 0.071 | 0.107 | ….. | …… | 19H |
−0.104 | −0.134 | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | 20C |
0.049 | 0.087 | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | 21H |
0.036 | 0.057 | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | 22H |
0.059 | 0.087 | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | 23H |
−0.133 | −0.122 | −0.065 | −0.062 | −0.306 | −0.412 | −0.110 | −0.095 | −0.092 | −0.056 | −0.117 | −0.127 | 24C |
−0.089 | −0.116 | −0.101 | −0.125 | −0.093 | −0.140 | −0.086 | −0.126 | −0.083 | −0.124 | −0.085 | −0.123 | 25C |
−0.084 | −0.124 | −0.106 | −0.127 | −0.125 | −0.175 | −0.094 | −0.115 | −0.091 | −0.117 | −0.092 | −0.113 | 26C |
−0.110 | −0.148 | −0.108 | −0.121 | ……. | …… | −0.111 | −0.139 | −0.051 | −0.082 | −0.111 | −0.137 | 27C |
−0.111 | −0.139 | −0.144 | −0.129 | .….. | .….. | −0.112 | −0.141 | −0.044 | −0.083 | −0.108 | −0.139 | 28C |
−0.098 | −0.131 | −0.087 | −0.085 | −0.285 | −0.440 | −0.100 | −0.130 | −0.187 | −0.171 | −0.095 | −0.126 | 29C |
0.116 | 0.149 | 0.127 | 0.151 | 0.137 | 0.163 | 0.116 | 0.145 | 0.125 | 0.161 | 0.115 | 0.146 | 30H |
0.117 | 0.144 | 0.121 | 0.155 | 0.135 | 0.162 | 0.117 | 0.147 | 0.125 | 0.159 | 0.121 | 0.146 | 31H |
0.114 | 0.143 | 0.116 | 0.152 | 0.161 | 0.186 | 0.113 | 0.145 | 0.125 | 0.160 | 0.113 | 0.145 | 32H |
0.113 | 0.144 | 0.123 | 0.154 | …… | …… | 0.113 | 0.144 | 0.127 | 0.160 | 0.113 | 0.144 | 33H |
0.112 | 0.143 | .….. | .….. | …… | …… | 0.112 | 0.142 | .…. | .….. | 0.112 | 0.143 | 34H |
…… | …… | …… | ……. | 0.280 | 0.591 | ……. | …… | ….. | …… | …… | …… | 35S |
0.062 | 0.021 | −0.078 | −0.069 | 0.043 | 0.038 | 0.045 | 0.037 | 0.065 | 0.066 | 0.130 | 0.114 | 36C |
−0.159 | −0.148 | −0.097 | −0.120 | −0.121 | −0.146 | −0.131 | −0.160 | −0.148 | −0.168 | −0.158 | −0.172 | 37C |
0.006 | 0.056 | −0.090 | −0.120 | −0.131 | −0.164 | −0.123 | −0.146 | −0.179 | −0.200 | −0.195 | −0.208 | 38C |
−0.100 | −0.122 | −0.104 | −0.127 | −0.091 | −0.089 | −0.085 | −0.085 | −0.070 | −0.099 | −0.011 | −0.042 | 39C |
---|---|---|---|---|---|---|---|---|---|---|---|---|
−0.114 | −0.151 | −0.149 | −0.127 | −0.086 | −0.116 | −0.091 | −0.116 | −0.064 | −0.101 | 0.008 | −0.051 | 40C |
−0.078 | −0.124 | −0.100 | −0.088 | −0.084 | −0.113 | −0.085 | −0.116 | −0.116 | −0.111 | −0.244 | −0.217 | 41C |
0.134 | 0.157 | 0.127 | 0.152 | 0.124 | 0.151 | 0.123 | 0.153 | 0.125 | 0.153 | 0.134 | 0.165 | 42H |
0.116 | 0.153 | 0.119 | 0.153 | 0.124 | 0.152 | 0.123 | 0.153 | 0.131 | 0.152 | 0.140 | 0.164 | 43H |
0.119 | 0.160 | 0.124 | 0.156 | 0.117 | 0.147 | 0.117 | 0.147 | 0.115 | 0.145 | 0.121 | 0.160 | 44H |
0.128 | 0.154 | 0.124 | 0.156 | 0.117 | 0.147 | 0.117 | 0.147 | 0.116 | 0.146 | 0.124 | 0.161 | 45H |
