Normal Modes, Molecular Orbitals and Thermochemical Analyses of 2,4 and 3,4 Dichloro Substituted Phenyl-N-(1,3-thiazol-2-yl)acetamides: DFT Study and FTIR Spectra

A detailed spectroscopic analysis of two dichloro substituted phenyl-N-(1,3-thiazol-2-yl)acetamides at 2,4 and 3,4 positions of the phenyl ring has been carried out by using B3LYP method with 6-31+G(d, p) basis set within density functional scheme.The scaled theoretical wave numbers are in perfect agreement with the experimental values and the vibrational modes are interpreted in terms of potential energy distribution (PED).The internal coordinates are optimized repeatedly to maximize the PED contributions.The molecular HOMO-LUMO surfaces, their respective energy gaps, andMESP surfaces have also been drawn to explain the chemical activity of both molecules. Various thermodynamic parameters are presented at the same level of theory.


Introduction
Acetamide constitutes a distinguished class of biologically active molecules having an amide bond same as that between amino acids in proteins.Amides are also popular for their coordinating ability and which enable them to be used as ligands [1].In general, a large number of natural products and drugs comprises of heterocyclic moieties containing nitrogen and sulphur atoms [2,3] and interesting biological activities have been found to be associated specially with thiazole derivatives [4,5].In continuation to our previous studies on vibrational dynamics of biomolecules [6,7], we intend here to report a detailed analysis of vibrational modes of molecules consisting of thiazole ring with acetamide ligand.More recently, such molecules have been shown to possess anti-HIV activities with suitable substitutions [8].
We present density functional based theoretical studies on two molecules, namely, 2-(2,4-dichlorophenyl)-N-(1,3thiazol-2-yl)acetamide and 2-(3,4-dichlorophenyl)-N-(1,3thiazol-2-yl)acetamide.The two molecules differ only in the position of two chlorines substituted on the phenyl ring.This provides us an opportunity to analyse the effect of position of substitution on vibrational properties.Keeping it in mind, we offer a complete assignment of all normal modes of vibration.The calculated vibrational spectra are compared with the observed ones.The chemical reactivity of molecules is also explained with the help of molecular orbital analysis.The thermochemistry of molecules is discussed by calculating various thermodynamical parameters.

Computational Method and FTIR Spectra
All the computations were carried out with Gaussian 09 program [9] and Chem3D Ultra 8.0 program [10] was used for a visual presentation of the graphics.The geometries of both molecules were optimized using a hybrid type B3LYP exchange-correlation functional with 6-31+G(d, p) basis set in the framework of DFT.The present computational scheme is very popular and extensively employed in the biomolecular studies due to reliability of its results as compared to experimental data [11].Vibrational analyses of molecules were performed at the same level of theory.The normal mode frequencies were scaled by equation, ] scaled = 22.1 + 0.9543] calculated as recommended by many studies [12][13][14] in order to make comparison with the observed wavenumbers.
To perform experimental FTIR spectroscopy, the title compounds were purchased from Sigma Aldrich with a purity of 98% and used as such without further purification for spectroscopic processing.The FTIR spectra were recorded by using Shimadzu-Model Prestige 21 spectrometer in the region 400-4000 cm −1 with samples in KBr pellet.The FTIR spectra of title molecules are shown in Figure 1.

