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QUANTUM COMPUTATIONAL AND SPECTRAL INVESTIGATION OF 4-CHLORO PHENYLACETYL CHLORIDE

V. George Fernandeza, Dr. B.Rajamannana*, Dr. S. Periandyb, K. Jayasheelab a Directorate of School Education, Anna Nagar, Puducherry 605 005. a* Department of Physics, FEAT, Annamalai University, Chidambaram, Tamil Nadu 608 002. b Department of Physics KMGIPGR, Pondicherry University, Puducherry 605 008

A B S T R A C T

Spectral and quantum chemical studies have been undertaken on 4-Chloro phenyl acetyl chloride in this study. The Density Functional Theory (DFT), using B3LYP functional and 6-311++G (d,p) basis set, was used along with recorded spectra. Potential energy scan analyses were carried out to find out the stable conformers. FT-IR and FT-Raman spectra were recorded in the region of 4000-500 cm-1 for identification of all the fundamental modes of vibrations and were compared with the wave numbers predicted theoretically. The NBO, FMO analyses were carried out which were the most probable electronic transitions in the molecules. The prominent donor and acceptor orbitals were identified with their occupancy and hybridisation states. The structural analysis was carried out using the calculated bond lengths and bond angles and comparing it with the experimental values. The wave numbers were assigned using the PED values predicted. The atomic charges were calculated and were correlated with the experimental NMR chemical shift values. The most probable electronic transitions were tested experimentally using the recorded UV- vis spectrum and the oscillator strength and H-L contributions were analysed for such transitions. Docking studies were carried out to find out the antimutagenic activity of the molecule.

Key words: FT-IR, FT-RAMAN, UV-analysis and DOCKING studies.

Introduction Phenyl acetyl chloride is used as a key precursor in the total synthesis of vialinin B. It is employed as a linker to prepare den drimers and also used in the synthesis of various conjugated aromatic small molecules. Phenyl acetyl chloride is incompatible with strong oxidizing agents, alcohols, bases (including amines) may react vigorously or explosively if mixed with di-isopropyl ether or other ethers in the presence of trace amounts of metal salts[1]. It may cause severe burns to skin and eyes, when it its contacted with molten substances. Reaction with water or moist air will release toxic, corrosive or flammable gases.

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Reaction with water may generate heat that will increase the concentration of fumes in the air. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated or if contaminated with water[2].The major use of chloroacetyl chloride is as an intermediate in the production of herbicides in the chloroacetanilide family including metolachlor, acetochlor, alachlor and butachlor. Some chloroacetyl chloride is also used to produce phenacyl chloride, another chemical intermediate, also used as tear gas. Phenacyl chloride is synthesized in a Friedel-Crafts acylation of benzene, with aluminium chloride as catalyst[3]. Experimental Methods The compound 4-Chloro phenylacetyl chloride was purchased from sigma Aldrich in spectroscopic grade and used for recording the spectra. The NMR 13C spectrum was recorded in the range of 20-200 ppm with the scanning interval of 20 ppm. The Hydrogen 1H NMR

spectrum was recorded in region 1-10 ppm. The (CDCl3) chloroform solvent was used for recording both the spectra. The FT-IR spectrum was recorded by KBr pellet method on a Burker IFS 66V spectrometer in the range of 4000- 500 cm-1 with the spectra resolution of 2 cm-1. The FT- Raman spectrum was also recorded in the same instrument in the range of 4000- 500 cm-1 with FRA 106 Raman module equipped with Nd: YAG Laser with 200 mW powers. Ge detector with liquid nitrogen was used; the frequencies of all sharp bands are precise to 2 cm-1. The UV spectrum was recorded with the UV-1700 spectrophotometer, for the spectral wavelength range of 200- 400 nm for a scanning interval of about 0.2 nm. Computational Method The entire computations of the 4-Chloro phenylacetyl chloride were performed using the GAUSSIAN 09 software on Pentium IV processor [4] personal computer. The geometry of the titled compound was optimized using B3LYP functional with 6-311++G (d,p) basis set. The NMR chemical shift was carried out by GIAO functional along with B3LYP and 6-311++G (d,p) basis set combination. In addition, Mullikan atomic charges and natural charges of the title molecule were also computed using B3LYP method and same basis set. The optimized parameters of the compound were used for harmonic vibrational frequency calculations. The electronic properties such as NBO and HOMO-LUMO of the titled compound were calculated using time- dependent TD-SCF-B3LYP method under the same basis set. The dipole moment, the linear polarisability and first-order hyper polarisability of the title molecule were also computed using B3LYP method and same basis set.

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Result and Discussion Conformational analysis The optimized molecular structure of the present molecule was used for conformational analysis, which was performed by potential energy surface scan techniques using B3LYP, by varying the dihedral angle 14CL-13C-12C-17H in the steps of 100 over one complete rotation. The graphical result, total energy (in Hartree) verses scan coordinates of the conformer is presented in Fig 13. The graph clearly shows that conformer at minimum energy level occurs at 1600 and 3100 with energy value -0.0622 and -0.0622 Hartree. This conformer serves as the most stable conformer of the compound. The maximum energy is observed for the conformer at 2450with energy value -0.0604 Hartree, this is the least stable or most unstable conformer of the compound. The most stable conformer is used for all the computations in the present work.

Fig.1. Conformational analysis for 4-Chloro phenylacetyl chloride

Structural analysis The structural analysis of 4-Chloro phenylacetyl chloride was carried out using B3LYP functional and 6-311++G (d,p) basis set for the most stable conformer of the compound. The bond lengths and bond angles of the compound calculated using this method is listed in the Table 1. The optimised structure of the compound is shown in Fig 2.