….. | ….. | ….. | ….. | −0.076 | −0.133 | −0.096 | −0.164 | 0.469 | 0.469 | 0.411 | 0.474 | 46C |
….. | ….. | ….. | ….. | ….. | ….. | ….. | ….. | −0.147 | −0.174 | −0.150 | −0.177 | 47F |
….. | ….. | ….. | ….. | ….. | ….. | ….. | ….. | −0.145 | −0.173 | −0.141 | −0.175 | 48F |
−0.097 | −0.108 | ….. | ….. | ….. | ….. | ….. | ….. | −0.142 | −0.172 | −0.149 | −0.175 | 49F |
….. | ….. | ….. | ….. | 0.067 | 0.103 | 0.066 | 0.100 | ..….. | .….. | ……. | ……. | 50H |
….. | ….. | ….. | ….. | 0.066 | 0.075 | 0.067 | 0.103 | ..….. | .….. | …… | …….. | 51H |
….. | ….. | ….. | ….. | ……. | ……. | ……. | ….. | ..….. | .….. | …….. | …….. | 52H |
….. | ….. | ……. | ….. | 0.076 | −0.017 | 0.071 | −0.019 | ..….. | .….. | ..…. | ……. | 53C |
….. | ….. | ….. | ….. | 0.034 | 0.075 | 0.054 | 0.106 | ..….. | .….. | ……. | .…… | 54H |
….. | ….. | .…. | .…. | 0.034 | 0.075 | 0.037 | 0.076 | ……. | .….. | ……. | ……. | 55H |
….. | ….. | ….. | ….. | −0.344 | −0.361 | −0.341 | 0.385 | ……. | ……. | ……. | ……. | 56O |
….. | ….. | ….. | ….. | 0.207 | 0.219 | 0.203 | 0.216 | ……. | ……. | ……. | ……. | 57H |
….. | ….. | −0.064 | −0.020 | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | 58Cl2 |
of the HOMO is directly related to the ionization potential, while the energy of the LUMO is directly related to the electron affinity. The energy gaps are largely responsible for the chemical and spectroscopic properties of the molecules [
The ionization energy associated with a relationship with a higher energy of occupied orbital as follows [
Patent 5 | Patent 4 | Patent 3 | Patent 2 | Patent 1 | Fluoxetine | Atoms | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
DFT | HF | DFT | HF | DFT | HF | DFT | HF | DFT | HF | DFT | HF | |
−0.257 | 0.243 | ……. | ……. | −0.268 | −0.244 | −0.267 | −0.244 | ……. | .…… | −0.261 | −0.240 | 1C |
0.147 | 0.169 | ……. | ……. | 0.151 | 0.169 | 0.149 | 0.164 | ……. | .…… | 0.148 | 0.163 | 2H |
0.153 | 0.169 | ……. | ……. | 0.128 | 0.138 | 0.119 | 0.137 | …… | .…. | 0.119 | 0.137 | 3H |
0.149 | 0.135 | ……. | ……. | 0.149 | 0.163 | 0.151 | 0.168 | ..…. | ..…. | 0.148 | 0.163 | 4H |
−0.455 | −0.693 | −0.736 | −0.888 | −0.589 | −0.781 | −0.590 | −0.780 | −0.733 | −0.889 | −0.596 | −0.787 | 5N |
…. | .…. | 0.290 | 0.336 | 0.290 | 0.341 | 0.295 | 0.339 | 0.291 | 0.331 | 0.291 | 0.334 | 6H |
…. | ……. | 0.294 | 0.331 | ….. | ……. | ……. | …… | 0.294 | 0.339 | ……. | ……. | 8H |
−0.104 | −0.092 | −0.119 | −0.094 | −0.123 | −0.106 | −0.123 | −0.107 | −0.103 | −0.079 | −0.101 | −0.084 | 8C |
0.148 | 0.144 | 0.124 | 0.169 | 0.123 | 0.153 | 0.121 | 0.173 | 0.118 | 0.147 | 0.116 | 0.174 | 9H |