Results and Discussions
3.1.Crystal Structure and Molecular Geometry.We have already reported X-ray crystallographic studies on these compounds [15,16].All these compounds belong to triclinic 1 space group.In crystal phase, molecules are linked by pairs of N-H⋅ ⋅ ⋅ N hydrogen bonds.There is also a weak C-H⋅ ⋅ ⋅ O interaction in case of 2,4 substitution.
The crystallographic parameters were used to model initial structure for the process of geometry optimization.The optimized geometries of both molecules are displayed in Figure 2. The mean plane of dichlorophenyl ring is almost perpendicular to that of thiazole ring in both molecules thus forming a sofa shaped structure.The angular changes in hexagonal ring geometry have also been proven to be a sensitive indicator of the interaction between the substituent and the ring [17].The structural changes in the carbon skeleton involve changes in the bond distances as well as bond angles.They are most pronounced at the place of substitution and depend on the electronegativity as well as on the /, donor/acceptor character of the substituent.All bond-lengths and bond angles are nearly same in both molecules except those in phenyl ring attached with chlorine atoms at different positions.For instance, C-Cl, bond-length 1.752-1.756Å in 2,4 substituted molecule is reduced to 1.744-1.745Å for 3,4 substitution.
In Figure 3, we have shown a linear correlation between DFT calculated and X-ray experimental bond-lengths for title molecules.Note that C-H bond-lengths are not included here.A correlation coefficient ( 2 ) of greater than 0.99 in both molecules supports the fact that DFT can efficiently reproduce the experimental geometry.

Normal Mode Analysis.
The calculated IR and observed FTIR spectra of both molecules are shown in Figure 4 for comparison in the wavenumber range of 1800-400 cm −1 .The calculated wavenumbers are scaled by using the equation mentioned earlier.All the vibrational modes were properly assigned on the basis of the potential energy distribution (PED).Tables 1 and 2 list calculated frequencies (unscaled as well as scaled), FTIR observed frequencies, IR intensities, and assignments of all normal modes for title molecules.Both molecules contain two ring system, a phenyl ring (R1) and a thiazole ring (R2) connected by acetamide fragment (-NHCOCH 2 -).For the clarity of discussions, we classified their vibrations into three broad categories.

Phenyl Ring (R1) Vibrations.
The phenyl ring vibrations contain the C-H stretching modes in the region 3100-3000 cm −1 , which is the characteristic region for the identification of C-H stretching vibrational modes [18].In this region, the bands are not much affected by the nature of the substituents.The scaled C-H modes are found between 3096-3060 cm −1 which are observed at 3055 cm −1 for 2,4 substituted molecule polarized along 3C-6C and at 3034 cm −1 for 3,4 substitution.These modes are purely stretching having PED greater than 90%.Most of the C-H stretching modes are found to be weak due to charge transfer from hydrogen to carbon atom.Other C-H modes coming from bending (inplane and out-of-plane), breathing and twisting of ring are found in the region below 1500 cm −1 having medium to weak intensities.
The C-C ring stretching vibrations are expected within the region 1650-1200 cm −1 [19].Most of these ring modes are affected by the substitution to aromatic ring.Scaled frequencies for C-C stretching modes at B3LYP/6-31+G(d, p) are 1580 cm −1 , 1548 cm −1 , and 1477 cm −1 for 2,4 and 1583 cm −1 , 1549 cm −1 , and 1476 cm −1 for 3,4 substitution on the ring.Some other C-C modes associated with bending, twisting and breathing vibrations are also found to lie in lower frequency region as well as overlapped with other modes.Most of C-C modes are comparatively stronger than C-H modes.

Thiazol Ring (R2)
Vibrations.The vibrations of thiazole ring associated with C-H stretching are calculated in between 3145-2950 cm −1 for title molecules which are essentially independent on the substitutions in the phenyl ring.These values are in agreement with observed bands in thiazoles and its derivatives [20].The most intense bands corresponding to C-N stretching in thiazole are calculated at 1532-1531 cm −1 .These vibrational modes are found to be coupled with N-H stretching and polarized along phenyl ring.The same bands are observed at 1544 cm −1 -1527 cm −1 in the FTIR spectra.
Other weak modes of thiazole ring vibration associated with breathing and twisting of rings are calculated below 1500 cm −1 and those specially associated with S atom are found near 600 cm −1 .

