Synthesis, Spectral and Microbial Studies of Some Novel Schiff Base

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ISSN: 0973-4945; CODEN ECJHAO E-Journal of Chemistry 2009, 6(4), 1205-1210

Synthesis, Spectral and Microbial Studies of Some Novel Schiff Base Derivatives of 4-Methylpyridin-2-amine J. J. VORA*, S. B. VASAVA, K. C. PARMAR, S. K. CHAUHAN and S.S. SHARMA Department of Chemistry, Hemchandrachraya North Gujarat University, Patan -384265, Gujarat, India. [email protected] Received 24 October 2008; Accepted 15 December 2008 Abstract: Schiff base derivatives of N-{(1E)-[3-(mono or di-substituted aryl)-1phenyl-1H-pyrazol-4-yl]methylene}-4-methylpyridin-2-amine were synthesized by the acid catalyzed condensation of 3-(mono- or di- substituted aryl)-1-phenyl1H-pyrazole-4-carbaldehyde derivatives with 4-methylpyridin-2-amine. Schiff base derivatives were characterized by FT-IR, 1H-NMR, Mass spectral analysis and elemental analysis. All the synthesized compounds have been screened for their antimicrobial activities by using broth dilution method. Keywords: Schiff base derivatives, 4-Methyl pyridine-2-amine, Antimicrobial studies, Synthesis.

Introduction Azomethines are generally known as Schiff bases to honour Hugo Schiff, who synthesized such compounds. These are the compounds containing characteristic -C=N- group. Several methods have been reported for the preparation of azomethines. Selvam et. al1 have prepared sulfonamide and its derivatives as anti-HIV agents. More et. al2 have marked the biological activity of Schiff bases synthesized from aminothiazoles. Ernst Bayer3 has reported some metallocomplex Schiff bases derived from o-amino phenol. Schiff bases can be synthesized from an aromatic amine and a carbonyl compound by nucleophilic addition forming a hemiaminal, followed by a dehydration to generate an imine4. They are well known intermediates for the preparation of azetidinones, thiazolidinones, oxadiazolines and many other derivatives. Azomethines exhibit a wide range of pharmacological activities like antimicrobial5, antiparasitic6, antiinflammatory7, anticancer8 etc. A large number of substituted pyrazole derivatives are prepared and tested for variety of biological activities like anti HIV9, antiinflammatory10, antimicrobial11, fungicidal12 etc. Pyridine derivatives also possess wide therapeutic activities such as antiviral13, anti HIV14, anticancer15, antitumor16, antimicrobial17 etc.

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Experimental The reagent grade chemicals were obtained from commercial sources and purified by either distillation or recrystallization before use. The purity of synthesized compounds was checked by thin layer chromatography (TLC) on silica gel plate using benzene: ethyl acetate (8:10). Melting points were determined by open capillary method and are uncorrected. IR spectra are recorded on FT-IR Perkin-Elmer spectrophotometer RX1 using KBr disc. 1 H-NMR spectra are recorded in CDCl3 on a Bruker DRX-400 MHz using TMS as internal standard. The chemical shifts are reported as parts per million (ppm) and ESI MS were determined on Discovery Make Thermo Spectrometer. The compounds N-{(1E)-[3-(mono or di-substituted aryl)-1-phenyl-1H-pyrazol-4-yl] methylene}-4-methylpyridine-2-amines(V1-10 ) were obtained by preparation method (Scheme 1). R1

R2

H 3C

+

NH

C

NH2

R3

O

(I)

(II) Methanol -H 2 O

Gl. CH

3 COOH

R3 N R2

N H

POCl

CH3

R1

(III)

3

DMF R3

CHO

CH3

+

R2 R1

N

N H 2N

N

4-m ethyl pyridine-2-amine 4-Methylpyridine-2-amine

(IV ) -H 2 O

Alcohol Gl. CH

3 COOH

CH3

R3

HC

N

N Where, V

R2 R1

N

N

( V1-10 )

:

R

1 =H,

R

2 =H,

R

3

V2 :

R

1 =H,

R

2 =H,

R

3 =Cl

V3 :

