Synthesis and studies of novel optically active schiff's base derivatives and their antimicrobial activities

Article abstract of DOI:10.1155/2010/956242

Several new Schiff's base derivatives were prepared by condensing various substituted benzaldehyde with 1-(4-aminophenyl)-2-{4-[(S)-(4-chlorophenyl)(phenyl) methyl]-1-piperazinyl}ethanone in presence of acid catalyst under reflux condition. All the compou

Full text of DOI:10.1155/2010/956242

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2010, 7(2), 617-623
http://www.e-journals.net
Synthesis and Studies of Novel Optically
Active Schiff’s Base Derivatives and their
Antimicrobial Activities
ISHWAR J. PATEL* and SHAILESH J. PARMAR
Department of Chemistry,
SIR. P. T. Sarvajanik College of Science,
Veer Narmad South Gujarat University, Surat 395017, Gujarat, India.
s_parmar1981@yahoo.com
Received 15 October 2009; Accepted 5 December 2009
Abstract: Several new Schiff’s base derivatives were prepared by condensing
various substituted benzaldehyde with 1-(4-aminophenyl)-2-{4-[(S)-(4-
chlorophenyl)(phenyl) methyl]-1-piperazinyl}ethanone in presence of acid
catalyst under reflux condition. All the compounds were characterized by
elemental analysis and spectral studies. The newly synthesized compounds
were evaluated for their antibacterial and antifungal activity.
Keywords: Schiff’s base, Optically active, Chiral, Spectral studies, Specific optical rotation,
Antibacterial activity and Antifungal activity.
Introduction
Schiff’s base is a functional group or type of chemical compound containing a carbon-
nitrogen double bond with the nitrogen atom connected to an aryl group or an alkyl group
but not hydrogen1. A Schiff’s base (or azomethine) names after Hugo Schiff2. Schiff’s bases
can be synthesized from an aromatic amine and a carbonyl compound in a nucleophilic
addition to a hemiaminal followed elimination of water to the imine3. Schiff’s base ligands
derived from salicylaldehyde and chiral amines have been widely applied in enantioselective
cyclopropanation of styrenes4, asymmetric aziridination of olefins5, enantioselective
epoxidation6, enantioselective ring opening of epoxides7, asymmetric oxidation of methyl
phenyl sulfide8, enantioselective oxidation of silyl enol9 and trimethylsilylcyanation of
benzaldehydes10. Schiff’s base containing heterocycles have attracted much attention due to
their diverse biological activity such as anticancer11, antiviral12-13, fungicidal14, bactericidal15
and anti-HIV16.

618
ISHWAR J. PATEL et al.
Experimental
All melting points were taken in open capillary tubes and are uncorrected. Specific optical
rotations (SOR) were taken in Jasco digital polarimeter. Thin layer chromatography was
performed on precoated TLC plates with silica gel (Merck 60 F254) and detection was done
by UV lamp (254 nm). The IR spectra were obtained on a Simadzu FTIR-8400S
1
spectrophotometer using KBr pellets. The H NMR spectra in DMSO-d6 or CDCl3 were
recorded on Bruker WM 400FT MHz spectrometer and chemical shift were reported as parts
per million (δ ppm) down field using TMS as internal standard.
O
O
NH
NH
TEA
N
NH
N
N
O
+
O
H C
Toluene
3
Br
H C
3
( 1 )
Cl
Cl
1-[(S)-(4-chlorophenyl)
(phenyl)methyl]piperazine
N-[4-(bromoacetyl)
phenyl]acetamide
Hydrolysis
H2SO4
O
O
NH
2
R
+
N
N
Substituted
benzaldehyde
( 2 )
Cl
Methanol
Reflux
4-5 hours
R
Where,
O
f) R= 4-CH3
a) R= H
N
b) R= 2-Cl
c) R= 4-Cl
d) R= 2-OCH3
g) R= 3-NO2
h) R= 2-NO2
i) R= 2-OH
N
N
e) R= 4-OCH3
( 3a-j )
j) R= 2-OH-4-Br
Cl
Preparation of N-[4-(2-{4-[(S)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}
acetyl) phenyl]acetamide(1)
A mixture of 1-[(S)-(4-chlorophenyl)(phenyl)methyl]piperazine (35 g, 0.122 mol)
[SOR:-20.18°] and N-[4-(2-bromoacetyl)phenyl]acetamide (32 g, 0.125 mol) was taken in
methylene dichloride (140 mL). Triethylamine (12.6 g, 0.125 mol) was added drop wise
below 20 °C. The mixture was refluxed for 4-5 h. After completion of reaction, it was
cooled and washed with water. The organic mass was dry over sodium sulphate and solvent
was removed. The product was recrystalized from methanol.
Yield: 86% MP: 75-76 °C SOR: -9.25° IR [ν, cm-1, KBr]: 1666 (C=O), 2956 (-CH2),
757 (C-Cl). 1H NMR [400 MHz, δ, ppm, DMSO]: 2.12 (3H, s, –COCH3), 3.36 (2H, s, -COCH2),
10.61 (1H, s, -NH), 5.52 (1H, s, -CH-N), 2.59-4.12 (8H, m, CH2 piperazine), 7.05-7.94
(13H, m, Ar-H).

