INTRODUCTION:

Benzamide are known as important structural unit present in many compounds having likely biological activities, which are removed from natural sources. For example, molecules, like proteins which play anecessary role in almost all biological processes such as enzymatic catalysis, transport/storage (hemoglobin), immune protection (antibodies) and mechanical support (collagen). In amide all the three atoms in the O-C-N chain are reactive which makes them a useful moiety in organic compounds and hence become a main part for medicinal chemists.Some of the naturally occurring amides areshown in figure 1.

Figure 1: Two naturally structures occurring amides[1].

Benzamide (C₆H₅CONH₂) in figure 2 exhibits an angle of about 15º with the plane of the amide group, this indication that benzamide molecule is not flat [2, 3]. The rotation of the amide group relative to the aromatic ring may result from the repulsion interaction between the hydrogen atoms of the amide group and those of the aromatic ring. The nitrogen is in sp2 hybridization state and non-bonding electron pair of the nitrogen atom has an almost pure p orbital character. The bond length investigation reveals that the length of C = O bond is 1.26 Å which is greater than the standard length (1.20 Å). The length of the C-N (1.38 Å) bond shows deviation from the standard C-N length (1.47 Å) [4, 5]. In other words, the calculated bond length values are intermediate between the double bonds and single bonds. This confirms that the π electrons of the C-O bond are combined with the p lone pair of the nitrogen atom [6].

Figure 2: The Benzamide structure, where R= alkyl or aryl groups [2].

The complete medicinal chemistry database revealed that the carboxamide group appears in more than 25% of known drugs [7]. Benzamides have been reported to possess in vitro antibacterial activity. These benzamidesshowbest antimicrobial activity against staphylococcus aureus [8]. M L Carmellino et al. have synthesized the fluoro derivatives of dithiobis (benzamide) which showed anti-fungal activity [9]. Iodobenzamide derivatives were synthesized by D.Raffa et al. and showed anti-fungal activity against phytopathogenic fungi P.citrophthora, B.cinerea, R.solani and Alternaria species [10].

Computational details:

The density functional theory (DFT) method was implemented in the Gaussian 09 package of programs [11] to carried out the calculations. The molecular properties of the molecules had been computed by DFT using the standard 6-31G basis set. In the DFT calculations, Lee-Yang-Parr correlation functional is used together with Becke’s three parameters [12, 13] exchange functional B3LYP. Conformational analysis of the molecules had been performed to have an idea about the lowest energy structures of the species under study.

RESULTS AND DISCUSSION:

Figure 3 shows the relax structures of benzamide, ortho di-fluorine benzamide, meta di-fluorine benzamide and para di-fluorine benzamide, and they are labeled 1-4, respectively. Table 1 illustrated the optimized parameters of benzamide molecule and its adducts obtained from the relax structures at the full convergence for positions of all atoms in each structure with values of varial ratio (-V/T) for the optimized structures in the range (2.0045 – 0.0056). As observed, the bonds in phenyl ring remain in the same range of aromatic rings and agree with those in other studies [14, 15], this an indication for the effective density functional theory used here for relaxation.

(a) benzamide (b) ortho di-fluorine benzamide

(c) meta di-fluorine benzamide (d) para di-fluorine benzamide

Figure 3: The relax structures of benzamide and its adducts.

In all molecules, the LUMO is greater than the HOMO, in which, these molecules has low electron affinity and high ionization energy, all need high energies to donating an electron. Figure 3 showed the oxygen atom and amine subgroup in benzamide molecule have the significant contribution in the HOMO and LUMO. In the di-fluorine benzamide molecules, the contribution in the HOMO and LUMO is due to presence of the two fluorine atoms in the benzamide molecule, also the positions of fluorine atoms are play role in the constructed molecular orbitals. Benzamide molecule has (5.65 eV) energy gap, as in figure 4, the presence of the fluorine atoms few reduces the energy gap, meta di-fluorine benzamide has the lowest energy gap (5.51 eV). Density of states DOS in figure 4 for benzamide molecule was effected by adding the fluorine atoms in the terminal ends of phenyl ring, di-fluorine benzamide molecules have large number of degeneracy of energy levels in comparison with the reference benzamide molecule.

Molecule

Bond

Value (Å)

Angle

Value (Degree)

Benzamide

C=C

C--C

C-H

C-C

C=O

C--N

N-H

(1.387-1.404)

(1.389-1.41)

(1.083-1.084)

1.498

1.252

1.369

(1.006-1.009)

H-C---C

C---C---C

H-C---N

O=C---C

H-N-H

119.6

119.5

118.5

121.4

118.6

Di- fluorine benzamide

C-F

C=C

C--C

C-H

C-C

C=O

C--N

N-H

(1.387-1.388)

(1.387-1.404)

(1.389-1.41)

(1.083-1.084)

1.498

1.252

1.369

(1.006-1.009)

F-C=C

F-C---C

H-C---C

C---C---C

H-C---N

O=C---C

H-N-H

(119.8-120.2)

(119.1-119.9)

119.6

119.5

118.5

121.4

118.6

Benzamide:

Ortho di-fluorine benzamide

Meta di-fluorine benzamide

Para di-fluorine benzamide:

Figure 4: HOMO(left) and LUMO(right) of benzamide and its adducts(green color ≡ positive charge: red color ≡ negative charge).

Benzamide

ortho di-fluorine benzamide

Meta di-fluorine benzamidepara di-fluorine benzamide

Figure 5: The DOS of benzamide and its adducts.

Figure 6 illustrated the infrared spectra of the molecules under study. The number of modes of the vibrational frequencies are calculated according to 3N-6, they calculated for benzene molecule using B3LYP/6-31G method appear peaks at (691, 1066.3, 1528.28 and3202.34) cm^-1. By comparison these results with experimental results [15,16], it has been found that the calculations of B3LYP/6-31G method are in a good agreement with experimental data, where the peaks had been observed at (673, 1038, 1469, and 3210) cm^-1. The strong peak computed by B3LYP/6-31G observed at 691 cm^-1 and weak peak at 1066 cm^-1 are due to the bending of (C-H) bond, the peak observed at 1528 cm^-1 is due to the stretching of (C-C) bond, the peak at 3202 cm^-1is due to the stretching of(C-H) bond. The presence of oxygen atom and amine subgroup in the benzamide molecule gave peaks appear in low range of frequencies.

By comparison the IR spectrum of di-fluorine benzamide molecules in figure 6 with the IR frequency of benzamide molecule, it will be noted the differences between them, and it has been deduced that the differences due to the addition of fluorine atoms, where the vibrational modes have been increased with increasing of bonds, consequently the peaks have been increased.It is clear from figure 6 the IR spectrum for these molecules characters from that of benzene molecule by multiply the vibration mode due to existing of (N-H) bonds and (C-N) bonds, the stretching and bending of these bonds caused to new peaks or band of peaks to be appeared, the stretching (C-N) bond has been observed at (1200-1350) cm^-1, and the stretching (N-H) bond has been observed at (3200–3600) cm^-1, while the bending of (N-H) bond appeared at (1550–1650) cm^-1.

Benzamide

Ortho di-fluorine benzamide

Meta di-fluorine benzamide

Para di-fluorine benzamide

Figure 6: The IR-spectra of benzamide and its adducts.

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Received on 05.02.2018 Modified on 18.04.2018

Research J. Pharm. and Tech 2018; 11(9):3978-3982.

DOI: 10.5958/0974-360X.2018.00731.X