A series of nine number of substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazines has been synthesized by condensation of 4-methylphenylhydrazine with substituted benzaldehydes using Fly-ash–H2 SO4 catalyst under solvent free condition. This method is experimentally simple, high yielding process with shorter reaction time. The synthesized substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazines have been assigned by physical constants, UV, IR and NMR spectral data. This UV, IR and NMR spectral data have been utilized for spectral correlation analyses. From the results of spectral correlation analysis assessment of substituent effect have been studied. The antimicrobial activities of all the substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazines have been studied using disc diffusion method.

•    Antimicrobial
•    Hydrazones
•    Solvent free synthesis
•    Spectral correlations

Rajarajan M, Balaji S, Vijayakumar R, Senbagam R, Manikandan V, et al. (2016) Solvent Free Synthesis, Spectral Studies and Antimicrobial Activities of Substituted (E)-1-Benzylidene-2-(4-Methylphenyl) Hydrazine’s. JSM Chem 4(1): 1021.

Hydrazone containing azomethine –NH?N=CH? protons constitute an important class of compounds for development of new drugs. The general method for the synthesis of hydrazones by the condensation reaction of hydrazine with carbonyl compounds such as aldehydes or ketones in ethanol [1-3]. The azomethine (-CH=N-) carbon important role for biological activity that has been demonstrated various pharmacological activities such as antimicrobial [4], antiplatelet [5], anticancer [6], antiviral [7], antitubercular [8], anticonvulsant [9], analgesic [10], antiinflammatory [11], antitumoral [12], antimalarial [13], analgesic [14], ntiprotozoal [15], antiparasitic [16], cardioprotective [17], antidepressant [18] and anti-HIV [19] activities.

Green chemistry is used for designing chemical products and processes by reducing or eliminating the use of harmful chemicals and/or generating hazardous substances. Various green chemistry methods involving stirring, phase transfer catalyst, ionic liquid and many more techniques like microwave techniques include approaches for the creation of ‘‘benign-bydesign’’ synthetic methods which are now accepted worldwide [20]. This processes designed by green synthesis help in the promotion of resource and efficient utilization of energy. They involve low level of waste and hence the processes are becoming economically and environmentally beneficial.

The catalyst promoted organic synthesis has become one of the hot areas in organic synthesis in the last few decades. At present, a wide range of methods for synthesizing Schiff bases in the presence of catalysts are available viz., ZnCl2 [21], TiCl4 [22], K-10 clay [23], CaO [24], P2 O5 -SiO2 [25] and MnO2 [26]. No report has been found in the literature regarding the synthesis of (E)-1- benzylidene-2-(4-methylphenyl) hydrazines with Fly-ash-H2 SO4 catalyst under grinding method and spectral as well as biological activities. Therefore the authors have taken efforts for the synthesis of (E)-1-benzylidene-2-(4-methylphenyl) hydrazines from 4-methylphenylhydrazine with substituted benzaldehyde using Fly-ash-H2 SO4 catalyst under solvent-free conditions. The intention of the present methodology is a green protocol offering several advantages such as, excellent yield of products, minimizing production of chemical wastes, shorter reaction profile, mild reaction conditions, simple operational procedure, easy preparation of catalyst and its recyclability up to five cycles without any appreciable loss in catalytic activity. The various spectral data of these (E)-1-benzylidene-2-(4-methylphenyl) hydrazines have been utilized for studying the Hammett spectral correlation analyses. The antimicrobial activities of all the substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazines have been studied using disc diffusion method [27].

All the chemicals and solvents used in this work were purchased from Sigma-Aldrich and E-Merck chemical companies. Melting points of all the (E)-1-benzylidene-2-(4-methylphenyl) hydrazines were determined in open glass capillaries on Mettler FP51 melting point apparatus and are uncorrected. The UV spectra of all substituted (E)-1-benzylidene-2-(4- methylphenyl) hydrazines were recorded with SHIMADZU-1650 SPECTROMETER spectrophotometer λmax (nm) in spectral grade ethanol solvent. The IR spectra were obtained on a SHIMADZU-2010 Fourier transform spectrophotometer. The NMR spectra are recorded in Bruker AV400 NMR spectrometer operating at 400 MHz for 1 H NMR spectra and 100 MHz for 13C spectra in CDCl3 solvent, using TMS as internal standard.