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Fig.2. Optimized structure of 4-Chloro phenylacetyl chloride

This compound has eight C-C, six C-H, one C-O, and two C-CL bonds. The C-C single bonds are expected to value around 1.45Å and the C=C double bond around 1.35 [5]. In the present molecule, in benzene ring, all the CC bonds have bond length values around 1.39 Å. This shows they are neither single bonded nor double bonded, which is due to the conjugation of the electrons among these bonds. The variation in values among them is due to the slight variation in distribution of electron density within the ring among these bonds, which is naturally due to both the substitutional groups with the benzene. In the case of acetyl chloride, the C3-C12 and C12-C13 bonds are found to have length of 1.5087 & 1.5181 Å. These values are higher than the expected range for CC single bond, and there is also difference between them, which are all naturally due to the presence of oxygen and chlorine atoms in this acetyl group. The tendency of oxygen atom is to attract an electron towards itself; hence, it redistributes the occupancy of electrons present with these CC bonds. According to the literature [6], the CO double bond is expected to have value 1.22Å and single bond 1.35Å respectively. In the present compound, the CO at C13=O15 is found to have bond length 1.17 Å, which is still less than the expected value for a double bond, which may be naturally due to the conjugation of chlorine in this group. All the CH bonds in the benzene ring structure are expected to be of length 1.08 Å [7]. In the present compound, CH bonds in the benzene ring are found to have values 1.08 Å and that in acetyl group 1.09 Å, the slight variation is purely due to the changed electron density at these bonds due to the presence of O and Cl atoms. There are two C-Cl bonds in this compound whose values are predicted to be 1.75Å in C6-Cl11 and 1.83Å in C13-Cl 14, the difference in values indicate the influence of O on this bond length.

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The bond angle around each carbon atom is expected to be 120o [8]. In this molecule, the bond angle between C2-C1-H7, C4-C5-H10, C6-C5-H10, C2-C3-C12, C4-C3-C12 and C6-C1-H7 single bond angle are observed to be 120o as expected, but the other bond angles are varying between 118o-121o. Among the carbon atoms in the benzene ring, C6 at which the Cl is substituted shows much variation in the bond angles, whereas C3 at which the acetyl group is substituted, shows no variation in the angles, However, the carbon atoms in the acetyl group shows considerable variation from SP2 hybridisation value, which is naturally due to the electronegative atoms O and Cl.

Table No: 1. Optimized Geometrical parameter for 4-Chloro phenyl acetyl chloride Computed at B3LYP/6-311++G (d,p)

Bond length B3LYP/6-311++G (d,p) Bond Angle B3LYP/6-311++G (d,p) C1-C2 1.3921 C2-C1-C6 119.0778 C1-C6 1.3911 C2-C1-H7 120.7416 C1-H7 1.0824 C6-C1-H7 120.1805 C2-C3 1.3969 C1-C2-C3 121.0689 C2-H8 1.0850 C1-C2-H8 118.9941 C3-C4 1.3969 C3-C2-H8 119.9370 C3-C12 1.5087 C2-C3-C4 118.6522 C4-C5 1.3921 C2-C3-C12 120.6724 C4-H9 1.0850 C4-C3-C12 120.6751 C5-C6 1.3911 C3-C4-C5 121.0696 C5-H10 1.0824 C3-C4-H9 119.9351 C6-Cl11 1.7570 C5-C4-H9 118.9953 H9-O15 3.7049 C4-C5-C6 119.0763 C12-C13 1.5181 C4-C5-H10 120.7409 C12-H16 1.0940 C6-C5-H10 120.1826 C12-H17 1.0939 C1-C6-C5 121.0552 C13-Cl14 1.8371 C1-C6-Cl11 119.4715 C13-O15 1.1787 C5-C6-Cl11 119.4730

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Bond length B3LYP/6-311++G(d,p) Bond Angle B3LYP/6-311++G(d,p) C3-C12-C13 113.7862

C3-C12-H16 111.7352

C3-C12-H17 111.7368

C13-C12-H16 106.6912

C13-C12-H17 106.7158

H16-C12-H17 105.6658

C12-C13-Cl14 110.9063

C12-C13-O15 129.1304

Cl14-C13-O15 119.9633

Mullikan and Natural atomic charge analysis The atomic charge analysis plays important role in the prediction of the properties of the molecule, as the atomic charges affect parameters such as dipole moment, molecular reaction, Vibrational frequency, NMR chemical shift, etc[9]. The atomic charges are calculated by two methods in the present case for comparison purpose; Mullikan Population Analysis (MPA) and Natural Atomic Charges (NAC), by B3LYP/6-311++G (d, p) basis set method and the values are listed in the Table 2 and the graphical representation shown in the fig.3. Carbon atoms in the benzene ring C1, C2, C4, C5 are found to be equally negative as expected, but they are predicted to be highly positive in C3 and C6 in MPA and relatively less negative in NAC. The prediction of highly positive may be correct for C6 where Cl is attached in the benzene, whereas NAC may be correct for C3 where the acetyl group is attached, in comparison with the structural analysis. The C6 is predicted by highly positive 0.583 in MPA, while slightly negative -0.033 in NAC. C12 & C13 are in acetyl group, where C13 is directly attached O and Cl, hence C13 may be highly positive and C12 is slightly negative. This is found to be in resonance with NAC predictions. All hydrogen atoms which are in benzene ring are found to be equally positive, the hydrogen atoms in the acetyl group

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are found more positive relatively in comparison with that of benzene ring. All these observation for H atoms are in line with the expectation.

