Asian Journal of Spectroscopy, 14, 1-2, 2010, 57-61

Vibrational Properties of 2-chloro-10-(3-[4-(2-hydroxyethyl)-piperazin-1-yl) propyl phenothiazine - 'Perphenazine' : An Anti AIDS Drug

Y.P.Singha*, Arvind Singh Tomarb and S.K.Vijayc

a Department of Physics, Govt. Polytechnic College, Sagar (MP), INDIA 470001.E-mail: Y_P_S_2k@Yahoo.comb Department of Physics, S.V. Polytechnic College, Bhopal (MP), INDIA, c Department of Physics, Govt. Geetanjali Girls P.G. College, Bhopal (MP), INDIA Abstract Perphenazine has shown great promise in inhibiting the human immuno deficiency virus and in reducing mortality among AIDS patients. Fourier transform infra red spectrum was recorded and analyzed. Making use of the recorded data, the vibrational assignments are made and analysis of the observed fundamental bands of molecule is carried out. The experimental determinations of vibrational frequencies are compared with those obtained theoretically from Semi empirical, ab initio and DFT quantum mechanical calculations using semi emperical/PM3, ab-initio/6-311++G* , and B3LYP/6-311++G* methods. The spectra exhibit distinct features originating from low frequency vibrational modes caused by intra-molecular motion. The normal modes of vibrations obtained from ab initio and DFT (B3LYP) calculations are in good agreement with the experimentally observed data. Comparison of the simulated spectra provides important information about the ability of the computational method (B3LYP) to describe the vibrational modes. Introduction Acquired immune deficiency syndrome (AIDS) is a disease of the human immune system caused by the human immunodeficiency virus (HIV) has caused a worldwide concern for fighting this disease effectively1. Perphenazine {2-chloro-10-(3-[4-(2-hydroxyethyl)-piperazin-1-yl) propyl phenothiazine} is used to treat AIDS, severe nausea and vomiting. It is also used to treat the symptoms of psychosis. Perphenazine belongs to a class of psychoactive drugs called phenothiazines. Although the mechanism by

which they work is unknown, they have potent effects on the central nervous system and other organs2. It has been reported that some phenothiazines inhibit intracellular replication of viruses including HIV . 3-5

Spectroscopic studies of anti-AIDS drug have made a significant contribution of this noble endeavor of striving to eliminate the fear of this dreadful disease. The calculation of vibrational frequencies by computational methods is becoming increasingly important in many areas6. Infra red of molecules in their ground electronic states were predicted by molecular orbital theory7.

Thus the present study has been undertaken with a view to understand the

spectroscopy of this drug and experimental results are compared with calculated frequencies using semi empirical, ab initio and DFT (B3LYP) methods. Probably, this is the first time when we are reporting experimental frequencies with above cited calculated frequencies because we had surveyed lot of literature but we found nothing. Experimental and theoretical IR spectra have been compared.

Fig 1 Structure and Formula of Perphenazine Computational and Theoretical Details The PM3 semi empirical approaches were performed as implemented in MOPAC program 9 and the PRECISE keywords were used. DFT and Ab-initio calculations were performed using HYPER CHEM program 10 at the B3LYP 11 levels of theory with 6-311++G* basis set 12 . The vibrational IR spectra were calculated at the B3LYP/ 6-311++G* levels of theory. Vibrational frequencies calculated at 6-311++G* basis level were scaled by 0.95 and those calculated at ab initio level were scaled by 0.81. In order to obtain the most stable conformation, a combination of molecular mechanics and quantum chemical calculations at the semi-empirical level was used. Structure of the molecule (Fig. 1) was built by HyperChem Release 8 for Windows using a molecular mechanics procedure under MM+ . The geometry was optimized to an rms gradient of 0.001 in vacuo . Then a molecular dynamics program was run for 1 ps, with 0.001 ps steps and a relaxation time of 0.1 ps, at a simulation temperature of 300 K. This was followed by MM+ geometry optimization to an rms gradient of 0.2. The molecular dynamics run was repeated and a further MM+ protocol was carried out to a gradient of an rms 0.004 on the selected d rug..

Results and Discussions Vibrational Assignments: The theoretical prediction of vibrational spectra is of practical importance for the identification of known and unknown compounds, and has become an important part of spectrochemical and quantum chemical investigations13. According to theoretical calculations, Perphenazine has a planar structure of Cs point group symmetry. The title molecule consists of 53 atoms, which undergoes 153 normal modes of vibrations. Of the 153 normal modes of vibrations, 103 modes of vibrations are in-plane and remaining 50 are out-of plane. The bands that are in the plane of the molecule is represented as A' and out-of-plane as A". It has 52 bend stretching vibrations and 101 angle bending vibrations. Thus the 153 normal modes of vibrations are distributed as

Perphenazine

Empirical Formula C21H26ClN3OS

Molecular Weight 403.97 ΓVib = 103 A' + 50 A"