Preparation of Fly-ash–H2SO4 catalyst

In a 50 mL borosil beaker, 3 g of Fly-ash and 3 mL of sulphuric acid have been taken and mixed thoroughly with glass rod at room temperature. This mixture has been heated on a hot air oven at 10 ?C for 1 h, cooled to room temperature, stored in a borosil bottle and tightly capped.

Synthesis of substituted (E)-1-benzylidene-2-(4- methylphenyl) hydrazines

An appropriate equimolar quantity of 4-methylphenylhydrazine (2 mmol) with meta- and para- substituted benzaldehydes (2 mmol) and Fly-ash-H2 SO4 (0.5 g) was thoroughly ground with a pestle in an open mortar at room temperature for 5-10 minutes. Completion of the reaction was monitored by TLC. After the completion of reaction 10 mL of dichloromethane was added and the organic layer separated by filtration, yield solid product on evaporation. The crude product was obtained upon recrystallization from ethanol to give the pure substituted (E)-1-benzylidene-2- (4-methylphenyl) hydrazines and their melting points have been observed. The insoluble catalyst has been recycled by washing with ethyl acetate (10 mL) followed by drying in an air oven at 100°C for 1h and reused for further reactions. The general reaction is as shown in (Scheme 1).

In this work, we have synthesized a series of (E)-1- benzylidene-2-(4-methylphenyl) hydrazine derivatives by condensation of 4-methylphenylhydrazine with substituted benzaldehydes and Fly-ash-H2 SO4 was thoroughly ground with a pestle in an open mortar at room temperature for 5-10 minutes. After the completion of the reaction, the products have been isolated followed by washing the catalyst with ethyl acetate and filtered. To make this catalyst reusable for further reactions, it has been heated to 100°C. In this method is interesting to note that during the condensation there has been no appreciable change in the percentage of the yield of (E)-1-benzylidene-2- (4-methylphenyl) hydrazine, on reusing the same catalyst. It is noteworthy to mention that the green route method requires simple work-up procedure involving simple filtration to isolate the products as they are insoluble in water.

The synthesized (E)-1-benzylidene-2-(4-methylphenyl) hydrazines have been evaluating the assessment of substituent effect on the group frequency such as UV λmax (nm), IR ν(cm1 ) of CH=N, 1 H NMR chemical shift δCH=N(ppm) and 13C NMR chemical shift δC=N (ppm) carbon have been correlated with Hammett substituent constants F and R Swain-Lupton’s parameters using single and multi-linear regression analysis. The physical constants of synthesized (E)-1-benzylidene-2-(4- methylphenyl)hydrazineshave been given in (Table 1). The UV, IR and NMR spectral data of synthesized (E)-1-benzylidene-2-(4- methylphenyl) hydrazines given in (Table 2).

UV Spectral study

The UV absorption λmax (nm) values are correlated [29-33] with Hammett substituent constants and F and R Swain-Lupton’s parameters using single and multi-linear regression analyses [34]. In correlation analysis the Hammett equation employed, as shown in equation (1)

λ = ρ σ + λ0---(1)

Where λ0 is the absorption maximum of the parent member of this series.

The single parameter correlations are given in (Table 3). The correlation analysis of UV absorption maxima λmax (nm) values of all substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazines with Hammett substituent constants and F and R parameters are found to have failure correlations (r < 0.900) with negative ρ values. This shows that the reverse substituent effects operate in all the systems. The resonance conjugative structure of the substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazines is shown in (Figure 1). The multi regression analysis of the UV absorption maximum λmaxC=N (nm) values of all the (E)-1- benzylidene-2-(4-methylphenyl) hydrazine compounds with inductive, resonance and F and R Swain-Lupton’s [34] parameters produce satisfactory correlations as shown in equations (2) and (3).

λmax (nm) = 347.61(±5.23) + 4.90(±1.68)σI +4.61(±1.43)σR (2)

(R = 0.925, n = 9, P > 90%)

λmax (nm) = 349.29 (±5.22) + 1.26 (±0.24)F + 4.98 (±1.44)R (3)

(R = 0.919, n = 9, P > 90%)

IR Spectral study

The infrared νCH=N stretching frequencies (cm-1) values of all the synthesized substituted (E)-1-benzylidene-2-(4- methylphenyl) hydrazines have been recorded and presented n (Table 2). These infrared νC=N stretching frequencies (cm1 ) values are correlated [29-33] with Hammett substituent constants and Swain-Lupton’s parameters using single and multi-linear regression analyses [34]. The structure parameter correlation involving group frequencies, the employed Hammett equation is shown in equation (4).

