Synthesis , Evaluation of Substituent Effect and Antimicrobial Activities of Substituted ( E )-1-( 3-bromo-4-morpholinophenyl )-3-phenylprop-2-en-1-one Compounds

A series of ten substituted (E)-1-(3-bromo-4-morpholinophenyl)-3-phenylprop-2-en-1-one compounds were synthesized by Crossed-Aldol condensation of 3-bromo-4-marpholino acetophenone with various substituted and unsubstituted benzaldehydes in presence of sodium hydroxide. The entire ten compounds are novel and these have been newly synthesized compounds. The synthesized substituted 3phenylprop-2-en-1-one were characterized by their physical constants and UV, IR, NMR spectral data. These observed UV absorption maximum (λmax nm) value. The group frequencies of infrared absorption (cm) of νCO s-cis and s-trans, deformation modes of νCH out of plane and in-plane, νCH=CH out of plane, ν>C=C<out of plane values, H chemical shifts (ppm) vinyl protons, C chemical shifts (ppm) carbonyl carbons and vinyl carbons values were correlated with various Hammett substituent constants, and Swain-Lupton parameters using single and multi-regression analyses. From the results of statistical analysis, the effects of substituents on the functional group frequencies were studied. The antimicrobial activities of these synthesized substituted (E)1-(3-bromo-4-morpholinophenyl)-3-phenylprop-2-en-1-ones have been screened using Kirby-Bauer method.

Since prop-2-en-1-one compounds have anti-oxidant activity prevents and counteracts the damage of the human issue by the normal effects of physiological oxidation [19].Presence of the keto ethylenic group (-CO-CH=CH-) in the prop-2-en-1ones [20] and their analogues possesses the antioxidant activity.Prop-2-en-1-one compounds that associated with the antioxidant properties are hydroxyl and phenyl group [21].
Various methods are available for the synthesis of prop-2-en-1-one compounds the most convenient method is the one that involves the Crossed-Aldol condensation method, Crossed-Aldol condensation of equimolar quantities of acetylated aliphatic or aromatic ketone compounds with substituted benzaldehydes in the presence of aqueous alcoholic base [22].Spectral data values are useful for study of effect of substituents using Hammett substituent constants, F and R parameters by single and multi-regression analysis.Chemists in recent year have synthesized and studied spectral correlations of pyrazolines [21], some aryl prop-2-en-1-ones [23][24] and Schiff bases [25].In such case, satisfactory correlations were observed with Hammett substituent constants, F and R parameters.Literature survey shows that there is no information available regarding the study of UV, IR and NMR spectral data and correlation of substituted (E)-1-(3bromo-4-morpholinophenyl)-3-phenylprop-2-en-1one compounds.Therefore, the authors have taken efforts to synthesis (E)-1-(3-bromo-4morpholinophenyl)-3-phenylprop-2-en-1-one compounds from 3-bromo-4-morpholino acetophenone with various substituted and unsubstituted benzaldehydes by crossed-aldol condensation reaction.The various spectral data of these substituted (E)-1-(3-bromo-4morpholinophenyl)-3-phenylprop-2-en-1-one compounds have been utilized for studying the quantitative structure activity relationships through Hammett correlations.The antimicrobial activity of the entire synthesized substituted (E)-1-(3-bromo-4morpholinophenyl)-3-phenylprop-2-en-1-ones have been screened using Kirby-Bauer [26] method.