1

0.8

0.6

0.4

0.2

0 1 C 2 C 3 C 4 C 5 C 6 C 7 H 8 H 9 H 10 H 11 Cl 12 C 13 C 14 Cl 15 O 16 H 17 H -0.2

-0.4 MULLIKEN CHARGE

-0.6 NATURAL CHARGE

-0.8 Fig.3.Charge analysis of 4-Chloro phenyl acetyl chloride

Table No: 2. Mulliken Charges for 4-Chloro phenyl acetyl chloride computed at B3LYP/6-311++G (d, p) basis set.

Atoms Mulliken Atomic Charge Natural atomic Charge 1 C -0.63797 -0.21363 2 C -0.48615 -0.17132 3 C 0.782071 -0.04899 4 C -0.49482 -0.17143 5 C -0.63924 -0.21368 6 C 0.583019 -0.03315 7 H 0.193128 0.22376 8 H 0.174907 0.20858 9 H 0.174437 0.20855 10 H 0.193128 0.22375 11 Cl 0.428922 0.0076 12 C -0.23122 -0.50114 13 C -0.64022 0.57244 14 Cl 0.319672 -0.11428 15 O -0.07035 -0.47627 16 H 0.174965 0.24964 17 H 0.175728 0.24957

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NMR Chemical Shift analysis The Experimental and theoretical values of 1H NMR and 13C NMR chemical shift of 4-Chloro phenyl acetyl chloride are presented in Table 3. Chemical shifts are calculated in ppm and relative to TMS for 1H NMR and 13C NMR spectra, using the hybrid functional B3LYP and basis set 6-311++G (d, p), supported by Gauge Including Atomic Orbital (GIAO) technique. The theoretical and experimental chemical shifts of 1H NMR and 13C NMR spectra are as shown in fig. 4 and 5.

Aromatic carbons usually give the spectrum with chemical shift values from 120-130 ppm [10]. The experimental chemical shifts in the benzene ring are C1 (129.7 ppm), C2 (130.8 ppm), C3 (133.9 ppm), C4 (130.8 ppm), C5 (129.7 ppm) and C6 (133.9 ppm). All these values are relatively large when compared to unsubstituted benzene ring. This shows that the overall conjugation pattern is changed slightly due to the substitutions within the ring. C3 & C6 values show they are identical which contradict with the charge prediction in the previous section. The carbon atom in the acetyl group C12 and C13 are found to be 51 ppm and 171 ppm respectively. C12 value though it appears to be very less, it is relatively high for a aliphatic carbon which usually lie around 35 ppm; hence the increase in the value is due to the deshielding of O and Cl attached to C13. The C13 atom shows very high value (171 ppm) which is in accordance with charge prediction, by NAC method, due to the presence of O and Cl atoms in the acetyl chloride group. This very high value for a carbon atom indicates that the molecule can serve as biologically active molecule.

The chemical shift value of 1H atoms in benzene ring is expected between 7.0 ppm and 8.0 ppm[11]. The chemical shifts obtained in this case are found in between 7.2 ppm and 7.4 ppm, which also indicate the changed conjugation pattern within the ring. The two H atoms in the acetyl group are found to have values 4.19 ppm, which though appears to be less, it is actually high for an aliphatic group, which is naturally due to the presence of O atoms.

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SOLVENT (Chloroform) (C)

2.0

1.8

1.6

1.4 Degeneracy

1.2

1.0

40 60 80 100 120 140 160 180 200 Chemical shift (ppm)

Fig.4(a).Theoretical 13C Chemical shifts analysis of 4-Chloro phenyl acetyl chloride

SOLVENT (Chloroform) (H)

3.0

2.5

2.0 Degeneracy 1.5

1.0

4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 Chemical shift (ppm)

Fig. 4(b).Theoretical 13C Chemical shifts analysis of 4-Chloro phenyl acetyl chloride

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Graphical Representation NMR Chemical shifts

C13CPD CDCl3 {D:\CIF} CIF_NMR 1 NAME G2I EXPNO 2 PROCNO 1 Date_ 20190624 Time 12.24 INSTRUM spect PROBHD 5 mm BBO BB-1H

PULPROG zgpg30

171.59 133.94 130.83 129.74 128.93 77.48 77.16 76.84 51.94 39.94 TD 65536 SOLVENT CDCl3 NS 256 DS 4 SWH 24038.461 Hz FIDRES 0.366798 Hz AQ 1.3631988 sec RG 40.3 DW 20.800 usec DE 6.00 usec Fig. 5 (a) TE 295.0 K D1 2.00000000 sec d11 0.03000000 sec DELTA 1.89999998 sec TD0 1

======CHANNEL f1 ======NUC1 13C P1 9.95 usec PL1 -1.00 dB SFO1 100.6228298 MHz ======CHANNEL f2 ======CPDPRG2 waltz16 NUC2 1H PCPD2 90.00 usec PL12 14.95 dB PL13 120.00 dB PL2 -1.00 dB SFO2 400.1316005 MHz SI 32768 SF 100.6127923 MHz WDW EM SSB 0 LB 1.00 Hz GB 0 PC 1.40

200 180 160 140 120 100 80 60 40 20 0 ppm Fig.5 (a). Experimental 13C NMR Chemical shifts analysis of 4-Chloro phenyl acetyl chloride