Synthesis and Studies of Novel Optically Active Schiff’s Base
619
Preparation of 1-(4-aminophenyl)-2-{4-[(S)-(4-chlorophenyl)(phenyl)methyl]-1-
piperazinyl}ethanone(2)
N-[4-(2-{4-[(S)-(4-Chlorophenyl)(phenyl)methyl]-1-piperazinyl}acetyl)phenyl]acetamide (40 g,
0.087 mol) was dissolve in methanol (200 mL). Sulfuric acid (22 g, 0.22 mol) was added
drop wise by maintaining temperature below 15 °C with constant stirring. The reaction
mixture was refluxed for 3 h. After the completion of reaction, solvent was removed and
added water (300 mL), made alkaline with concentrated ammonium hydroxide. The solid
was separated and recrystalized from methanol.
Yield: 78% MP: 110-112 °C SOR: -5.45° IR [ν, cm-1, KBr]: 1674 (C=O), 3363
1
(-NH2), 758 (C-Cl). H NMR [400 MHz, δ, ppm, DMSO]: 3.39 (2H, s,–COCH2), 10.10
(2H, s, –NH2), 5.51 (1H, –CH-N), 2.56-4.09 (8H, m, CH2 piperazine), 6.70-8.22
(13H, Ar-H).
Preparation of 2-{4-[(S)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}-1-(4-
{[aryl methylidene]amino}phenyl)ethanone(3a-j)
A mixture of 1-(4-aminophenyl)-2-{4-[(S)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}
ethanone (0.01 mol) and substituted benzaldehyde (0.01 mol) in presence of glacial acetic
acid (0.5 mL) in methanol (25 mL) was taken. It was refluxed gently for 4-5 h. The solvent
was removed and the product was isolated. It was recrystalized from acetic acid. The
remaining compounds 3a-j was synthesized by using substituted benzaldehyde similarly.
Their characterization data were recorded in Table 1.
Table 1. Characterization data of compounds (3a-j).
Molecular
Formula,
(M.Wt)
Elementary Analysis
% Found (Calculated)
Comp.
No.
MP
°C
SOR Yield
[α]d °
R
%
74
79
73
71
66
75
72
76
69
74
% C
75.61 5.92
(75.65) (5.95) (8.27)
70.83 5.32 7.84
(70.85) (5.39) (7.75)
70.81 5.38 7.80
(70.85) (5.39) (7.75)
73.69 5.95 7.85
(73.66) (5.99) (7.81)
73.65 5.98 7.80
(73.66) (5.99) (7.81)
75.90 5.17 8.01
% H % N
C32 H30 Cl N3 O
(508)
8.25
H
138-139 -1.96
204-205 -2.15
125-126 -1.90
179-180 -2.08
148-150 -2.19
141-142 -3.10
146-147 -3.58
171-172 -3.27
133-134 -1.89
156-158 -2.45
1a
1b
1c
1d
1e
1f
C32 H29 Cl2 N3 O
(542)
2 - Cl
C32 H29 Cl2 N3 O
(542)
4 - Cl
C33 H32 Cl N3 O2
(538)
2 - OCH3
4 - OCH3
4 - CH3
3 - NO2
2 - NO2
2 - OH
C33 H32 Cl N3 O2
(538)
C33 H32 Cl N3 O
(522)
(75.92) (6.18) (8.05)
69.45 5.26 10.09
(69.49) (5.29) (10.1)
69.47 5.22 10.02
(69.49) (5.77) (10.1)
C32 H29 Cl N4 O3
(553)
1g
1h
1i
C32 H29 Cl N4 O3
(553)
C32 H30 Cl N3 O2
(524)
73.31 5.78
(73.34) (5.29) (8.02)
60.30 4.60 6.15
(60.32) (4.62) (6.21)
8.00
4 - OH C32 H29 Br Cl N3
3 - Br O2(603)
1j

