The First Synthesis of Some Novel 4 ‐ Chloro Chalcone Based Oxime Ethers : An Experimental and Computational Study

In this study; a series of novel oxime ethers, 3-(4-chlorophenyl)-1-phenyl-2-propen-1-one O -benzyl oximes, have been synthesized and characterized by several spectroscopic methods. To the best of our knowledge, this is the first synthesis of 3-(4-chlorophenyl)-1-phenyl-2-propen-1-one O -benzyl oximes. The study consists of two parts. In the first part, the synthesis and the characterization of the selected compounds have been carried out. In the second part of our study some DFT (Density Functional Theory) calculations have been performed on the synthesized molecules and the obtained results have been compared with the experimental results. In the study; single point energy calculations, geometry optimizations, frequency analysis, NMR spectral analysis,  molecular electrostatic potential map calculations, frontier molecular orbital calculations, determination of some global reactivity descriptors and Mulliken atomic charge calculations have been performed. All DFT calculations were carried out at the B3LYP/6-31G(d), B3LYP/6-311G(d,p) and B3LYP/6-311+G(2d,p) level of theories.


Introduction
Chalcones are important compounds in organic synthesis because of being important precursors of some important organic compounds such as flavonoids and isoflavonoids.Chalcones can be found widespread in natural products [1] and they have broad spectrum of biological activity [2,3] Recent studies showed that chalcones are promising anticancer [4], antimalarial [5][6][7], antiinflammatory [8], antitubercular [9], antihyperglycemic [10] and antimitotic agents.[11] Oximes and related compounds are of significant interest because of their synthetic values as intermediates in organic synthesis and their industrial importance.[12] Chalcone oximes are also important compounds in organic chemistry.[13,14].
In this study, some novel 4-chloro chalcone based oxime ethers, 6a-e, were synthesized and characterized.To the best of our knowledge this is the first synthesis of 3-(4-chlorophenyl)-1-phenyl-2propen-1-one O-benzyl oximes, 6a-e.In Figure 1, a typical chalcone structure and its oxime and oxime ether forms are represented.

Experimental
The literature contains several reports on the synthesis of chalcones from corresponding ketones and aldehydes [2,[15][16][17] and on the synthesis of chalcone oximes from corresponding chalcones [18][19][20][21].The synthetic pathway for the synthesis of novel 3-(4-chlorophenyl)-1-phenyl-2-propen-1-one Obenzyl oximes was given in Figure 2. In the synthesis of chalcone 3 from corresponding ketone 1 and aldehyde 2, a well known condensation method, Claisen-Schmidt condensation, was used.In the synthesis of oxime 4, from corresponding ketone 3, hydroxylaminehydrogenchloride and sodium sulfate was used and the reaction carried out at reflux temperature in ethanol.[12] In the synthesis of oxime ethers 6a-e from corresponding oxime 4 and aryl halide 5a-e, t-BuOK was used as a base and the reaction was carried out in THF at room temperature.

Theoretical calculations
In the second part of our study we have done some density functional theory (DFT) calculations on the selected molecules 3, 4 and 6a-e and we have made a comparison between experimental and theoretical data.Geometry optimization and frequency analysis were carried out at the DFT B3LYP/6-31G(d), B3LYP/6-311G(d,p) and B3LYP/6-311+G(2d,p) level of theories.NMR calculations were also performed at the same level of theories using both GIAO (Gauge-Independent Atomic Orbital) and CSGT (Continuous Set of Gauge Transformations) models.All theoretical calculations have been performed using Gaussian 09, Revision D.01 Program Package [22] and GaussView5 [23] was used for the visualization of the computational results.

Single Point Energies for Optimized Structures
Single point energies of the compounds 3, 4 and 6a-e were calculated at the DFT B3LYP/6-31G(d), B3LYP/6-311G(d,p) and B3LYP/6-311+G(2d,p) level of theories and single point energies for compounds 3 and 4 were given in Table 1.

Optimized Structure Analysis
Geometric parameters such as bond lengths, bond angles and dihedral angles were determined theoretically at the same level of theories.The calculated molecular structures and molecular parameters of compounds 3, (E)-4, (Z)-4, (E)-6a and (Z)-6a at the B3LYP/6-311+G(2d,p) level of theory were given in Appendices.