PROTON CDCl3 {D:\CIF} CIF_NMR 1

NAME G2I EXPNO 1 PROCNO 1 Date_ 20190624

Time 12.20

7.427 7.411 7.406 7.281 7.264 4.191 3.725 INSTRUM spect PROBHD 5 mm BBO BB-1H PULPROG zg30 TD 65536 SOLVENT CDCl3

NS 16

7.427 7.411 7.406 7.281 7.264 DS 2 SWH 8223.685 Hz FIDRES 0.125483 Hz AQ 3.9846387 sec Fig. 5 (b) RG 36 DW 60.800 usec DE 6.00 usec TE 294.9 K D1 1.00000000 sec TD0 1

======CHANNEL f1 ======NUC1 1H P1 14.35 usec PL1 -1.00 dB 7.5 7.4 7.3 ppm SFO1 400.1324710 MHz SI 32768 SF 400.1299776 MHz WDW EM

SSB 0 1.03 1.00 LB 0.30 Hz GB 0 PC 1.00

11 10 9 8 7 6 5 4 3 2 1 0 ppm

1.03 1.00 1.04 Fig.5 (b). Experimental 1H NMR Chemical shifts analysis of 4-Chloro phenyl acetyl chloride

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Table No: 3. Calculated both 1H and 13C NMR Chemical shifts (ppm) of 4-Chloro phenylacetyl chloride

Gas CDCl 3 Experimental Atom B3LYP/6-311++G(d,p) B3LYP/6-311++G(2d,p) CDCl GIAO (ppm) GIAO (ppm) 3 1C 133.9 133.9 129.7 2C 135.2 136.0 130.8 3C 136.2 137.1 133.9 4C 135.2 136.0 130.8 5C 133.9 133.9 129.7 6C 148.8 147.7 133.9 12C 55.1 55.3 51.9 13C 183.3 186.1 171.5 7H 7.4 7.5 7.41 8H 7.1 7.3 7.40 9H 7.1 7.3 7.28 10H 7.4 7.5 7.42 16H 3.9 4.1 4.19 17H 3.9 4.1 4.19

Vibrational analysis The 4-Chloro phenyl acetyl chloride, the molecule under investigation has 17 atoms and 45 normal modes of fundamental vibrations. Vibrational wave numbers for all the modes were computed using DFT (B3LYP) methods with 6-311++G basis sets and the values along with the experimental values are presented in Table 4. The experimentally recorded and theoretically constructed FT-IR and FT Raman spectra of the title compound are shown in Fig. 6 and 7 respectively.

The calculated wave numbers are found slightly higher than the observed values for the majority of the normal modes. Two factors may be responsible for the discrepancies between the experimental and computed wave numbers; the first is caused by the unpredictable electronic distribution among the different bonds in the molecule and the second reason is a harmonic nature of the vibrations which cannot be accounted completely by theory. Scaling strategies were used to bring computed wave numbers to coincide with observed values. In this, study, the scaling factor used is 0.956 in accordance with earlier work on similar molecules [12].

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C-H VIBRATION The aromatic structure represents the presence of C-H stretching vibration in the characteristic region of 3100-3000 cm-1[13]. The C-H stretching modes usually appear with the strong Raman intensity due to their high polarization. In this compound, the experimental aromatic stretching vibrations are observed at 3110, 3082, 3024, 3013 cm-1 in FT-Raman and the corresponding calculated fundamentals using B3LYP/6-311++G (d, p) theoretically calculated values are at 3158, 3157, 3123, 3043 cm-1 respectively. All these values indicate that these benzene CH modes remain unaffected by the substitutional groups, this is in accordance with results of the structural and NMR chemical shift analysis as seen in the previous sections.

The bands due to C-H in plane bending vibrations are observed in the region 1000- 1300 cm-1[14]. For this compound, the C-H in-plane bending vibration is observed at 1220, 1170, 1145 cm-1 in FT-Raman and at 1092 and 1015 cm-1 in FT-IR. The theoretically scaled vibrations by B3LYP/6-311++G (d, p) level method also shows good agreement with experimentally recorded data. The C-H out-of-plane bending vibrations appear within the region 900-675 cm-1 [15]. The vibrations are identified at 620, 501, 491 and 412 cm-1 in FT- IR and 614, 498, 485, 403 and 394 cm-1 in FT-Raman are assigned to C-H out-of-plane bending for the title is theoretical C-H vibrations are in good agreement with the experimental values and literature.

CC Vibration:

The C-C stretching vibrations are expected in the range from 1600 – 1400 cm-1 which is not normally influenced by the nature of the substituent [16]. The C-C single and double bonded stretching vibrations of the titled molecule were observed at 1614, 1592, 1502, 1429, 1416, 1320, 1318 and 1301 cm-1 by theoretical study. In this present experimental study, the C-C stretching vibrations are found at 1491, 1452 and 1340 cm-1 in FT-IR and 1640, 1583, 1532, 1463, 1357, 1334, 1320 and 1300 cm-1 in FT-Raman respectively. Enough values are observed in the expected range for benzene ring, which shows they are not affected by the substitutional groups, the remaining vibrations are in the lower end of the aliphatic region which accounts for influence of the O and Cl atoms present in acetyl chloride groups.

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CO vibration: C-O stretching bonds produce a strong band in the region of 1800-1700cm-1[17]. In the titled compound, the theoretical C-O double stretching bands were computed at 1868 cm-1 and the corresponding experimental peaks are observed at 1784 cm-1 in FT-IR respectively. This is obviously at the higher end of the expected region, which is naturally due to the contribution of Cl atom that is directly attached to C=O group in this molecule.