0.114 | 0.170 | 0.144 | 0.152 | 0.140 | 0.177 | 0.144 | 0.150 | 0.143 | 0.170 | 0.148 | 0.144 | 10H |
−0.234 | −0.274 | −0.228 | −0.275 | −0.229 | −0.292 | −0.220 | −0.244 | −0.307 | −0.315 | −0.239 | −0.276 | 11C |
0.148 | 0.104 | 0.140 | 0.165 | 0.149 | 0.186 | 0.148 | 0.168 | 0.139 | 0.173 | 0.151 | 0.180 | 12H |
0.155 | 0.177 | 0.144 | 0.179 | 0.150 | 0.176 | 0.146 | 0.137 | 0.140 | 0.177 | 0.152 | 0.180 | 13H |
0.099 | 0.109 | −0.274 | −0.266 | 0.130 | 0.120 | 0.103 | 0.100 | …… | …… | 0.005 | 0.120 | 14C |
0.159 | 0.199 | 0.156 | 0.211 | 0.161 | 0.200 | 0.156 | 0.194 | ……. | …….. | 0.160 | 0.202 | 15H |
−0.588 | −0.799 | ….. | ….. | −0.587 | −0.795 | −0.608 | −0.804 | −0.598 | −0.790 | −0.589 | −0.830 | 16O |
……. | ……. | ……. | …… | ……. | …… | …….. | ...... | −0.078 | −0.001 | ….. | …… | 17C |
……. | ……. | ….. | …… | ….. | ….. | ……. | ……. | 0.182 | 0.194 | …… | …… | 18H |
……. | ……. | …… | ….. | …… | ….. | …….. | ……. | 0.180 | 0.194 | ….. | …… | 19H |
−0.257 | −0.230 | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | 20C |
0.147 | 0.166 | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | 21H |
0.149 | 0.168 | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | 22H |
0.116 | 0.135 | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | 23H |
−0.089 | −0.045 | −0.103 | −0.100 | −0.451 | −0.552 | −0.106 | −0.101 | 0.059 | 0.009 | −0.117 | −0.127 | 24C |
−0.161 | −0.194 | −0.122 | −0.155 | −0.074 | −0.139 | −0.145 | −0.216 | −0.136 | −0.213 | −0.085 | −0.123 | 25C |
−0.150 | −0.214 | −0.106 | −0.214 | −0.047 | −0.107 | −0.148 | −0.214 | −0.152 | −0.213 | −0.160 | −0.214 | 26C |
−0.145 | 0.219 | −0.154 | −0.210 | ……. | …… | −0.145 | −0.224 | −0.123 | −0.148 | −0.144 | −0.215 | 27C |
−0.143 | −0.213 | −0.146 | −0.162 | .….. | .….. | −0.164 | −0.218 | −0.118 | −0.148 | −0.143 | −0.215 | 28C |
−0.133 | −0.216 | −0.240 | −0.312 | −0.299 | −0.391 | −0.133 | −0.195 | −0.017 | −0.206 | −0.160 | −0.214 | 29C |
0.151 | 0.235 | 0.173 | 0.255 | 0.192 | 0.245 | 0.150 | 0.229 | 0.164 | 0.246 | 0.147 | 0.212 | 30H |
0.147 | 0.228 | 0.157 | 0.253 | 0.165 | 0.240 | 0.146 | 0.218 | 0.171 | 0.246 | 0.147 | 0.223 | 31H |
0.146 | 0.221 | 0.160 | 0.236 | 0.169 | 0.253 | 0.145 | 0.219 | 0.175 | 0.266 | 0.148 | 0.223 | 32H |
0.147 | 0.221 | 0.173 | 0.238 | …… | …… | 0.145 | 0.220 | 0.174 | 0.266 | 0.153 | 0.230 | 33H |
0.152 | 0.222 | .….. | .….. | …… | …… | 0.145 | 0.219 | .…. | .…. | 0.152 | 0.233 | 34H |
…… | …… | …… | ……. | 0.380 | 0.453 | ……. | …… | ….. | …… | …… | …. | 35S |
0.279 | 0.355 | −0.133 | −0.127 | 0.266 | 0.340 | 0.283 | 0.353 | 0.285 | 0.336 | 0.311 | 0.440 | 36C |
−0.133 | −0.203 | −0.160 | −0.155 | −0.134 | −0.210 | −0.152 | −0.216 | −0.148 | −0.205 | −0.138 | −0.235 | 37C |