620
ISHWAR J. PATEL et al.
2-{4-[(S)-(4-Chlorophenyl)(phenyl)methyl]-1-piperazinyl}-1-(4-[phenylmethylidene]amino}
phenyl)ethanone(3a)
1
IR [ν, cm-1, KBr]: 1672 (C=O), 1593 (–C=N), 757 (C-Cl). H NMR [400 MHz, δ, ppm,
DMSO]: 3.31 (2H, s, –COCH2), 8.71 (1H, s, –CH=N), 5.48 (1H, s, –CH-N), 2.54-4.11
(8H, m, CH2 piperazine), 7.04-7.89 (18H, m, Ar-H).
1-(4-{[(2-Chlorophenyl)methylidene]amino}phenyl)-2-{4-[(S)-(4-chlorophenyl)(phenyl)
methyl]-1-piperazinyl}ethanone(3b)
1
IR [ν, cm-1, KBr]: 1681 (C=O), 1595 (–C=N), 774 (C-Cl). H NMR [400 MHz, δ, ppm,
DMSO]: 3.33 (2H, s, –COCH2), 8.80 (1H, s, –CH=N), 5.42 (1H, s, –CH-N), 2.58-4.17
(8H, m, CH2 piperazine), 7.05-7.85 (17H, m, Ar-H).
1-(4-{[(4-Chlorophenyl)methylidene]amino}phenyl)-2-{4-[(S)-(4-chlorophenyl)(phenyl)
methyl]-1-piperazinyl}ethanone(3c)
1
IR [ν, cm-1, KBr]: 1678 (C=O), 1597 (–C=N), 768 (C-Cl). H NMR [400 MHz, δ, ppm,
DMSO]: 3.38 (2H, s, –COCH2), 8.78 (1H, –CH=N), 5.44 (1H, s, –CH-N), 2.59-4.18 (8H, m,
CH2 piperazine), 7.00-7.82 (17H, m, Ar-H).
2-{4-[(S)-(4-Chlorophenyl)(phenyl)methyl]-1-piperazinyl}-1-(4-{[(2-methoxyphenyl)
methylidene]amino}phenyl)ethanone(3d)
IR [ν, cm-1, KBr]: 1667 (C=O), 1594 (–C=N), 2827 (Ar-OCH3), 756 (C-Cl). 1H NMR [400
MHz, δ, ppm, DMSO]: 3.70 (3H, s, –OCH3), 3.35 (2H, s, –COCH2), 8.68 (1H, -CH=N),
5.51 (1H, s,-CH-N), 2.57-4.16 (8H, m, CH2 piperazine), 6.96-7.85 (17H, m, Ar-H).
2-{4-[(S)-(4-Chlorophenyl)(phenyl)methyl]-1-piperazinyl}-1-(4-{[(4-methoxyphenyl)
methylidene]amino}phenyl)ethanone(3e)
IR [ν, cm-1, KBr]: 1675 (C=O), 1588 (–C=N), 2822 (Ar-OCH3), 755 (C-Cl). 1H NMR [400
MHz, δ, ppm, DMSO]: 3.74 (3H, s, –OCH3), 3.32 (2H, s, –COCH2), 8.79 (1H, s, -CH=N),
5.49 (1H, s, –CH-N), 2.57-4.10 (8H, m, CH2 piperazine), 6.90-7.87 (17H, m, Ar-H).
2-{4-[(S)-(4-Chlorophenyl)(phenyl)methyl]-1-piperazinyl}-1-(4-{[(4-methylphenyl)
methylidene]amino}phenyl)ethanone(3f)
1
IR [ν, cm-1, KBr]: 1672 (C=O), 1596 (–C=N), 1332 (Ar-CH3), 757 (C-Cl). H NMR [400
MHz, δ, ppm, DMSO]: 2.25 (3H, s, –CH3), 3.34 (2H, s,–COCH2), 8.71 (1H, –CH=N), 5.56
(1H, s,–CH-N), 2.55-4.13 (8H, m, CH2 piperazine), 7.01-7.85 (17H, m, Ar-H).
2-{4-[(S)-(4-Chlorophenyl)(phenyl)methyl]-1-piperazinyl}-1-(4-{[(3-nitrophenyl)
methylidene]amino}phenyl)ethanone(3g)
1
IR [ν, cm-1, KBr]: 1692 (C=O), 1587 (–C=N), 1344 (Ar-NO2), 756 (C-Cl). H NMR [400
MHz, δ, ppm, DMSO]: 3.36 (2H, s, –COCH2), 8.64 (1H, s, –CH=N), 5.52 (1H, s, -CH-N),
2.54-4.20 (8H, m, CH2 piperazine), 7.04-7.98 (17H, m, Ar-H).
2-{4-[(S)-(4-Chlorophenyl)(phenyl)methyl]-1-piperazinyl}-1-(4-{[(2-nitrophenyl)
methylidene]amino}phenyl)ethanone(3h)
IR [ν, cm-1, KBr]: 1695 (C=O), 1583 (–CH=N), 1349 (Ar-NO2), 752 (C-Cl). 1H NMR [400
MHz, δ, ppm, DMSO]: 3.37 (2H, s, –COCH2), 8.68 (1H, s, –CH=N), 5.53 (1H, s, –CH-N),
2.56-4.17 (8H, m, CH2 piperazine), 7.02-8.08 (17H, m, Ar-H).