CCL Vibration:

The title molecule contains two Cl atoms attached to C atoms; hence there should be C-Cl stretching vibration. The C-Cl vibrations are expected in the region of 760-505 cm-1 [18] and experimentally C-Cl vibrations are observed at 686 cm-1 in FT-IR and 632 cm-1 in FT- Raman respectively. The C-Cl in plane and out of plane vibration are assigned in the range of 385-265 cm-1 and 100-250 cm-1 [19] respectively. In the present case the C-Cl in plane and out of plane are experimentally observed at 422 and 418 cm-1 FT-IR and 401cm-1 FT-Raman respectively. All these C-Cl modes are found to be almost unaffected by the presence of other modes in this molecule, though possibilities are there for overlapping or mutual interference of many modes in this lower frequency region. This may be due to the relatively high mass and atomic number of the Cl atom.

Fig. 6(a) Experimental FT-IR analysis of 4-Chloro phenyl acetyl chloride

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700

600

500

400

300

200 Ramanactivity 100

0

-100

0 1000 2000 3000 Wavenumber

Fig. 6(b) Experimental FT-Raman analysis of 4-Chloro phenyl acetyl chloride

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0

200

400

Fig. 7 (a) Transmittance

600

800 3000 2000 1000 Wavenumber (cm-1)

Fig.7(a). Theoretical FT-IR analysis of 4-Chloro phenyl acetyl chloride

8

6 Fig. 7 (b)

4

RamanIntensity 2

0

4000 3500 3000 2500 2000 1500 1000 500 Wavenumber (cm-1)

Fig. 7(b).Theoretical FT-Raman analysis of 4-Chloro phenyl acetyl chloride

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Table No: 4.Observed method B3LYP/6-311++G (d, p) level calculated Vibrational frequencies of 4-Chloro phenylacetyl chloride

Experimental frequency B3LYP/6-311++G (d,p) (cm-1) Assignment PED % FT-IR FT-RAMAN Unscaled (cm-1) Scaled (cm-1) 3110 3203.28 3158.434 ν CH ν CH 44 3082 3202.36 3157.527 ν CH ν CH 51 3024 3168.03 3123.678 ν CH ν CH 57 3013 3167.55 3123.204 ν CH ν CH 38 3004 3086.39 3043.181 ν CH ν CH 49 3000 3051.91 3009.183 ν CH ν CH 49 1784 1894.92 1868.391 ν OC ν OC 92 1640 1637.81 1614.871 ν CC ν CC 31 1583 1614.83 1592.222 ν CC ν CC 27 1532 1523.88 1502.546 ν CC β HCC 19 1491 1463 1449.32 1429.03 ν CC β HCH 73 1357 1436.49 1416.379 ν CC β HCC 11 1334 1339.59 1320.836 ν CC β HCC 18 1320 1337.09 1318.371 ν CC ν CC 11 1300 1319.81 1301.333 ν CC ν CC 12 1220 1224.15 1207.012 βCH ν CC 32 1200 1204.89 1188.022 β CH ν CC 11 1170 1204.78 1187.913 β CH β HCC 17 1145 1130.94 1115.107 β CH β HCC 14 1092 1101.81 1086.385 β CH ν CC 26 1015 1032.69 1018.232 β CH β CCC 20 983 977.36 963.677 βOC τ HCCC 24 975 966.44 952.9098 βCC τ HCCC 22 954 946.29 933.0419 β CC β OCCl 17 903 913.58 900.7899 β CC τ HCCCl 32 857 875.32 863.0655 β CC τ HCCC 11 844 832 834.96 823.2706 β CC τ HCCC 28 802 809 818.67 807.2086 β CC ν CC 11 754 742 772.34 761.5272 τCH τ HCCC 10 686 682 713.29 703.3039 ν CL τ CCCC 12 645 632 649.65 640.5549 ν CL ν ClC 26 620 614 647.67 638.6026 τ CH β CCC 26 501 498 510.58 503.4319 τ CH τ HCCC 10 491 485 488.69 481.8483 τ CH β HCC 13 422 418 425.93 419.967 βCL β OCCl 34 412 403 418.6 412.7396 τCH β CCC 13 418 417.91 412.0593 βCL β OCCl 11 394 365.39 360.2745 τCH β CCC 40 378 326.1 321.5346 ϒCCC τ CCCC 24 264 249.56 246.0662 ϒ CCC β CCC 26 219 223.87 220.7358 ϒ CCC ν CC 14 163 154.21 152.0511 ϒ CCC β CCC 35 63 53.45 52.7017 ϒ CCCC ϒ CCCC 39 42 37.29 36.76794 ϒ CCCC ϒ CCCC 58 20 18.54 18.28044 ϒ CCCO ϒ CCCC 21

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NBO analysis The bonding and non-bonding (anti-bonding) interactions can be quantitatively described in terms of the NBO (Natural bonded orbitals) analysis, which can be predicted in terms of the second order perturbation interaction energy [E(2)][20]. This energy represents the estimation of the off diagonal NBO Fock matrix elements. It can be deduced from the second order perturbation relation [21]

F(,) i j 2 E(2)   E  q ij i  ji Where,

qi is the donor orbital occupancy,

εi and εj are diagonal elements (orbital energies) and F (i, j) is the off diagonal NBO Fock matrix elements.

