SYNTHESIS, CHARACTERIZATION AND DENSITY FUNCTIONAL THEORY INVESTIGATIONS OF MONOACYL ANILINE DERIVATIVES

We synthesized a number of aniline derivatives containing acyl groups to compare their barriers of rotation around the N-CO groups. Geometry optimization for all the rotamers have been performed using density functional theory (DFT) at the B3LYP/6-31G** level of theory. For each stationary point we carried out vibrational frequency calculations at the same level to characterize their nature as minima or transition states. The methoxy group substituent on the benzene ring causes some changes in the C–C bond distances. We carried out potential energy surface scanning to find out all possible low-energy conformations, which would be used as the initial structure for further molecular calculations. There were only three kinds of conformations with local minimum potential energy and two transition states. The optimized bond lengths and bond angles are in better agreement with the experimental values.


INTRODUCTION
Developments in the field of stereochemistry began in the nineteenth century. The concept of chirality was first introduced in 1815 by the French chemist Jean Baptiste Biot when he discovered optical activity in nature [1]. One of his students, Louis Pasteur achieved the first separation of enantiomers in 1948, he manually resolved a racemic mixture of a tartaric acid salt based on differently shaped crystals [2].
Since then, chirality has become of tremendous importance in our daily life. The chiral element is most usually a chiral center or, as it is sometimes called, a sterogenic center in the molecule which is an atom (usually carbon) bearing four different substituent [3]. Electronaccepting groups are supposed to increase the rotation energy barrier in contrast to electrondonating groups. The influence of the resonance and the field effect of amino and nitro groups on the electron density in the phenyl ring and the respective accelerating and decelerating effects on the rate of enantiomeriazation of atropisomerc biphenyls has been investigated [4]. Amide barriers to rotation have been studied extensively [5]. Clayden and co-workers [6] determined the barriers to rotation about the Ar-CO and N-CO bonds of naphthoyl amides. The amide is a particularly important functional group in biological and medicinal chemistry and is the means by which polypeptides and hence proteins are assembled. Recently, a number of studies have been carried out to shed light on the properties of interest [7].
In this work we will deal the molecules in which the element of chirality is an axis. An axis of chirality results from the non-planar arrangement of four groups about an axis. We have synthesized the monoacyl aniline derivatives and then investigated the rotation barrier by means of density functional theory.

General experimental procedure
We prepared a number of aniline derivatives containing acyl groups to compare their barriers of rotation around the N-CO groups. The general route for the synthesis of mono-aniline derivative is shown in Scheme 1. In general monoacylation of the aniline with acid chloride and pyridine proceeded in high yields and most of the products monoacylaniline were crystalline; with short reaction times and absence of excess acid chloride, formation of diacylation products was not competitive. 1 H and 13 C nuclear magnetic resonance (NMR) spectra were recorded on a Bruker (ARX-500 spectrometer at 500 MHz and 125 MHz, respectively) at room temperature in deuterochloroform (CDCl 3 ) (CH 3 Cl δ 7.26 singlet) at 500 MHz and deuterated dimethyl sulfoxide (DMSO-d 6 ) (CH 3 SOCH 3 δ 2.52 singlet) at 500 MHz unless other wise stated. 13 C NMR spectra were recorded on DRX-500 (125 MHz). Infrared (IR) spectra of crystalline compounds were determined using Nujol mulls and of liquids either in dichloromethane or chloroform solutions or neat on a JASCO FTIR-460 Plus spectrophotometer. Melting points (mps) were determined with a Bi/Bornsted electrothermal. Mass spectra were determined using a Kratos Concept mass spectrometer using electron impact (EI), chemical ionization (CI) or fast atom bombardment (FAB). Dichloromethane was distilled from calcium hydride and stored over 4 Å molecular sieves.

Physical data
For nuclear magnetic resonance (NMR) spectra, chemical shifts and expressed in ppm on the δscale relative to the internal standard (TMS). The following abbreviations are used s-singlet, ttriplet, q-quartet, d-doublet, h-heptet, m-multiplet, dd-doublet of doublets, ddd-doublet of doublet of doublet, dq-doublet of quartets, br-broad; J is the coupling constant (Hz). Assignment of 13 C signals was assisted by using DEPT. For intensity of infra-red (IR) spectra peaks, abbreviations used are: s-strong, m-medium, w-weak, br-broad. Mass spectra were determined in units of mass relative to change (m/z).

General procedure for mono-acylation of aniline derivatives MAA (2)
To a stirred solution of the aniline derivatives (2 g) in dichloromethane was added pyridine (1.2 eq.) followed by drop wise addition of the acid chloride (1.2 eq.). After 24 h, further dichloromethane (10 mL) was added, the solution then washed successively with saturated aqueous sodium hydrogen carbonate, hydrochloric acid (2 M), water, then dried and the solvent removed under reduced pressure to give the monoacyl aniline MAA (2), see Scheme 1.