Synthesis and Studies of Novel Optically Active Schiff’s Base
621
1-(4-{[(2-Hydroxyphenyl)methylidene]amino}phenyl)-2-{4-[(S)-(4-chlorophenyl)(phenyl)
methyl]-1-piperazinyl}ethanone(3i)
IR [ν, cm-1, KBr]: 1681 (C=O), 1595 (–C=N), 3374 (-OH), 754 (C-Cl). 1H NMR [400 MHz,
δ, ppm, DMSO]: 3.35 (2H, s, –COCH2), 4.50 (1H, s, -OH), 8.86 (1H, s, –CH=N), 5.50 (1H,
s, –CH-N), 2.59-4.15 (8H, m, CH2 piperazine), 6.92-7.84 (17H, m, Ar-H).
1-(4-{[(3-Bromo-4-hydroxyphenyl)methylidene]amino}phenyl)-2-{4-[(S)-(4-chlorophenyl)
(phenyl)methyl]-1-piperazinyl}ethanone(3j)
IR [ν, cm-1, KBr]: 1678 (C=O), 1591 (–C=N), 3364 (-OH), 763 (C-Cl), 687 (C-Br). 1H NMR
[400 MHz, δ, ppm, DMSO]: 3.41 (2H, s, –COCH2), 4.46 (1H, s, -OH), 8.69 (1H, s, –
CH=N), 5.40 (1H, s, –CH-N), 2.59-4.15 (8H, m, CH2 piperazine), 6.95-7.98 (16H, m, Ar-H).
Results and Discussion
The structures of substituted Schiff’s base 3a-j were confirmed by elemental analysis, IR
1
and H NMR spectra. IR spectra showed absorption band at 1596 cm-1 indicated the
stretching vibration of -CH=N (Schiff’s base) which confirming the condensation of
reactants. C-H stretching vibration of -CH2 appeared at 2956 cm-1 and –C=O stretching
appeared at 1666 cm-1 indicated which confirming the condensation of reactants. The other
1
peaks of IR spectra prove the structure of Schiff’s base derivatives. H NMR spectrum
displayed signals for the presence of one imine proton (-CH=N) at 8.70 ppm (1H, s), one
ketone group (-CO-CH2) at 3.39 ppm (2H, s), which also confirms the condensation of
reactants.
Biological screening
Antibacterial activities
Antibacterial activities of all the compounds were studied against gram-positive bacteria
[Staphylococcus aureus (MTCC96), Streptococcus pyogenes (MTCC442)] and gram-
negative bacteria [Escherichia coli (MTCC443), Pseudomonas aeruginosa (MTCC424)] by
the broth dilution method. Stock solutions of the series of compounds were prepared in
DMSO. Each synthesized drug was diluted obtaining 2000 microgram/mL concentration, as
a stock solution. Serial dilutions were prepared in primary and secondary screening. In
primary screening 500 µg/mL, 250 µg/mL and 125 µg/mL concentrations of the synthesized
drugs were taken. The active synthesized drugs found in this primary screening were further
tested in a second set of dilution against all microorganisms. The drugs found active in
primary screening were similarly diluted to obtain 100 µg/mL, 50 µg/mL, 25 µg/mL,
12.5 µg/mL, 6.250 µg/mL, 3.125 µg/mL and 1.5625 µg/mL concentrations. Under similar
condition using Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, and Norfloxacin
as a standard for comparison control experiment was carried out.
An examination of the data reveals that all compounds showed antibacterial activity.
The compounds 3e, 3j, were highly active against all four organisms employed. The
compounds 3a, 3c, 3d, 3e, 3f, 3g and 3i were highly active against Escherichia coli
(MTCC443) and Staphylococcus aureus (MTCC96). Results were presented in Table 2.
Antifungal activities
The compounds 3a-j were also screened for their antifungal activity against Candida
albicans (MTCC227), Aspergillus niger (MTCC282) and Aspergillus clavatus (MTCC1323)
at 2000 µg/mL concentration using broth dilution method. As shown in Table 2, the antifungal