R

1 =Cl,

R

2 =H,

R

3 =Cl

V4 :

R

1 =H,

R

2 =H,

R

3 =CH 3

1

=H

V5 :

R

1 =H,

R

2 =H,

R

3 =OCH 3

V

6

:

R

1 =OH,

R

2 =H,

R

3 =H

V

7

:

R

1 =H,

R

2 =OH,

R

3 =H

V

8

:

R

1 =H,

R

2 =H,

R

3 =OH

V

9

:

R

1 =H,

R

2 =NO 2 ,

10

:

R

1 =H,

R

2 =H,

V

R 3 =H

R

3 =NO 2

Scheme 1.

Preparation of (1E)-1-(4-chlorophenyl)ethanone phenylhydrazone(III) A mixture of phenyl hydrazine (1.08 g, 0.01 M) and 4-dichloro acetophenone (1.54 g, 0.01 M) in absolute ethanol was refluxed in water bath for 4 h in presence of 1 mL glacial acetic acid. Product obtained after cooling was crystallized from absolute ethanol. Yield, 2.18 g (89%),

Synthesis and Spectral Studies of Some Novel Schiff Bases

1207

M.P: 102 oC (C14H13N2Cl; Calculated: C, 68.71; H, 5.35; N, 11.45; Cl, 14.49%; Found: C, 68.79; H, 5.27; N, 11.38; Cl, 14.42%). It was used for the next step.

Preparation of 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde(IV) (1E)-1-(4-Chlorophenyl)ethanone phenylhydrazone (2.44 g, 0.01 M) was added in a mixture of Vilsmeier-Haack reagent (prepared by dropwise addition of 1.2 mL POCl3 in ice cooled 10 mL DMF) and refluxed for 6 h. The reaction mixture was poured into crushed ice followed by neutralization using sodium bicarbonate. Crude product was isolated and crystallized from methanol. Yield, 2.52 g (89%), M.P. 140 ˚C. (C16H11N2ClO; Calculated: C, 67.97; H, 3.92; N, 9.91; Cl, 12.54%; Found: C, 67.86; H, 3.99; N, 9.87; Cl, 12.49%). Exactly similar experimental procedure was followed to prepare other analogs of this series.

Preparation of N-{(1E)-[3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]methylene}-4methylpyridin-2-amine(V2) A mixture of 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.82 g, 0.01 M) and 4-methylpyridin-2-amine (1.08 g, 0.01 M) was taken in absolute ethanol and few drops of glacial acetic acid were added. Then the mixture was refluxed for 6 h on water bath. The excess solvent was distilled off, and then poured in to ice cold water. The separated solid was filtered, washed and recrystalized from ethanol. M.P. 128 °C, Yield, 3.12 g (83%), (C22H17N4Cl; Calculated :C, 70.87; H, 4.60; N, 15.03%; Found C, 70.80; H, 4.55; N, 14.97%). Similarly all the compounds (V1-10) were prepared by same method using various 3-(substituted aryl)-1phenyl-1H-pyrazole-4-carbaldehyde(IV). The characterization data of compounds (V1-10) are presented in Table 1 and antimicrobial data are shown in Table 2 & 3. Table 1. Physical and analytical data of title compound and its other derivatives (V1-10). Compd.

R

Molecular Formula

M.W.

V1

-H

C22H18N4

338.40

V2

p-Cl

V3 V4

C22H17N4Cl 372.85

o,p-di-Cl C22H16N4Cl2 406.07 p-CH3

C23H20N4

352.43

p-OCH3

C23H20N4O

368.43

V6

o-OH

C22H18N4O

354.40

V7

m-OH

C22H18N4O

354.40

V8

p-OH

C22H18N4O

354.40

m-NO2

C22H17N5O2 383.40

p-NO2

C22H17N5O2 383.40

V5

V9 V10

%Yield Color (Final step) 80 Goldy 83 Buff 85 White 82 Mustard 84 Parchment 81 Brown 80 Dark brown 79 Brown 83 Yellow 85 Yellow

%C M.P.ºC Rf 115 0.92 128 0.82 125 0.89 118 0.90 120 0.91 78 0.80 89 0.83 83 0.79 140 0.75 133 0.78