Fragment (-NHCOCH 2 -)
Vibrations.Amides show somewhat strong and broad band in the range between 3500 cm −1 and 3100 cm −1 for N-H stretch as well as a stronger band between 1700 cm −1 and 1650 cm −1 for C=O stretching [21].Carbonyl absorptions are very sensitive and both the carbon and the oxygen atoms move during the vibration having nearly equal amplitude.The scaled values, 3458 cm −1 -3456 cm −1 for N-H stretch and 1690 cm −1 -1685 cm −1 for C=O stretch agree with literature values.In FTIR spectra, the corresponding band for C=O stretching are observed at 1691 cm −1 -1689 cm −1 while N-stretching frequencies are lowered to 3199 cm −1 -3197 cm −1 .The differences between calculated and observed N-H stretch band are attributed to the presence of intermolecular H-bond in condensed phase which are absent in the isolated state of molecules.In acetamide fragment, the stretching of methylene (-CH 2 ) group and bending (scissoring and rocking) always occur in 3000 cm −1 -2850 cm −1 and below 1500 cm −1 , respectively [20].These vibrations are more common and so are not much of significance.The stretching mode polarized along to ring R2 corresponding to -CH 2 is calculated at 2950 cm −1 for 2,4 substitution and 2947 cm −1 for 3,4 substituted molecule.

Molecular Orbital Analysis.
The highest occupied molecular orbital (HOMO) represents ability to donate an electron while lowest unoccupied molecular orbital (LUMO) denotes ability to accept it.The HOMO-LUMO plots for title molecules are shown in Figure 5. Evidently, the HOMOs of both molecules are located on the thiazole ring including amide fragment while the LUMOs are contributed mainly by phenyl ring system.The transition from HOMO → LUMO in these molecules indicates charge transfer to phenyl ring.The energy difference ( gap ) between HOMO and LUMO describes the chemical reactivity of molecule.The smaller  gap , 4.89 eV in 2,4 substituted molecule as compared to 4.94 eV in 3,4 substitution may suggest that former is chemically more reactive than the latter one.The chlorine atoms attached to adjacent carbons on phenyl ring for 3,4 substituted molecule make it less reactive.
Figure 5 also plots the molecular electrostatic potential (MESP) surface for title molecules.The MESP, a map of electrostatic potential on uniform electron density, is used to visualize charge or electron density distribution within the molecule.The importance of MESP lies in the fact that it simultaneously displays molecular size, shape as well as positive, negative, and neutral electrostatic potential regions in terms of colour grading.In present context, colour code varies between positive region for red and negative for blue regions with an isovalue of 1.00000 eV.Evidently, the electronegative region lies in the vicinity of carbonyl group of amide fragment.On the basis of MESP plot, it can be asserted that an electrophile will be attracted towards the negative region of amide fragment in both molecules.
3.4.Thermochemical Analysis.Thermochemical properties of molecules are dominated by molecular vibrations as electronic contribution becomes negligible due to absence of free electrons, especially at the room temperature.Various thermal parameters for title molecules are calculated and reported in Table 3.These parameters are related to one another via standard thermodynamic relations and can be useful for the estimation of chemical reaction paths.Zero point energy (ZPE) is also given.Thermal energy of 3,4 substituted molecule is slightly higher than that with 2,4 substitution while heat capacity is smaller.The entropy values are closely related to the geometry of molecules.The substitution of chlorines at 3,4 position of ring leads to an increase in entropy value as compared to 2,4 substitution.The increase in thermal energy and entropy values may indicate the enhancement in molecular vibrations due to steric repulsion generated with chlorine atoms substituted at two consecutive (3,4) positions of the phenyl ring.

Conclusions
We have performed a theoretical density functional calculations on dichloro substituted phenyl-N-(1,3-thiazol-2yl)acetamides at 2,4 and 3,4 positions of the phenyl ring.The calculated structural parameter shows a good correlation

Table 3 :
Total energy and various thermodynamic parameters for title molecules calculated at B3LYP/6-31+G(d,p) level.