622
ISHWAR J. PATEL et al.
activity data clearly showed that the compound 3a-j having a good activity against Candida
albicans but less active against Aspergillus niger and Aspergillus clavatus. The antifungal
activity was compared with the known standard drugs greseofulvin, nystatin and the results
were presented in Table 2.
Table 2. Antimicrobial activity of compounds (3a-j).
Antibacterial activity
Minimum bactericidal
concentration µg/mL
Antifungal activity
Minimum fungicidal
concentration µg/mL
Comp.
S.aa
50
S.pb
250
500
500
100
250
500
500
50
E.cc
250
500
250
100
P.ad
250
500
250
500
C.ag
250
100
500
250
500
250
500
100
500
A.ne
500
A.cf
1000
1000
1000
1000
1000
1000
1000
1000
1000
3a
3b
250
62.5
100
200
250
50
1000
1000
500
3c
3d
62.5 125
1000
250
3e
3f
100
250
500
100
500
0.25
250
50
125
250
250
125
1000
1000
1000
3g
3h
500
250
100
0.05
100
50
500
125
1
3i
3j
250 >1000 1000 >1000
Gentamycin
Ampicillin
Chloramphenicol
Ciprofloxacin
Norfloxacin
Nystatin
Greseofulvin
0.5
100
50
50
10
-
-
-
-
100
50
-
-
-
-
-
-
25
10
25
10
50
10
-
-
-
-
-
-
-
-
-
100
500
100
100
100
100
-
-
-
-
S.aa - Staphylococcus aureus(MTCC96), S.pb- Streptococcus pyogenes(MTCC442), E.cc- Escherichia
coli(MTCC443), P.ad- Pseudomonas aeruginosa(MTCC441), A.ne- Aspergillus niger(MTCC282),
A.cf- Aspergillus clavatus(MTCC1323), C.ag- Candida albicans(MTCC227).
Conclusion
The antimicrobial activity of 3a-j carried out against some strain bacteria. The results show
that the prepared compounds were toxic against the bacteria. The comparison of the
antibacterial and antifungal activity of these compounds with standard drugs show that the
presence of nitro, methoxy and halogen (-Cl) group in the phenyl ring increases the activity.
Acknowledgments
Authors are thankful to the Principal, Sir P.T. Sarvajanik College of Science, Surat for
providing research facilities. Authors are also thankful to Praveen Laboratory Pvt. Ltd,
Jolwa, Surat for providing chemicals. Thanks are also due to Cadila Healthcare Limited,
Baroda and Microcare Laboratory, Surat for providing spectral data, elemental analysis and
antimicrobial activity.
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