General
All the used chemicals were purchased from Sigma-Aldrich, E-Merck and Himedia Chemical Companies.Melting points of all synthesized substituted (E)-1-(3-bromo-4-morpholinophenyl)-3phenylprop-2-en-1-ones were observed in open glass capillaries on Mettler FP51 melting point apparatus and were uncorrected.
The physical constants and analytical data are presented in Table 1.The UV, IR and NMR spectral value of these prop-2-en-1-ones are presented in Table 2.
The Hammett correlation gives positive ρ value some cases and negative ρ value reaming cases.The positive ρ value indicates operation of normal substitution effect and negative ρ value indicates operation of reverse substituent effect.
These observed absorption maxima (λmax nm) of all substituted (E)-1-(3-bromo-4-morpholinophenyl)-3-phenylprop-2-en-1-one compounds have been correlated with Hammett substituent constants and F & R parameters and the results are shown in Table 3. From the Table-3, it is evident that the UV absorption maximum λmax (nm) values of all substituted (E)-1-(3bromo-4-morpholinophenyl)-3-phenylprop-2-en-1one compounds, except that with 3-NO2 substituent have shown satisfactory correlations with only R (r = 0.906) parameter.The 3-NO2 substituent that has been given exception is included in regression it reduces the correlations considerably.However, UV absorption maximum λmax (nm) values of all substituted (E)-1-(3bromo-4-morpholinophenyl)-3-phenylprop-2-en-1one compounds have shown poor correlations (r < 0.900) with all the Hammett substituent constants σ, σ + , σI, σR and F parameter.This is attributed to the weak polar, inductive and field effect of the substituents for predicting their reactivity on the UV absorption maximum values through resonance as per the conjugative structure shown in Figure 1.

2. IR spectral study
The measured carbonyl stretching frequencies (cm -1 ) of s-cis and s-trans isomers values are presented in Table-2 and the corresponding conformers were shown in Figure 2. The stretching frequencies for carbonyl absorption are assigned based on the assignments made by Hays and Timmons for s-cis and s-trans conformers at 1690 and 1670 cm -1 , respectively.

NMR Spectral Study
In nuclear magnetic resonance spectra, the proton and the carbon chemical shifts (δ) depends on the electronic environment of the nuclei concerned.The assigned proton and carbon chemical shifts value (ppm) have been correlated with Hammett substituent constants and F and R parameters using Hammett equation in the form of where δ0 is the chemical shift of unsubstituted system.

1.1. 1 H NMR Spectral Correlations of Hα (ppm)
The assigned Hα chemical shift (δ, ppm) values are correlated with Hammett substituted constants [30][31][32][33][34][35] and F and R parameters, all substituents have shown satisfactory correlation with Hammett substituent constant σ (r = 0.906) except that with 3-Br substituent have shown satisfactory correlation with Hammett substituent constant σ + (r = 0.915) and except that with 3-NO2 substituent have shown satisfactory correlation with Hammett substituent constant σR (r = 0.906) and expect those with 3-F, 4-F and 3-C6H5 substituents have shown satisfactory correlation with R (r=0.938) parameter.When the substituent that has been given exception is included in regression it reduces the correlation considerably.The remaining few Hammett substituent constants σI, σR and F parameter [36] have shown poor correlations (r < 0.900).This is attributed to weak inductive, resonance and field effects of the substituents for predicting the reactivity on the chemical shifts through resonance as per the conjugative structure shown in Figure 1.All the correlations have shown positive ρ values.This indicates the operation of normal substituent effect.

1.2. 1 H NMR Spectral Correlations of Hβ (ppm)
The assigned Hβ chemical shifts (δ, ppm) values are correlated with Hammett substituted constants and F and R parameters, all substituent have shown poor correlation with all Hammett substituent Constants and F and R parameters.This is due to incapability to the polar, inductive, resonance and field effect of the substituents.All the correlations have shown positive ρ values.This indicates the operation of normal substituent effect.Some of the single regression analysis has shown poor correlations with Hammett substituent constants and Swain-Lupton's parameters [36].It is decided to go for multi-regression, the multi-regression analysis produced satisfactory correlations with the chemical shifts of (δ, ppm) Hα and Hβ.The multicorrelation equations are given in ( 18)- (21).