In this analysis, the occupancies, from bonding to anti-bonding levels, and their energy levels were calculated and presented in the Table 5. The highly probable π-π* and n- π* transitions are observed between C-C, C-O & C-Cl bonding orbitals with adjacent anti- bonding orbitals. The highest probable electronic transitions in 4-Chloro phenyl acetyl chloride based on the E2 values in descending order can be listed as O15 to C13-Cl 14 (n-π*, 54.8 kcal/mol), C3-C4 to C5-C6 (π-π*, 21.4 kcal/mol), C1-C2 to C5-C6 (π-π*, 20.98 kcal/mol), C1-C2 to C3-C4 (π-π*, 20.9 kcal/mol), C3-C4 to C1-C2 (π-π*, 20.34 kcal/mol), and C5-C6 to C3-C4 (π-π*, 18.92 kcal/mol), Cl 14 to C3-O15 (n-π*, 16.89 kcal/mol), O15 to C12-C13(π-π*, 16.76 kcal/mol), and CL 11 to C5-C6 (π-π*, 12.53 kcal/mol). The first n-π* transition in the list is due to the O in acetyl group, the remaining π-π* transitions are mainly due to phenyl ring. The transitions due to Cl in both the locations seem less probable as their E2 values are less. All these transitions though theoretically favourable, only a few transitions will be allowed by the selection rules, which can be identified by the oscillator strength and HOMO- LUMO contribution, as it is done in the following section.

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Table No: 5. Second order perturbation theory of Fock matrix in NBO basis of 4-Chloro phenylacetyl chloride

Type Type Energy E(j)- F(i,j) Occupa Donor of Acceptor of Occupancy e(2) e(i) ncy bond bond Kcal/mol O 15 n 1.77142 C 13 -Cl 14 π* 0.01557 54.84 0.37 0.127 C 3 - C 4 π 1.65486 C 5 - C 6 π* 0.02376 21.4 0.27 0.069 C 1 - C 2 π 1.66289 C 5 - C 6 π* 0.31871 20.98 0.27 0.068 C 3 - C 4 π 1.65486 C 1 - C 2 π* 0.02375 20.65 0.28 0.069 C 1 - C 2 π 1.66289 C 3 - C 4 π* 0.35462 20.34 0.29 0.068 C 5 - C 6 π 1.67087 C 1 - C 2 π* 0.0279 19.42 0.3 0.068 C 5 - C 6 π 1.67087 C 3 - C 4 π* 0.0279 18.92 0.3 0.068 Cl 14 n 1.90244 C 13 - O 15 π* 0.20053 16.89 0.3 0.065 O 15 n 1.77142 C 12 - C 13 π* 0.01557 16.76 0.65 0.097 Cl 11 n 1.92722 C 5 - C 6 π* 0.02376 12.53 0.33 0.062 Cl 14 n 1.9721 C 13 - O 15 σ* 0.02375 5.62 0.95 0.065 C 12 - H 16 σ 1.95831 C 13 - O 15 σ* 0.02375 5.25 0.51 0.048 C 12 - H 17 σ 1.95848 C 13 - O 15 σ* 0.02375 5.22 0.51 0.047 C 1 - C 2 σ 1.9697 C 6 -Cl 11 σ* 0.31871 5.06 0.85 0.059 C 4 - C 5 σ 1.9697 C 6 -Cl 11 σ* 0.02375 5.06 0.85 0.059 C 2 - H 8 σ 1.97886 C 3 - C 4 σ* 0.14117 4.49 1.09 0.063 C 4 - H 9 σ 1.97886 C 2 - C 3 σ* 0.02376 4.49 1.09 0.063 C 1 - H 7 σ 1.97842 C 5 - C 6 σ* 0.06886 4.34 1.09 0.061 C 5 - H 10 σ 1.97841 C 1 - C 6 σ* 0.0279 4.34 1.09 0.061 Cl 11 n 1.97157 C 1 - C 6 σ* 0.0279 4.16 0.88 0.054 Cl 11 n 1.97157 C 5 - C 6 σ* 0.0279 4.16 0.88 0.054 C 3 - C 4 π 1.65486 C 12 - C 13 σ* 0.0279 3.93 0.61 0.047 C 2 - C 3 σ 1.97337 C 3 - C 4 σ* 0.0223 3.64 1.28 0.061 C 3 - C 4 σ 1.97338 C 2 - C 3 σ* 0.03271 3.64 1.28 0.061 C 1 - C 2 σ 1.9697 C 3 - C 12 σ* 0.38593 3.63 1.11 0.057 C 4 - C 5 σ 1.9697 C 3 - C 12 σ* 0.0279 3.63 1.11 0.057 C 1 - C 6 σ 1.97955 C 5 - C 6 σ* 0.35462 3.58 1.29 0.061 C 5 - C 6 σ 1.97955 C 1 - C 6 σ* 0.02482 3.58 1.29 0.061 C 1 - C 2 σ 1.9697 C 1 - C 6 σ* 0.20053 3.56 1.27 0.06 C 4 - C 5 σ 1.9697 C 5 - C 6 σ* 0.06886 3.56 1.27 0.06 C 1 - H 7 σ 1.97842 C 2 - C 3 σ* 0.14117 3.55 1.1 0.056 C 5 - H 10 σ 1.97841 C 3 - C 4 σ* 0.0279 3.55 1.1 0.056 C 12 - H 17 σ 1.95848 C 2 - C 3 σ* 0.02376 3.43 1.09 0.055 C 12 - H 16 σ 1.95831 C 3 - C 4 σ* 0.02376 3.4 1.09 0.055 C 2 - H 8 σ 1.97886 C 1 - C 6 π* 0.14117 3.38 1.09 0.054 C 4 - H 9 σ 1.97886 C 5 - C 6 σ* 0.02482 3.37 1.09 0.054 C 1 - C 2 σ 1.9697 C 2 - C 3 π* 0.38593 3.34 1.28 0.058 C 4 - C 5 σ 1.9697 C 3 - C 4 σ* 0.0279 3.34 1.28 0.058 C 3 - C 12 σ 1.97113 C 13 -Cl 14 σ* 0.0279 3.31 0.72 0.045 C 2 - C 3 σ 1.97337 C 1 - C 2 π* 0.38593 3.04 1.28 0.056 C 3 - C 4 σ 1.97338 C 4 - C 5 σ* 0.03271 3.04 1.28 0.056