Frequency Analysis
Frequency analysis for the compounds 3, 4 and 6a-e were carried out at the same level of theories.As an example calculated IR spectra for compound 6a was given in Figure 3.

NMR Spectral Analysis
Nuclear magnetic shield tensors were computationally determined at the same level of theories using both GIAO (Gauge-Independent Atomic Orbital) and CSGT (Continuous Set of Gauge Transformations) models.Calculated and experimental1 H-NMR chemical shifts for compounds (E)-6a and (Z)-6a were given in Table 2 and Table 3, respectively.

Molecular Electrostratic Potential Maps
Molecular electrostatic potential maps provides information about the electron rich and electron deficient parts of the investigated molecule.Molecular electrostatic potential maps were calculated at the same leve of theories.Calculated MEP diagrams for compound 3, (E)-4, (Z)-4, (E)-6a and (Z)-6a at the B3LYP/6-311+G(2d,p) level of theory were given in Figure 4, 5, 6, 7 and 8, respectively.
Ionization potential is the minimum energy required to remove an electron from an atom or molecule and can be calculated with Eq. ( 1) and electron affinity is the amount of energy released when an electron is added to a neutral atom or molecule in the gaseous state and can be calculated with Eq. ( 2).[24] ( 1 ) ( 2 ) Electronegativity, chemical hardness, chemical softness, electronic chemical potential and electrophilic index can be calculated with Eq.( 3)-Eq.(7).

Mulliken Atomic Charges
The Mulliken charge distribution of the synthesized molecules were determined theoretically at the same level of theories.The Mulliken atomic charges for compounds (E)-6a and (Z)-6a were given in Figure 14 and Figure 15, respectively.

Discussion and Conclusion
In conclusion, we have prepared some novel chalcone based oxime ethers, 3-(4-chlorophenyl)-1-phenyl-2propen-1-one O-benzyl oximes and we have characterized them using various characterization methods.We have also carried out some DFT calculations on the synthesized molecules.
In the synthesis of chalcone 3 from corresponding ketone 1 and aldehyde 2, the only product is (E)isomer.It is not surprising to obtain only (E)-isomer because of its more stable molecular structure than the (Z)-isomer.The DFT calculations also support these experimental results.In all cases, the (E)isomers were approximately 0.2 eV lower in energy from the (Z)-isomers.The energies calculated for the (E)-and (Z)-isomers of the compound 3 at the B3LYP/6-31G(d), B3LYP/6-311G(d,p) and B3LYP/6-311+G(2d,p) level of theories and the energy difference between (E)-and (Z)-isomers were given in Table 1.
In the synthesis of compound 4 from corresponding chalcone 3, the product is a mixture of (E)-and (Z)isomers.The E:Z molar ratio was found to be approximately 70:30.In all cases, the calculated energies for (E)-isomers were lower than the energies for (Z)-isomers but this energy differences are relatively small compared to the energy differences between the (E)-and (Z)-isomers of chalcone 3.This explains why (E)-isomer is not the only product in the conversion of chalcone to the corresponding chalcone oxime.The energies calculated for the (E)-and (Z)-isomers of the compound 4 and the energy difference between (E)and (Z)-isomers were given in Table 1.
In the NMR spectral analysis, it can be said that there was a good agreement between the computational and experimental results.For the CSGT based NMR calculations it was found that the higher basis sets gave the best results.In GIAO based NMR calculations especially for certain protons the higher basis set overestimate the chemical shifts.When compared to the experimental values, it can be said that the best computational methods for the estimation of chemical shifts for the synthesized molecules are DFT B3LYP/6-311G(d,p) GIAO and DFT B3LYP/6-311+G(2d,p) CSGT.

Figure 1 .
Figure 1.A typical chalcone and its oxime and oxime ether forms.

Table 1 .
Calculated energies for the (E)-and (Z)-isomers of compound 3 and 4.

Table B . 1 .
Calculated Bond Lengths, Bond Angels and Dihedral Angles for Compound 3.

Table B . 2 .
Calculated Bond Lengths, Bond Angels and Dihedral Angles for Compound (E)-4