ν = ρ σ + ν0

Where ν0 is the frequency for the parent member series

The results of single parameter statistical analysis [29-33] of all the (E)-1-benzylidene-2-(4-methylphenyl) hydrazine compounds except those with 4-CH3 and 4-OCH3 substituent’s have shown better correlation with Hammett substituent constants σI (r = 0.907) and Swain-Lupton F (r = 0.900) parameters. When the substituent’s that have been given exception are included in regression, they reduce the correlations considerably. The infrared frequency νC=N (cm-1) values of all the (E)-1-benzylidene-2-(4-methylphenyl) hydrazine compounds have shown failure correlations (r < 0.900) with the remaining Hammett constants σ, σ+ , σR and R parameters. This is due to the reason stated earlier, with resonance conjugative structure as shown in (Figure 1). All the correlations gave negative ρ values (except σR and R) parameters. This indicates that reverse substituent effect operates in (E)-1-benzylidene-2-(4- methylphenyl) hydrazines. The multi regression analysis of the infrared νC=N (cm-1) values of all the (E)-1-benzylidene-2-(4- methylphenyl) hydrazines with inductive, resonance and SwainLupton’s [34] parameters produce satisfactory correlations are given in equations (5) and (6).

nC=N(cm-1)=1613.34(±9.80)-55.91(±4.00)σI+24.66(±3.27)
σR (5)
(R = 0.957, n = 9, P > 95%)
nC=N (cm-1)=1611.74(±10.01)-51.64(±3.63)F + 9.61(±2.02)
R (6)
(R = 0.972, n = 9, P > 95%)

NMR Spectral study

1H NMR Spectral study: The 1 H NMR spectra of synthesized (E)-1-benzylidene-2-(4-methylphenyl) hydrazines have been recorded in deuterio chloroform solutions employing tetramethylsilane (TMS) as internal standard. The δCH=N (ppm) chemical shifts values of all the substituted (E)-1-benzylidene-2- (4-methylphenyl) hydrazines were assigned and are presented in (Table 2). These δCH=N (ppm) chemical shifts have been correlated [29-33] with reactivity parameters. Hammett correlation involving group frequencies, the form of the Hammett equation employed is as shown in (7).

δ = ρσ +δ0 (7)

Where δ0 is the chemical shift of the corresponding parent compound.

The results of statistical analysis are presented in (Table 3). From (Table 3), it is evident that the 1 H NMR chemical shift δCH=N (ppm) values of all the (E)-1-benzylidene-2-(4- methylphenyl)hydrazine compounds except those with 4-F and 3-NO2 substituent’s have shown better correlations with Hammett substituent constants namely σ (r = 0.901) and σ+ ( r = 0.900) parameters.

The entire (E)-1-benzylidene-2-(4-methylphenyl) hydrazine compounds except those with 4-F substituent has shown satisfactory correlations with Hammett substituent constants viz., σR (r = 0.900) and R (r = 0.902) parameters. When the substituent’s that have been given exception are included in regression they reduce the correlations considerably. The 1 H NMR chemical shift δCH=N (ppm) values of all the (E)-1- benzylidene-2-(4-methylphenyl) hydrazine compounds have shown poor correlations (r < 0.900) with the remaining σI and F parameters. This is attributed to the weak inductive and field effects of the substituent’s for predicting the reactivity on the δCH=N (ppm) chemical shift through resonance as per the conjugative structure given in (Figure 1). All the correlations with few Hammett substituent constants namely σ, σ+ , σR and F and R parameters have shown positive ρ values. It indicates that the normal substituent’s effect operates with respect to1 H NMR chemical shift δCH=N (ppm) values of all the (E)-1-benzylidene2-(4-methylphenyl) hydrazine compounds.

The multi regression analysis of the 1 H NMR chemical shift δCH=N (ppm) values of all the (E)-1-benzylidene-2-(4- methylphenyl) hydrazine compounds with inductive, resonance and Swain-Lupton’s [34] parameters produce better correlations as shown in equations (8) and (9).