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UV-Visible analysis The UV-Visible spectrum of the 4-Chloro phenyl acetyl chloride is recorded in the range of 200-400 nm in Ethanol solvent phase [22]. The theoretical UV-Vis studies which analyse various possible electronic excitation, wavelength, oscillation strength and also major FMO contribution in both gas phase and ethanol phase is carried out using TD-SCF functional along with B3LYP/6-311++G (d, p) combination, all these parameters both experimental and theoretical are presented in Table 6. The UV-Visible spectra of 4-Chloro phenyl acetyl chloride both theoretical and experimental are a shown in Fig.8.

On the basis of HOMO & LUMO, the excitation energies, oscillator strength (f), absorption wavelength () of the prominent probable transitions in the present molecule, in gas phase and ethanol solution were calculated and the values are presented in Table 6. The computed absorption bands, in gas phase, are observed at 256, 240, 235, 227, 222, 210, 200, 196, 195 and 194 nm with excitation energies 4.830, 5.157, 5.273, 5.438, 5.578, 6.173, 6.312, 6.3451 and 6.369 eV respectively. The major HOMOLUMO contribution is observed in the transition O15 to C13-Cl 14 (n-π*, 54.8 kcal/mol) with 89 % using Gauss sum program [23].

In ethanol solution, the absorption bands are observed at 258, 239, 231, 230, 224, 206, 197.9, 197.7, 196, 193.5 nm with excitation energies 4.796, 5.175, 5.352, 5.376, 5.536, 6.008, 6.264, 6.27., 6.304, 6.406 eV respectively. The major H L contribution for the transition O15 to C13-Cl 14 (n-π*, 54.8 kcal/mol) is found to be 94%. The oscillator strength values indicate that only 5th, 7th and 10th transitions will have greater intensity with absorption wavelength at 224, 197 and 193nm respectively when compared to other transitions. This is what shown in theoretical spectrum. The n-π* transition is not supported by the oscillator strength. However, in experimental spectrum all these transitions have appeared from 200 to 300nm, with many peaks very closely.

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25000

20000

15000

10000 Absorbance

5000

0

100 150 200 250 300 350 Fig. 8 (a) Wavenumber (nm)

Fig. 8(a). Theoretical analysis of 4-Chloro phenyl acetyl chloride

6

5

4

3

absorbance 2

1

0

200 300 400 Fig. 8 (b) wave length (nm)

Fig. 8(b).Experimental analysis of 4-Chloro phenyl acetyl chloride

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TableNo: 6. Theoretical electronic absorption spectra of 4-Chloro phenylacetyl chloride absorption wavelength λ (nm), excitation energies E (ev) and oscillator strengths (f) using TD-DFT/B3LYP/6-311++G (d, p) method.

λ (nm) Exp. E(eV) (f) Major contribution

GAS 256.65 4.8309 0.0018 HOMO->LUMO (89%) 240.40 5.1575 0.0003 HOMO->L+2 (57%) 235.11 5.2735 0.0000 H-2->LUMO (73%) 227.99 5.4380 0.0752 H-1->LUMO (54%) 222.26 5.5783 0.2076 HOMO->L+1 (43%) 210.28 5.8962 0.0062 HOMO->L+3 (87%) 200.83 6.1737 0.0000 H-4->LUMO (89%) 196.43 6.3120 0.1749 H-1->L+1 (50%) 195.40 6.3451 0.0149 HOMO->L+4 (38%) 194.64 6.3698 0.0074 H-2->L+1 (41%) Ethanol 258.50 257 4.7963 0.0013 HOMO->LUMO (94%) 239.54 5.1759 0.0002 HOMO->L+2 (61%) 231.65 5.3522 0.0043 H-1->LUMO (90%) 230.62 5.3760 0.0000 H-2->LUMO (89%) 224.35 220 5.5263 0.3562 HOMO->L+1 (81%) 206.34 6.0088 0.0006 HOMO->L+3 (72%) 197.90 6.2649 0.2968 H-1->L+1 (58%) 197.73 6.2703 0.0037 H-4->LUMO (91%) 196.65 6.3049 0.0328 HOMO->L+5 (43%) 193.52 190 6.4068 0.2124 H-1->L+2 (31%)

Frontier Molecular orbitals (FMO)

The Highest Occupied Molecular Orbital (HOMO) represents electrons filled orbits while the Lowest Unoccupied Molecular Orbital (LUMO) represents electrons accepting orbitals. These orbitals are known as frontier molecular orbital. The frontier molecular orbitals are very much useful for studying the electric and optical properties of the organic molecules. The energy gap (eV) between the HOMO and LUMO is very important parameters to study the chemical behaviour of a compound [25]. Also, the energy gap between HOMO-LUMO of the molecules determines whether it can have high reactivity or low kinetic stability [26]. All the parameters calculated from the HOMO –LUMO are presented in Table 7 and the diagrammatic view of these orbits is shown in Fig. 9.