−0.149 | −0.359 | −0.107 | −0.151 | −0.138 | −0.219 | −0.141 | −0.210 | −0.144 | −0.206 | −0.155 | −0.250 | 38C |
0.245 | 0.212 | −0.174 | −0.230 | −0.094 | −0.041 | −0.172 | −0.219 | −0.190 | −0.224 | −0.138 | −0.130 | 39C |
---|---|---|---|---|---|---|---|---|---|---|---|---|
−0.138 | −0.211 | −0.104 | −0.205 | −0.177 | −0.218 | −0.188 | −0.218 | −0.174 | −0.225 | 0.116 | −0.131 | 40C |
−0.157 | −0.209 | −0.233 | −0.317 | −0.183 | −0.219 | −0.094 | −0.036 | 0.100 | −0.027 | −0.021 | −0.029 | 41C |
0.150 | 0.247 | 0.175 | 0.255 | 0.147 | 0.236 | 0.145 | 0.226 | 0.164 | 0.225 | 0.171 | 0.253 | 42H |
0.152 | 0.252 | 0.159 | 0.255 | 0.146 | 0.228 | 0.143 | 0.229 | 0.171 | 0.225 | 0.163 | 0.246 | 43H |
0.153 | 0.235 | 0.175 | 0.238 | 0.145 | 0.227 | 0.143 | 0.233 | 0.147 | 0.231 | 0.176 | 0.266 | 44H |
0.165 | 0.234 | 0.160 | 0.238 | 0.155 | 0.231 | 0.157 | 0.227 | 0.150 | 0.231 | 0.175 | 0.266 | 45H |
….. | ….. | ….. | ….. | −0.318 | −0.328 | −0.338 | −0.351 | 0.687 | 1.136 | 0.682 | 1.136 | 46C |
….. | ….. | ….. | ….. | ….. | ….. | ….. | ….. | −0.287 | −0.406 | −0.293 | −0.419 | 47F |
….. | ….. | ….. | ….. | ….. | ….. | ….. | ….. | −0.291 | −0.414 | −0.293 | −0.409 | 48F |
−0.344 | −0.471 | ….. | ….. | ….. | ….. | ….. | ….. | −0.291 | −0.414 | −0.290 | −0.415 | 49F |
….. | ….. | ….. | ….. | 0.150 | 0.149 | 0.141 | 0.187 | ….. | ….. | ……. | ……. | 50H |
….. | ….. | ….. | ….. | 0.150 | 0.149 | 0.151 | 0.182 | ….. | ….. | …… | …….. | 51H |
….. | ….. | ….. | ….. | ……. | ……. | ……. | ….. | ….. | ….. | …….. | …….. | 52H |
….. | ….. | ……. | ….. | 0.015 | −0.047 | −0.022 | −0.043 | ….. | ….. | …. | …. | 53C |
….. | ….. | ….. | ….. | 0.140 | 0.165 | 0.141 | 0.168 | ….. | ….. | ……. | …… | 54H |
….. | ….. | .…. | .…. | 0.140 | 0.165 | 0.156 | 0.183 | ……. | ….. | ……. | ……. | 55H |
….. | ….. | ….. | ….. | −0.656 | −0.805 | −0.649 | 0.800 | ……. | ……. | ……. | ……. | 56O |
….. | ….. | ….. | ….. | 0.382 | 0.426 | 0.378 | 0.423 | ……. | ……. | ……. | ……. | 57H |
….. | ….. | 0.020 | 0.044 | ……. | ……. | ……. | ……. | ……. | ……. | ……. | ……. | 58Cl2 |
as in
The energy of electron affinity is given by the equation: EA = −ELUMO [
The observed and calculated frequencies using four methods (AM1, PM3, HF/6-31G, DFT/B3LYP/6-31G) with their absolute intensities were shown in
shows IR-spectra of the fluoxetine and its derivatives in four method (AM1, PM3, HF, DFT). The present study, theoretical calculations of vibrational spectra using different methods and different basis sets were compared drugs with the derivatives to obtain the best expectation. The best frequencies calculated by DFT which was in a good agreement with drug frequencies results.