δCH=N(ppm) =7.84(±0.60) - 0.14(±0.01) σI-0.12(±0.01)σR
 (8)
(R= 0.949, n= 9, P> 90%)
δCH=N(ppm) =7.83(±0.56) + 0.17(±0.01) F - 0.06(±0.01) 
R (9)
(R = 0.957, n= 9, P> 95%)

13C NMR Spectral study: The chemical shift δC=N (ppm) values of (E)-1-benzylidene-2-(4-methylphenyl) hydrazines carbon, have been assigned and are presented in (Table 2). The assigned δC=N chemical shift (ppm) values have been made to correlate [29-33] with Hammett substituent constants, field and resonance parameters, with the help of single and multiregression analyses [34] the results of statistical analysis are presented in (Table 3). From (Table 3), it is evident that the 13C NMR chemical shift δC=N (ppm) values of all the (E)-1- benzylidene-2-(4-methylphenyl) hydrazine compounds except that with 4-F substituent has shown better correlations with Hammett substituent constants namely σ (r =0.903) and σ+ (r =0.904) parameters. When the substituent’s that have been given exception included in regression they reduce the correlations considerably.

The 13C NMR chemical shift δC=N (ppm) values of all the (E)-1- benzylidene-2-(4-methylphenyl) hydrazines have shown failure correlations (r < 0.900) with the remaining Hammett substituent constants σI, σR and F and R parameters. The failure correlation is attributed to the conjugated structure shown in (Figure 1). All the correlations have shown negative ρ values with all the Hammett substituent constants and F and R parameters. This indicates the operation of reverse substituent effect with respect to chemical shift δC=N (ppm) values of all the (E)-1-benzyliden -2-(4-methylphenyl) hydrazine compounds. The multi regression analysis of the chemical shift δC=N (ppm) values of all the (E)- 1-benzylidene-2-(4-methylphenyl) hydrazine compounds with inductive, resonance and Swain-Lupton’s [34] parameters produce satisfactory correlations as shown in equations (10) and (11).

δC=N(ppm) = 147.75(±0.93) – 0.25(±0.09)σI – 2.75(±0.12)
σR (10)
(R = 0.946, n = 9, P>90%)
δC=N(ppm) = 147.36(±0.90) + 0.48(±0.07)F – 2.43(±0.18)
R (11)
(R = 0.949, n = 9, P>90%)

Antimicrobial Activities

Antibacterial activity: The antibacterial activities of all the substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazines have been evaluated against three gram positive pathogenic strains Bacillus substilis, Micrococcus luteus and Staphylococcus aureus and two gram negative strains Escherichia coli and Pseudomonas aeruginosa. The disc diffusion technique was followed using the Kirby–Bauer [27] method, at a concentration of 250 µg/mL with ciprofloxacin used as the standard drugs. The measured antibacterial activities of all substituted (E)-1- benzylidene-2-(4-methylphenyl) hydrazines are presented in (Table 4). The antibacterial activity of all the synthesized (E)- 1-benzylidene-2-(4-methylphenyl) hydrazines are shown in (Figure 2) (Plates 1-10) and the clustered column chart is shown in (Figure 3). There is considerable antibacterial activity was possessed by all substituent’s on the five bacterial species in general.

The (E)-1-benzylidene-2-(4-methylphenyl) hydrazines with 3-Cl, 4-CH3, 4-OCH3 and 3-NO2 substituent’s have shown good antibacterial activity against B. subtilis. The (E)-1-benzylidene-2- (4-methylphenyl) hydrazines with parent (H), 3-Br, 4-Br, 4-F and 4-NO2 substituent’s have shown moderate antibacterial activity against B. subtilis. The 3-Cl, 4-CH3, 4-OCH3 , 3-NO2 and 4-NO2 substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazine have shown good antibacterial activity against M. luteus. The (E)-1-benzylidene-2-(4-methylphenyl) hydrazines with 3-Cl, 4-F, 4-CH3 , 4-OCH3 , 3-NO2 and 4-NO2 substituent’s have shown good antibacterial activity against S. aureus. The (E)-1-benzylidene2-(4-methylphenyl) hydrazines with parent (H), 3-Br and 4-Br substituent’s have shown moderate antibacterial activity against S. aureus.