2.1. 13 C NMR spectral correlation of δCα carbon
The assigned Cα chemical shifts values (δ, ppm) correlated with Hammett substituent constants [30][31][32][33][34][35] and F and R parameters, except that with 3-NO2 substituent have shown satisfactory correlation with Hammett substituent constant σ (r = 0.915).Except that with H (parent), and those with 4-CH3 and 3-NO2 substituents have shown satisfactory correlation with Hammett substituent constant σI (r = 0.900).When the substituent that has been given exception is included in regression it reduces the correlation considerably.The remaining few Hammett substituent constants σ + , σR and F and R parameters have shown poor correlations (r < 0.900).This is attributed to weak inductive and resonance and field effects of the substituent.This is due to the reason stated earlier and associated with resonance-conjugative structure shown in Figure 2. All the correlations (except R) have shown positive ρ values.This indicates the operation of normal substituent effect.

2. 2. 13 C NMR spectral correlation of δCβ carbon
The assigned Cβ chemical shifts values (δ, ppm) have correlated with Hammett substituent constants and F and R parameters.All the compounds expect that with 3-Br substituent have shown satisfactory correlation with Hammett substituent constant σ (r = 0.966), σ + (r = 0.967), σI (r = 0.957) and F (r = 0.905) parameter.When the substituent that has been given exception is included in regression it reduces the correlation considerably.The remaining one Hammett substituent constants σR and R parameter [36] have shown poor correlations (r < 0.900).This is attributed to the resonance effect of the substituents.This is due to the reason stated earlier and associated with resonance-conjugative structure shown in Figure 1.All the correlations have shown negative ρ values.This indicates the operation of reverse substituent effect.

2.13 C NMR spectral correlation of δCO carbon
The assigned CO chemical shifts values (δ, ppm) are correlated with Hammett substituent constants and F and R parameters, all the substituent have shown satisfactory correlation with Hammett substituent constants σ (r = 0.958), σ + (r=0.970),σI (r = 0.974).The remaining one Hammett substituent constants σR and F and R parameters have shown poor correlations (r < 0.900).This is attributed to the resonance and field effect of the substituents.All the correlations have shown negative ρ values.This indicates the operation of reverse substituent effect.Some of the single regression analysis have shown poor correlations with Hammett substituent constants and Swain-Lupton's parameters [36].So it is decided to go for multi-regression, the multi-regression analysis produce satisfactory correlations with the chemical shifts of (δ, ppm) Cα, Cβ and CO.The multi correlation equations are given in ( 22)- (27).

Antifungal Sensitivity Assay
The antifungal activities of all synthesized substituted (E)-1-(3-bromo-4-morpholinophenyl)-3phenylprop-2-en-1-one compounds have been studied against five fungal species namely A. niger, A. flavus, C. albicans, T. viride and M. species.The disc diffusion technique has been followed using the Kirby-Bauer method [25], Micnazole was used as standard.The antifungal screening effect of prepared substituted (E)-1-(3-bromo-4-morpholinophenyl)-3-phenylprop-2-en-1-one compounds is shown in Figure 5, (Plates 21-30).The measured zone of inhibition values are given in Table 5 and the corresponding Clustered column chart is shown in Figure 6.All the compounds have shown moderate, good and excellent activity against all the five fungal species evaluated in general.

CONCLUSION
A series of substituted (E)-1-(3-bromo-4morpholinophenyl)-3-phenylprop-2-en-1-one compounds has been synthesized by crossed-aldol condensation method.These compounds were confirmed by their physical constants UV, IR and NMR spectral data.The spectral data values of these compounds have been correlated with Hammett sigma constants and F & R parameters using single and multilinear regression analysis.Most of the single linear regression analyses have been satisfactory correlations, for all multi-linear regression analysis have been satisfactory correlations.

The 4 -
OCH3 and 3-NO2 substituted compounds have shown excellent activity against Enterococcus species, E. coli and P. mirabilis.The 3-NO2 substituted compound has shown excellent activity against B. subtilis, E. coli and P. mirabilis.The 3-OC6H5 substituted compound has shown excellent activity against E. coli and P. mirabilis.The 4-Br and 4-F substituted prop-2-en-1-ones have shown excellent activity against M. species.

Table 2 .
The