4-Nitro-N-o-tolyl-benzamide MAA (2d)
The general procedure for the N-acylation of of aniline derivative was followed using 2-methyl aniline (2 g, 18.   [8]. Geometry optimization for all the rotamers have been performed using density functional theory (DFT) at the B3LYP functional and 6-31G** basis set which has been proved to be an excellent method [9][10][11][12]. Moreover, B3LYP/6-31G(d,p) level is adequate which has been applied to computed the different properties and successfully reproduce the experimental data previously [13]. Recently, rotational energy barrier for quinazolinone derivatives has been computed at different levels of theory B3LYP/6-31G**, PM3, AM1, MNDO, HF/6-31G* and found that AM1 is rational and reasonable approach which reproduce the experimental data (details can be found in reference 14). In the present study, we have optimized the geometries at B3LYP/6-31G** and B3LYP/6-31+G** level of theories. We have also applied AM1 method. We found that basis set has no significant effect thus we focused on B3LYP/6-31G** and B3LYP/6-31G** level of theory.

Geometrical parameters
The optimized structures of the aniline derivatives (2a-d) for the most stable conformer with labelling are presented in Figure 1. The experimental and optimized geometric parameters (bond lengths, bond angles and dihedral angles) have been listed in Table 1. The theoretical results are comparable with the reported structural parameters of related molecules [15][16][17][18][19].    The methoxy group on the benzene ring causes some changes in the C-C bond distances. Also, their ortho positions play vital role in shaping the structural and electronic properties of the molecules. The methoxy group oxygen shares its loan pair of electrons with the p electrons in a ring and also interacts with the nearby π systems. Therefore, the interaction of amide groups with the ortho-substituents enhances intermolecular interaction including π-π stacking from phenyl groups. The existence of an intermolecular hydrogen bonding between the hydrogen atom of amine and the oxygen atom of the methoxy group (N-H---O), which was confirmed by the short distance found (2.094-2.111 Å). The hydrogen bonding is critical in determining the structure stability. In general the hydrogen bond strength is indicated by the length, e.g. shorter hydrogen bonds lengths typically indicate stronger hydrogen bonds and Vice versa.

Barriers to rotation
Planarity of the amide plane and information about amide bond are the key factors for investigation of the peptide molecules. The dihedral angle between amide moieties with respect to a plane of aromatic ring is important for consideration. It is well known that the conformation is restricted by partial double bond. So, we carried out a further potential energy surface scanning to find out all possible low-energy conformations, which would be used as the initial structure for further molecular calculation and dynamic simulations. MAAs (2a-d) was selected for this purpose. The dihedral angle (ϕ = C5-C6-N1-C7, for MAA 2a and 2d, C1-C6-N1-C7 for MAA (2b) and C5-C6-N1-C8 of MAA (2c) were subjected to rotate from 180 o to -180 o with a step of 5 o . The energy values in the vertical axis were the relative, which were obtained by all energy values minus the maximum energy value at the dihedral angle. We found that there are four local minimum potential energies, where the torsion angles of the corresponding conformations range 180-150 o , 55 o , -55 o and -150 to -180 o , respectively. Herein the conformations with torsion angles of 180 to 150 o and -155 to -180 o were in fact the same. So there were only three kinds of conformations with local minimum potential energy. There are also two transitions states: TS1 where the torsion angles were found to be very close to 0 o . The TS2 was found to be more stable than TS1 one, which may be due to the electron shell repulsion between electrons pairs of oxygen atoms (Table 2).

CONCLUSIONS
The N-(2-methoxyphenyl)acetamide, N-(2-methoxy-phenyl)-4-nitro-benzamide, N-(2-methoxyphenyl)-4-bromo-benzamide, and 4-nitro-N-o-tolyl-benzamidehave been synthesized. The theoretical results obtained are in good agreement with the reported structural parameters and experimental values. The experimental X-ray and the predicted bond lengths and angles were compared by linear regressional analysis. The methoxy group substituent on the benzene ring causes some changes in the C-C bond distances. The methoxy group oxygen shares its loan pair of electrons with the p electrons in a ring and also interacts with the nearby π systems. Therefore, the interaction of amide groups with the ortho-substituents enhances intermolecular interaction including π-π stacking from phenyl groups and also existence of an intermolecular hydrogen bonding between the hydrogen atom of amine and the oxygen atom of the methoxy group. Four local minimum potential energies and two transition states have been observed.