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It is observed that HOMOs are occupying acetyl chloride groups along with the attached part of the benzene ring, while LUMOs are restricted to only acetyl part. The calculated energies of HOMO are -0.2739 eV and -0.0265 eV in gas phase and ethanol

solution respectively. The energy gap (EHOMO - ELUMO) is -0.2473 eV in gas phase. The HOMO-LUMO energy gap reveals the unlimited possibility of charge transfer within the molecule. The electro negativity determines the attraction of an electron in a covalent bond was found to be 0.1502. The global hardness defines the resistance of an atom or a group of atoms to receive electrons and is equal to reciprocal of global hardness and it is found to be 0.1236. The global softness explains the capacity of an atom or a group of atoms to receive electrons and is equal to reciprocal of global hardness and it is found to be 0.494.

Fig.9.HOMO-LUMO analysis of 4-Chloro phenyl acetyl chloride

Table No: 7. HOMO, LUMO, global electronegativity, global hardness and softness, global electrophilicity index of 4-Chloro phenylacetyl chloride

Parameters Gas

EHOMO (ev) -0.27391

ELUMO (ev) -0.02653

∆EHOMO-LUMO gap (ev) -0.24738

Elecronegativity (χ) 0.15022

Global hardness (η) 0.12369

Global softness (S) 0.49476

Chemical Potential (µ) 0.09122

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MEP:

Fig.10. MEP analysis of 4-Chloro phenyl acetyl chloride

Electrostatic potential maps, also known as electrostatic potential energy maps, or molecular electrical potential surfaces, illustrate the charge distributions of molecules three dimensionally. These maps help in visualizing the charged regions of a molecule and charge related properties of molecule, which in turn determine how molecule interacts with one another.

The red region corresponds to the region of greatest electron density/concentration and lowest electrostatic potential. The blue region corresponds to the region of lowest electron concentration and highest electrostatic potential. Intermediate colours represent intermediary electrostatic potentials. As shown in Fig.10, yellow colors indicate negative regions of MEP and are related to electrophilic reactivity, blue colors indicate for positive regions to nucleophilic reactivity. According to MEP surface, electrostatic potential increases in the order red

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MEP is calculated using B3LYP/6-311++G (d, p) approach. In our title compound, green regions are observed over chlorine atoms. They are strong regions for nucleophilic attacks. Yellow/red regions are observed on Oxygen and the blue regions over the H atoms.

Molecular Docking Study Bioactivity Information to Organic Chemist (BAITOC) is an application software that screens protein structures against the input organic compound, in a short time and provides information on proteins (PDBID). All molecular docking calculations were performed on Auto Dock-Vina software [28,29] and visualized through Discovery Studio Visualize software 4.0[30]. For docking, the ligand was prepared by minimizing its energy at B3LYP/6-311++G (d, p) and Hydrogen atoms are added to the target protein and Kollaman atomic charges was calculated. Water molecules and other co-crystallized agents were removed. Lamarckian genetic algorithm (LGA) is used for molecular docking analysis. The binding protein of the target proton was specified using grid size 84x84x84 A0 with the aid of Autogrid.

Docked conformation which has the lowest binding energy was chosen to investigate the mode of binding. The results are shown in table .8. The bond length is shown in Fig. 11. The 3D crystal structure was obtained from Protein Data Bank. In molecular docking, the receptor is the protein which is the host. The title compound, acts as ligand which binds to the receptor (PDB ID: 3NUO). PDB files have a variety of potential problems, such as, missing atoms, added waters, more than one molecule, chain breaks, alternate locations etc. At two sites through the hydrogen bonds of length 1.9 Å each, the molecule is found to bind with the protein 3NUO, with the same binding energy 5. 47 Kcal/mol.

Table No:8. The Docking binding pose for 4-chlorophenyl acetyl chloride

Binding Intermolecular Protein energy energy Bond Residue Distance (Å) ID (kcal/mol) (kcal/mol)

3NUO -5.47 -6.07 SER 28 1.9 GLU 130 1.9

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Fig.11. Docking analysis of 4-Chloro phenyl acetyl chloride

Conclusion: The conformation analysis reveals that the molecule possesses different conformers through the variation of dihedral angle 14CL-13C-12C-17H. The minimum energy conformers were obtained at 1600 and 3100 with energy value -0.0622. Through structural analysis, it is found that in acetyl chloride, the bonds C3-C12 and C12-C13 are found to have values 1.5087 & 1.5181 Å, which is higher than the expected range for even CC single bond, and there is also difference between them, which are all naturally due to the presence of oxygen and chlorine atoms in this acetyl group. The carbon atom in the acetyl group C12 and C13 are found to have chemical shift values 51 and 171 ppm respectively. C12 value though it appears to be less, it is relatively high for an aliphatic carbon which usually lie around 35 ppm; hence the increase in the value is due to the deshielding of O and Cl attached to C13. The C13 atom shows very high value (171 ppm) which is in accordance with charge prediction. The prominent n-π* transition in the molecule is due to the O in acetyl group, the remaining π-π* transitions are mainly due to phenyl ring. The transitions due to Cl in both the locations are found to be less probable. The docking with protein 3NUO was found to be possible through hydrogen bonds at two sites of length 1.9 Å each, with the same binding energy 5. 47 Kcal/mol.

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