%H

% N

Found Found Found (Calcd.) (Calcd.) (Calcd.) 77.96 78.08 70.80 70.87 64.79 64.88 78.27 78.38 75.06 74.98 74.48 74.56 74.50 74.56 74.49 74.56 68.97 68.92 68.99 68.92

5.24 5.36 4.55 4.60 3.83 3.96 5.81 5.72 5.39 5.47 5.06 5.12 5.09 5.12 5.05 5.12 4.41 4.47 4.43 4.47

16.51 16.56 14.97 15.03 13.65 13.76 16.04 15.90 15.25 15.21 15.90 15.81 15.88 15.81 15.86 15.81 18.22 18.27 18.20 18.27

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J. J. VORA et al. Table 2. Antibacterial activity of synthesized compounds (V1-V10).

Comp.

R

V1 V2 V3 V4 V5 V6 V7 V8 V9 V10

-H p-Cl o, p-di-Cl p-CH3 p-OCH3 o-OH m-OH p-OH m-NO2 p-NO2

Gentamycine Ampicillin Chloramphenicol

Antibacterial activity Minimal Bactericidal Concentration, µg/mL E. coli P. aeruginosa S. aures S. pyogenus MTCC 443 MTCC 1688 MTCC 96 MTCC 442 1000 1000 1000 1000 1000 1000 1000 500 500 500 100 1000 500 500 100 1000 100 500 500 500 500 500 500 1000 200 200 1000 100 500 1000 1000 1000 200 500 1000 200 200 500 1000 1000 The Standard Drugs (MBC), µg/mL) 0.05 1 0.25 0.5 100 100 250 100 50 50 50 50

Table 3. Antifungal activity of synthesized compounds (V1-V10). Antifungal activity Minimal fungicidal Concentration, µg/mL Comp. R C.albicans A.niger A.clavatus MTCC 227 MTCC 282 MTCC 1323 -H 1000 500 500 V1 p-Cl 1000 1000 1000 V2 o,p-di-Cl 1000 500 500 V3 p-CH3 500 1000 1000 V4 p-OCH3 1000 1000 1000 V5 o-OH 500 1000 1000 V6 m-OH 200 200 200 V7 p-OH 1000 500 1000 V8 m-NO2 1000 1000 1000 V9 p-NO2 1000 1000 1000 V10 The Standard Drugs (MFC), µg/mL Nystatin 100 100 100 Greseofulvin 500 100 100

Result and Discussion The synthesis of N-{(1E)-[3-(mono- or di- substituted aryl)-1-phenyl-1H-pyrazol-4-yl] methylene}-4-methylpyridin-2-amine(V1-10) involved the reaction between appropriate 3(mono- or di- substituted aryl)-1-phenyl-1H-pyrazole-4-carbaldehyde(IV1-10) and 4-methyl pyridine-2-amine, as described in the general procedure. IR spectrum showed absorption band at 1569 cm-1 indicated the stretching vibation of -CH=N- (Schiff-base) which confirming the condensation of reactants. The pyridine ring breathing appeared at 1010.2 cm-1 and C-H stretching vibration of –CH3 appeared at 2829.9 cm-1