The parent (H), 4-Br, 3-Cl, 4-F, 4-CH3, 4-OCH3 , 3-NO2 and 4-NO2 substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazine compounds have shown good antibacterial activity against E. coli alone. The 3-Br substituted (E)-1-benzylidene2-(4-methylphenyl) hydrazine compound has shown improve the antibacterial activity against E. coli. The 3-Cl, 4-F, 4-CH3 and 4-NO2 substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazine compounds have shown good antibacterial activity against P. aeruginosa. The (E)-1-benzylidene-2-(4-methylphenyl) hydrazines with parent (H), 3-Br and 3-NO2 substituent’s have shown moderate antibacterial activity against P. aeruginosa. The remaining 4-Br and 4-OCH3 substituted (E)-1-benzylidene2-(4-methylphenyl) hydrazine compounds have shown poor antibacterial activity against P.aeruginosa.

Antifungal activity

Measurement of antifungal sensitivities of all the (E)- 1-benzylidene-2-(4-methylphenyl) hydrazines have been performed using disc diffusion technique [27]. The antifungal activity while for the three strains A. niger, M. species and T. viride the disc diffusion method was adopted. The drugs dilution was 250µg/mL. Miconazole has been taken as the standard drug. The zone of inhibition values of all the (E)-1-benzylidene-2- (4-methylphenyl) hydrazine compound presented in (Table 5). The anti fungal activities of all the (E)-1-benzylidene-2-(4- methylphenyl) hydrazines compounds in the present study are shown in ( Figure 4) (Plates1-6) and the clustered column chart, shown in (Figure 5). All the (E)-1-benzylidene-2-(4-methyl) hydrazine compounds have shown good to moderate activity against all the three fungal species evaluated in general.

The (E)-1-benzylidene-2-(4-methylphenyl)hydrazines having parent (H), 3-Br, 3-NO2 and 4-NO2 substituents have shown good antifungal activity against A. niger.The4-Br, 3-Cl, 4-F, 4-CH3 and 4-OCH3 substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazine compounds have shown improved activity antifungal activity against A. niger. The (E)-1-benzylidene-2-(4-methylphenyl)hydrazines having parent (H), 3-Br, 4-CH3 , 4-OCH3 , 3-NO2 and 4-NO2 substituent’s have shown good antifungal activity against M. Speciesalone. The (E)-1-benzylidene-2-(4-methylphenyl) hydrazines compounds with parent (H), 3-Br, 4-F, 4-CH3 , 4-OCH3 , 3-NO2 and 4-NO2 substituent’s have shown good antifungal activity against T. viride. The (E)-1-benzylidene-2-(4-methylphenyl) hydrazines having 4-Br, 3-Cl and 4-F substituent’s have shown improve antifungal activity against M. Species. The 4-Br and 3-Cl substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazines compounds have shown improved antifungal activity against T. viride alone.

Table 1: Physical constants of substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazines.

Table 2: UV, IR and NMR Spectral data of substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazines.

Table 3: The results of statistical analysis of UV λmax (nm), IR ν (cm-1) of CH=N, 1 H NMR chemical shift δCH=N (ppm) and 13C NMR chemical shift δC=N (ppm) data of substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazines with Hammett constants σ, σ+, σI & σR and F and R parameters.

Table 4: Antibacterial activity of substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazines.

Table 5: Antifungal activity of substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazines.

In the present research work, we have synthesized a series of substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazine compounds from substituted benzaldehydes with 4-methylphenylhydrazine using Fly-ash-H2 SO4 catalyst under solvent free condition. This method involves simple work-up procedure, shorter reaction time (5-10 minutes), eco-friendly, non-hazarders with excellent yield more than 90%. The synthesized substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazine compounds conformed by their physical constant, UV, IR and NMR spectral data. The UV λmax (nm), IR ν (cm-1) of CH=N, 1 H NMR chemical shift δ CH=N (ppm) and 13C NMR chemical shift δC=N (ppm) data have been correlated with Hammett substituent constants and Swain-Lupton’s constants using single and multiregression analysis. From the results some of the single parameter correlations gave satisfactory correlation coefficients. The multiregression analysis gave satisfactory correlation coefficients in all spectral data. The antimicrobial activity of all the substituted (E)-1-benzylidene-2-(4-methylphenyl) hydrazine compounds have shown good to moderate and poor activity against all the microorganism

The authors thank to DST NMR Facility Unit, Department of Chemistry, Annamalai University, Annamalainagar-608002 for recording NMR spectra of all the (E)-1-benzylidene-2-(4- methylphenyl) hydrazine compounds.

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