Thionylchloride catalyzed aldol condensation: Synthesis, spectral correlation and antibacterial activities of some 3,5-dichloro-2-hydroxyphenyl chalcones

A series of substituted styryl 3,5-dichloro-2-hydroxyphenyl ketones [1-(3, 5-dichloro-2-hydroxy)-3-phenylprop-2-en-1-one] were synthesized using thionyl chloride assisted Crossed-Aldol reaction. The yields of chalcones were more than 80 %. The synthesized chalcones were characterized by analytical and spectroscopic data. From the spectroscopic data the group frequencies were correlated with Hammett substituent constants, F and R parameters. From the results of statistical analysis the effect of substituents were discussed. The antibacterial activities of these chalcones have been evaluated using Bauer-Kirby method.


INTRODUCTION
Chalcones are α, β unsaturated ketones possess methylene structural moieties and they belongs to biomolecules. Many alkyl-alkyl, alkyl-aryl and aryl-aryl categories of chalcones have been synthesized [1] and extracted from natural plants [2] by organic chemists. Various methods available for synthesizing chalcones such as Aldol, Crossed-Aldol, Claisen-Schmidt, Knovenagal, Greener methods-Grinding of reactants, solvent free and oxides of nanoparticles with microwave heating. Also microwave assisted solvent free Aldol and Crossed-Aldol condensation [3][4][5] were useful synthesis of carbonyl compounds. Due to C-C single bond rotation [6] of carbonyl and alkene carbons, they exist as E s-cis and s-trans and Z s-cis and Z s-trans conformers. These structural conformers of chalcones have been confirmed by NMR and IR spectroscopy.

General
All chemicals used were purchased from Sigma-Aldrich chemical company Bangalore. Melting points of all chalcones have been determined in open glass capillaries on Suntex melting point apparatus and are uncorrected. The ultra violet spectra of the chalcones synthesized have been recorded using ELICO-double beam BL222 Bio-Spectrophotometer. Infrared spectra (KBr, 4000-400cm -1 ) have been recorded on AVATAR-300 Fourier transform spectrophotometer. BRUKER-500MHz NMR spectrometers have been utilized for recording 1 H and 13 C spectra in CDCl 3 solvent using TMS as internal standard.

Synthesis of chalcones
Appropriate mixture of 3,5-dichloro-2-hydroxyacetophenone (100 mmol) and substituted benzaldehydes (100 mmol), 15mL of diethyl ether and (100 mmol) of thionylchloride were added. The reaction mixture was vigorously stirred at room temperature for 30 minutes (Scheme 1). After complete conversion of the ketones as monitored by TLC, the mixture was allowed to stand 20 minutes. The reagents were removed by filtration. The filtrate was washed with distilled water and recrystallized from absolute ethanol, dried well and kept in a desiccator.

RESULTS AND DISCUSSION
In our organic chemistry research laboratory, we attempts to synthesize aryl chalcone derivatives by Crossed-Aldol condensation of electron withdrawing as well as electron donating group substituted aryl methyl ketones and benzaldehydes in the presence of vigorous acidic catalyst thionyl chloride in diethyl ether except acid or base or its salt in atmospheric temperature condition. Hence the authors have synthesized the chalcone derivatives by the reaction between 100 mmol of aryl methyl ketones 100 mmol substituted benzaldehydes, 100 mmol of thionyl chloride and 15 mL of ether at room temperature (Scheme 1). During the course of this reaction the acidic thionyl chloride catalyzes Aldol reaction between aryl ketone and aldehydes and elimination of water gave the chalcones. The yields of the chalcones in this reaction are more than 80 %. The proposed general mechanism of this reaction is given in Fig. 1. Further we investigated this reaction with equimolar quantities of the 3,5-dichloro-2-hydroxyacetophenone and benzaldehyde (entry 27). In this reaction the obtained yield is 83 %. The physical constants yield and mass spectral data are presented in Table 1. We have studied the effect of solvent for this Aldol condensation by observing the yield of the products. The solvents such as ethanol, methanol, dichloromethane, dimethyl formamide and water have been used for this Aldol reaction with 3,5-dichloro-2hydroxyacetophenone and benzaldehyde. Carrying out this Aldol reaction with above solvents the resulting yields are 73 %, 68 %, 65 %, 66 % and 65 % of chalcones respectively. The same reaction was carried out with reflux conditions and there is no improvement for the yield of the products. Here the authors have achieved the aim of this synthetic method with the observation of more than 82% yields of aryl chalcones by condensation of 3,5-dichloro-2-hydroxyacetophenone and benzaldehyde in presence of SOCl 2 /Et 2 O in room temperature.  The Ultra-violet, infrared and NMR spectral data of unknown chalcones, substituted 3,5dichloro-2-hydroxy phenyl ketones were summarized below (27-36). In the present investigation UV absorption maxima form UV spectra, the spectral linearity of chalcones has been studied by evaluating the effect of substituents. The assigned group frequencies of all chalcones like carbonyl stretches νCO, the deformation modes of vinyl part CH out of plane, in-plane, CH=CH and >C=C< out of planes (cm -1 ), the vinyl hydrogen from IR spectra and chemical shifts δ(ppm), of H α , H β , C α , C β and CO from 1 H and 13 C NMR spectra have been correlated with various substituent constants.