The vibrational assignments are given in Table 2. The comparative experimental and theoretical spectra of experimental and calculated are given in Figs. 2 and 3. Normal Modes: We can get information from computational vibrational spectra only when we compare it with experimental spectra. As the table 1 is self-explanatory and experimental values and corresponding calculated values are shown in table 1, we shall discuss here only some important points. The experimental bands are shown in figure 2 and theoretical bands are shown in figure 3. The OH stretch of the title molecule is identified at 3600 cm .-1 In the title molecule, the band have been assigned at 2925 cm−1 to C–H ring stretching vibrations. These assignments are in line with the literature14. The (C=C) stretching modes are normally observed between 1400 and 1650cm−1. Only two C=C stretching vibrations have been found at 1600 cm−1 and 1520 cm−1. The C–C stretching peak is at 1630 cm . -1 The C–N stretching vibrations are always mixed with other bands and normally occur in the region 1266–1382cm−1. A band is observed at 1360cm−1, which is in close agreement with the literature value15 and this vibration is combined with C–C stretching vibration. The CCC bending bands always occur below 600cm−1 as reported in literature16. In the present work band at 570 cm-1

is assigned to CCC in plane bending and 490 to out of plane bending. In experimental spectrum we got number of peaks in between 2500 cm - 1200 cm . In calculated IR spectrum we got less

-1

-1

number of peaks because our calculations are based on a frozen molecule at 0K in a vacuum and do not take into account that the structure is vibrating at all. In experimental IR spectrum there is influence of the medium in which chemical species are found. Conclusions Based on the semi-empirical at PM3, ab initio at 6-311++G* and DFT with B3LYP/6-311++G* levels, complete vibrational properties of Perphenazine have been investigated by FTIR spectroscopy. On the basis of agreement between the calculated and observed results, assignments

of fundamental vibrational modes of Perphenazine were examined and some assignments were proposed. Comparison of the experimental and calculated spectra showed that DFT-B3LYP method is in good agreement with experimental data. The results confirm the ability of the methodology (DFT) applied for interpretation of vibrational spectra of the title molecule. The correlation between the computed IR frequencies for semi-empirical and ab-initio and the experimental is less satisfactory, but this is not the case with DFT method. The graph is linear which shows that theoretical and experimental results are in good agreement.

Table 1 Principal Experimental and Calculated IR Signals (cm-1) and their Assignments in Perphenazine

Frequencies (in cm ) 1−Assignment

Experimental Frequencies

(in cm ) 1−

Assignments

semi-empirical (PM3)

DFT/ B3LYP (6-311++G*)

Ab-initio 6-311++G*)

Species a' 1 3600 OH str 3195.75 3506.29 3201.45 2 2925 CH str 3169.24 2961.33 3005.71 3 1630 CC Str 1776.85 1656.05 1694.86 4 1600 C=C aromatic ring vibration 1526.81 1564.54 1578.25 5 1520 C=C aromatic ring vibration 1518.71 1517.79 1563.21 6 1390 C-O str 1363.37 1387.82 1362.37 7 1360 CN str 1225.66 1367.16 1351.61 8 1150 C=S str 1138.96 1151.45 1143.96 9 860 CH o.p. plane 879.17 879.17 870.49 10 750 C-Cl str 755.96 745.35 766.38 11 570 CCC i. p. bending 651.73 588.61 601.75 12 520 CN o. p. bending 589.36 613.42 628.67 13 490 CCC o. p. bending 503.72 474.58 491.39

Frequencies (in cm ) 1−Assignment

Experimental Frequencies

(in cm ) 1−

Assignments

Semi-empirical (PM3)

DFT/ B3LYP (6-311++G*)

Ab-initio 6-311++G*)

Species a'' 1 OH o.p.def 332.80 244.82 228.61 2 580 CH wagging 878.89 587.72 678.74

Figure 2: IR Spectrum (Experimental) of Perphenazine

Figure 3: IR Spectrum (Theoretical) of Perphenazine

Correlation Diagram

Experimental Wavenumbers

0 500 1000 1500 2000 2500 3000 3500 4000

Cal

cula

ted

Wav

enum

bers

0

500

1000

1500

2000

2500

3000

3500

4000

Exp Vs PM3Exp Vs DFTExp Vs Ab-initio

Figure 4: Correlation Diagram for Experimental Vs Calculated Frequencies References 1. www. wikipedia.com, 2010 2. Paul Han and Bob Arnold, The challenge of Chronic AIDS Related Nausea and Voniting, Journal of Palliative Medicine, 4, 1, 2001 3. A.R.trivedi, A.B.Siddiqui and V.H. Shah, Design, synthesis, characterization and antitubercular activity of some 2-hetro- substituted phenothiazines, Arkivoc, 210-217, 2008 4. Flyod R A, Scheider J E, Zhu Y Q, North T W, Schinazi F, Inhibition of HIV and FW by methylene blue and light in vitro, Proc Am.

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Chemical Physics, 289, 201-219, 2003 14. W.O. George, P.S. Mcintyre, Infrared Spectroscopy, John Wiley & Sons, London, 1987. 15. M. Robert, G. Clayton Bassier, C.T. Morrill, Spectrometric Identification of Organic Compounds, John Wiley & Sons, Singapore, 1981 16. Ramalingam S, Periandy S, Govindarajan M and Mohan S; FT-IR and FT-Raman vibrational spectra and molecular structure investigation of nicotinamide: A combined experimental and theoretical study, Spectrochim acta A, 75, 1552-1558, 2010