Synthesis and Spectral Studies of Some Novel Schiff Bases

1209

indicated the presence of pridine moiety in the compound. The pyrazole moiety also appears around 1594.9 cm-1 (C=N str.) and 1224.1 cm-1 (C-N str.) as intense bands. The other peaks of IR spectra prove the structure of Schiff base derivatives. 1H NMR spectrum displayed signals for the presence of one methyl group at 2.6130 ppm (3H, s), one imine proton (CH=N-) at 10.0357 ppm (1H, s) which also confirms the condensation of reactants, one proton of pyrazole ring at 8.6218 ppm (1H, s), three protons of pyridine ring as at 7.5030 ppm -7.5523 ppm (3H, m), four protons (2H+2H, m) of p-chloro phenyl ring as at (7.7459-7.8213) ppm and (7.8477-7.8815) ppm and five protons (2H+3H, m) of phenyl ring at (7.4537-7.4873) ppm and (7.3838-7.4323) ppm. The molecular formula of compound (V2) was found to be C22H17N4Cl on the basis of m/z 373 [MH]+ a base peak being a quasi molecular ion18. The molecular weight is 372.11 (isotopic mass) as per the Nitrogen Rule. As per the even electron rule the m/z 373 quasi ion cleaves to fragment with even mass at fragment peaks at m/z 359 formed by the loss of methyl (-CH3) from the base peak. It indicated the presence of methyl group and m/z 111 due to the removal of chloro benzene. The mass spectrum of comp. (V2) also shows the presence of 1-Cl atom in a molecule by the ratio of 373 and 375 is 9:3 as per the natural abundance. Intensity of 374 is 25.27% 373 peak from that there are 22 carbons present in the molecule.

Spectral study of N-{(1E)-[3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]methylene}4-methylpyridin-2-amine(V2) IR (KBr) cm -1: 1569.9 (C=N stretching of Schiff base); 727.1 (C-Cl stretching); 2975.5 (C-H str. asym.); 1353.9 (C-H def. sym.); 3062.5 (Ar C-H stretching); 1597.1 (C=N str. of pyrazole ring); 1224.0 (C-N stretching); 1010.2 (pyridine ring breathing); 2829.9 (CH3 sym. str.) 1

H-NMR (CDCl3) δ (ppm): 10.0357 (1H, s, -CH=N-); 8.6218 (1H, s, pyrazol ring); 2.6130 (3H, s, -CH3 group ) 7.7459-7.8815 (4H, m, P-Cl phenyl ring ); 7.5030-7.5523 (3H, m, pyrido); 7.3838-7.4873 (5H, m, phenyl ring). Mass Spectra (m/z) : 373 [MH]+, 374, 375[M+2], 359, 281, 247, 172, 111

Conclusion The characterization of Schiff base was carried out for all ten Schiff base derivatives through elemental analysis, FT-IR, 1H-NMR and Mass spectral analysis. Antibacterial and antifungal studies of these compounds indicated that some compounds show potential antimicrobial activity but over all the synthesized compounds were less active than the standard drugs.

Antimicrobial activity Minimal bactericidal concentration (MBC) values of the synthesized compounds were determined by using broth dilution method. The synthesized compounds and references were dissolved in dimethylsulfoxide (DMSO), sterilized by filtration using sintered glass filter and store at 4 0C. All the synthesized compounds were screened for their antibacterial and antifungal activities against the E. coil, P. auregenosa, S. aures, S. pyogenus and the fungi C. albicans, A. niger, and A. clavatus. The compounds were tested at 500, 250, 100 and 50 µg/mL concentration using nutrient agar tubes. The highest dilution showing at least 99% inhibition was taken as MBC (minimal bacterial concentration). Standard drugs were used as reference. As shown in Table 2, some of the target compounds had good activity against gramnegative and gram-positive bacteria. The target compounds V3, V4 were more active against S. Aureus than the standard drug ampicillin and the compounds V5 (against E. coli), V7 (against

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J. J. VORA et al.

S. pyogenus ) were equal active as the standard drug ampicillin. But these compounds were less active against P. Aeruginosa a gram-negative bacteria. When the chemical structures of the active compounds were taken into consideration, the di-substituted o,p di-chloro derivative (V3) was more active than the mono substituted p-chloro derivative (V2) and the m-hydroxy derivative (V7) was more active than the o-hydroxy and p-hydroxy derivatives (V6, V8). As shown in Table 3, the anti fungal activity data clearly show that the compounds V7 having a hydroxy substituent in m-position of the phenyl ring exhibited good activity against C. albicans, A. niger, and A. clavatus. Compounds V7 showed more antifungal activity as greseofulvin (against C. albicans) and less activity against A. niger and A. clavatus. Compounds V4 and V6 showed equal antifungal activity as greseofulvin (against C. albicans) but very low activity against A. niger, and A. clavatus. The result suggests that a hydroxy (-OH) group in m-position of the phenyl ring is suitable for antifungal activity.

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18.

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