1. Ultra violet spectral study
The UV spectra of all synthesized chalcones were recorded in SHIMADZU-1650 SPECTROMETER ( max nm) in spectral grade methanol. The measured absorption maxima ( max nm) of these chalcones are presented in Table 2. These values are correlated with Hammett substituent constants and F and R parameters using single and multi-linear regression analysis. Hammett correlation involving the group frequencies and absorption maxima, the form of the Hammett equation employed is where λ o is the frequency for the parent member of the series.
The results of statistical analysis of these values with Hammett substituent constants are presented in Table 3. From Table 3, Hammett substituent constants σ, σ + , σ I, σ R , F and R values gave poor correlations with λmax. All constants gave negative ρ values. This is due to 24 ILCPA Volume 4  The inability of effect of substituents on absorption and the resonance conjugative structure shown in Fig. 2. regression analysis of these frequencies of all ketones with inductive, resonance and Swain -Lupton's [22] constants produce satisfactory correlations as evident in equations 2 and 3.

2. IR spectral study
The carbonyl stretching frequencies (cm -1 ) of s-cis and s-trans isomers of present study are presented in Table 2. The stretching frequencies for carbonyl absorption are assigned based on the assignments made by Hays and Timmons [23] for s-cis and s-trans conformers at 1690 and 1670 cm -1 , respectively. As anticipated the lowest carbonyl frequency is observed in both the conformers when strongest electron withdrawing group is present in phenyl ring while highest frequency is noted when strongest electro attracting group present in phenyl ring. A similarly trend in absorption was earlier noted by Perjessy and Hrnciar [24] too whose investigated on chalcones demonstrates that s-trans conformers transmit more effectively than s-cis conformers due to reason stated earlier. The difference in carbonyl frequencies between the s-cis and s-trans conformers is higher in this study than the difference observed by Silver and Boykin [25] between similar conformers in phenyl styryl ketones. These data have been correlated with Hammett substituent constants and Swain-Lupton constants [22]. In this correlation the structure parameter Hammett equation employed is as shown in the following equation: Where υ is the carbonyl frequencies of substituted system and υ 0 is the corresponding quantity of unsubstitued system; σ is a Hammett substituent constant, which in principle is characteristics of the substituent and ρ is a reaction constant which is depend upon the nature of the reaction. Hammett equation is one of the important tools for studying linear free energy relationships and it has been widely used in structures of the chemical reactivity of substituted aromatic system.
From Table 2, the s-cis conformers gave satisfactory correlation with Hammett ,  + , and  I constants. And the s-trans conformers, the correlation  C=O fails with Hammett  parameters. All correlations gave positive ρ values and it implies that there is a normal substituent effects operates in all systems.
The correlation of CH in-plane and out of plane modes with Hammett σ constants were fails in correlation. The CH in-plane modes gave negative ρ values in all correlations.
A satisfactory correlation obtained for CH=CH out of plane modes with Hammett σ R constants. Also all correlation were fails with C=C out of plane modes with Hammett constants. Similarly the OH stretches also fail in correlations. This is due to the inability polar, resonance and inductive effects substituent constant to predict the reactivity of the frequencies along with the resonance conjugative structure shown in Fig. 2. The correlation of νOH stretches were fails in correlation with Hammett substituent constants, F and R parameters.. Some of the individual single parameter correlations were fails with hammett substituent constants and F and R parameters. While the multi-regression analysis seems worthwhile with Swain-Luptons [22] constants and the generated equations are shown in 5-18.

CONCLUSION
We have developed an efficient Crossed-Aldol condensation for synthesis of chalcones using thionyl chloride catalyst. The yield of the reaction is more than 80 %. The purities of these synthesised chalcones are checked by their physical constants, analytical and spectral data. The spectroscopic data of the chalcones were correlated with Hammett substituent constants, F and R parameters. The antibacterial activities of all synthesized chalcones have been studied using Bauer-Kirby method.