The assignment of carbon-hydrogen stretching mode is straightforward on the basis set of the scaled four methods predicted frequencies as well known group frequencies. The heteroaromatic structure shows the presence of C-H stretching vibrations in the region 3150 - 3050 cm−1 [
Which is the characteristic region for ready identification of C-H stretching vibration? In this region, the bands are affected appreciably by the nature of the substituents. In the present theoretical study, there are three C-H stretching vibrations observed in the aromatic ring [
Fluoxetine | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Experimental [ | AM1 | PM3 | HF | DFT | ||||||||
Freq∙cm−1 | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | ||||
N-H | 3300 - 3500 | 3395 | 23.31 | 3361 | 3.84 | 3772 | 31.36 | 3502 | 31.02 | |||
C-Haromatic | 3150 - 3050 | 3190 | 96.40 | 3073 | 62.75 | 3434 | 6.83 | 3263 | 5.97 | |||
C-C | 1400 - 1650 | 1540 | 405.3 | 1468 | 570.3 | 1401 | 442.9 | 1339 | 447.4 | |||
C-N | 1358 | 4.11 | 1334 | 11.6 | 1298 | 2.77 | 1268 | 84.58 | ||||
C-F | 1250 | 1278 | 127.7 | 1208 | 58.94 | 1285 | 181.9 | 1114 | 226.2 | |||
Patent 1 | ||||||||||||
Experimental [ | AM1 | PM3 | HF | DFT | ||||||||
Freq∙cm−1 | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | ||||
N-H | 3300 - 3500 | 3472 | 18.17 | 3517 | 7.40 | 3859 | 137.5 | 3609 | 167.18 | |||
C-Haromatic | 3150 - 3050 | 3402 | 215.8 | 3065 | 55.15 | 3402 | 43.39 | 3239 | 14.15 | |||
C-C | 1400 - 1650 | 1321 | 318.3 | 1462 | 86.82 | 1458 | 468.1 | 1336 | 500.06 | |||
C-N | 1358 - 1130 | 1331 | 3.37 | 1367 | 44.98 | 1350 | 6.16 | 1430 | 23.63 | |||
C-F | 1250 | 1321 | 318.3 | 1371 | 168.43 | 1245 | 373.06 | 1117 | 221.78 | |||
Patent 2 | ||||||||||||
Experimental [ | AM1 | PM3 | HF | DFT | ||||||||
Freq∙cm−1 | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | ||||
N-H | 3300 - 3500 | 3393 | 29.21 | 3373 | 4.32 | 3795 | 2.77 | 3530 | 0.39 | |||
C-Haromatic | 3150- 3050 | 3181 | 65.67 | 3074 | 34.36 | 3392 | 18.73 | 3218 | 59.91 | |||
C-C | 1400 - 1650 | 1450 | 61.27 | 1376 | 75.20 | 1331 | 97.67 | 1561 | 212.04 | |||
C-N | 1358 - 1130 | 1465 | 22.42 | 1416 | 1.16 | 1251 | 21.49 | 1376 | 75.20 | |||
O-H | 3500 - 3450 | 3478 | 79.15 | 3879 | 15.69 | 4005 | 62.59 | 3633 | 16.69 | |||
Patent 3 | ||||||||||||
Experimental [ | AM1 | PM3 | HF | DFT | ||||||||
Freq∙cm−1 | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | ||||
N-H | 3300 - 3500 | 3394 | 28.81 | 3373 | 4.36 | 3798 | 3.36 | 3532 | 0.33 | |||
C-Haromatic | 3150 - 3050 | 3242 | 161.49 | 3125 | 116.3 | 3359 | 29.38 | 3195 | 33.91 | |||
C-C | 1400 - 1650 | 1670 | 177.4 | 1431 | 32.96 | 1691 | 179.6 | 1558 | 152.25 | |||
C-N | 1358 - 1130 | 1403 | 6.91 | 1415 | 1.01 | 1380 | 8.25 | 1268 | 7.17 | |||
O-H | 3500 - 3450 | 3482 | 97.55 | 3899 | 23.27 | 4014 | 63.29 | 3648 | 11.78 | |||
Patent 4 | ||||||||||||
Experimental [ | AM1 | PM3 | HF | DFT | ||||||||
Freq∙cm−1 | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | ||||
N-H | 3300 - 3500 | 3459 | 16.73 | 3516 | 7.52 | 3798 | 3.36 | 3532 | 0.33 | |||
C-Haromatic | 3150 - 3050 | 3187 | 91.65 | 31.25 | 116.3 | 3359 | 29.38 | 3195 | 33.91 | |||
C-C | 1400 - 1650 | 1620 | 69.78 | 1431 | 32.96 | 1691 | 179.6 | 1558 | 152.25 | |||
C-N | 1358 - 1130 | 1479 | 12.62 | 1415 | 1.01 | 1380 | 8.25 | 1268 | 7.17 | |||
C-Cl | 3482 | 97.55 | 3899 | 23.27 | 4014 | 63.29 | 3648 | 11.78 | ||||
Patent 5 | |||||||||
---|---|---|---|---|---|---|---|---|---|
Experimental [ | AM1 | PM3 | HF | DFT | |||||
Freq∙cm−1 | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | Freq∙cm−1 | Intensity | |
C-Haromatic | 3150 - 3050 | 3190 | 54.16 | 3072 | 69.66 | 3386 | 44.27 | 3229 | 25.11 |
C-C | 1400 - 1650 | 1691 | 227.25 | 1684 | 191.61 | 1691 | 179.6 | 1549 | 197.89 |
C-N | 1358 - 1130 | 1497 | 25.04 | 1393 | 5.78 | 1429 | 1.81 | 1306 | 6.79 |
There are six equivalent C-C bonds in benzene and consequently, there will be six C-C stretching vibrations. Due to the high symmetry of benzene, many modes of vibrations are infrared inactive. In general, the bands around 1400 - 1650 cm−1 in drug are assigned to skeletal stretching C-C bands [
Infrared spectra of a number of tri-fluoro group have been studied, they assigned the frequency 1250 cm−1 to a C-F stretching mode of vibration [
Stretching type vibrations of amine functional group have 3300 - 3500 cm−1 characteristic IR absorption frequencies [
DFT method was applied to predict the molecular electrostatic potential surface of the drug and its derivatives.
Theoretical studies were conducted using (AM1, PM3, HF, and DFT) methods to calculate the physical and chemical properties of fluoxetine and its five
derivatives as a patent, but its biological activity has not been studied.
To make an evaluation for derivatives as a drug, the energies, dipole moment, static charge, bond length, HOMO-LUMO energies and a spectrum was calculated for the optimum structure. The results of the four methods were not very clear, but a correlation between the dipole moment (potential character), static distribution (an active site character) and HOMO-LUMO energies (energy for electron transfer) show that the Patent 1, 5 was important derivatives as a recommended drug relative to fluoxetine drug.
The authors declare no conflicts of interest regarding the publication of this paper.
AL-Makhzumi, Q.M.A.H., Abdullah, H.I. and AL-Ani, R.R. (2018) Theoretical Study of N-Methyl-3-Phenyl-3-(4-(Trifluoromethyl)Phenoxy) Propan as a Drug and Its Five Derivatives. Journal of Biosciences and Medicines, 6, 80-98. https://doi.org/10.4236/jbm.2018.68007