Synthesis and Characterization of Novel Transition Metal Complexes of 4-Methyl-7-Hydroxy 8-Formyl Coumarin and Their Biological Activities

 

Vijaya Pawar¹, Sangeeta V. Chavan¹, Ramesh S. Yamgar¹, R. G. Atram², B.R. Thorat²,  Swati Bisht²and Sudhir S. Sawant²*

¹Department of Chemistry, Patkar College of Arts and Science, Goregaon (W), Mumbai 400 062, India.

²P. G. Dept of Chemistry, Govt. of Maharashtra’s  Ismail Yusuf College of Arts, Science and Commerce, Jogeshwari (East), Mumbai 400 060 INDIA

*Corresponding Author E-mail: sawantsudhir@hotmail.com

ABSTRACT:

Novel transition metal Cu(II), Ni(II), Co(II) and Zn(II) ions complexes of bidentate Schiff base ligand obtained from 4-Methyl 7-hydroxy 8-formyl coumarin, and Dimethylamino propylene diamine have been prepared and characterized by physical, spectral and analytical data. The synthesized Schiff base act as   bidentate   ligand for the complexation reaction with Cu(II), Ni(II), Co(II) and Zn(II) ions. The new compounds, possessing the general formula [M(L)₂.2H₂O] where [M= Cu(II), Ni(II), Co(II) and Zn(II)] show octahedral geometry. In order to evaluate the effect of metal ions upon chelation, the Schiff base and their metal complexes have been screened for antimicrobial activity. The transition metal complexes  have shown enhanced antimicrobial activities as compared to  Schiff base.

 

KEYWORDS: Schiff bases, 4-Methyl 7-hydroxy 8-formyl coumarin, transition metal complexes

 

INTRODUCTION:

Schiff bases form an important group of compounds in chemistry not only because of their useful physical and chemical properties and large number of reactions they undergo but also because of their wide use in industry and their interesting pharmacological activity. Schiff bases derived from substituted aliphatic amines and aromatic aldehydes have a wide variety of applications in many fields, e.g. biological, inorganic and analytical chemistry^1-5

 

Among the organic reagents generally used, Schiff bases possess excellent characteristics, structural similarities with natural biological substances, relatively simple preparation procedures and the synthetic flexibility that enables design of suitable structural scaffolds^6,7. Many biologically important Schiff bases have been reported in the literature possessing, antibacterial^8-10, antifungal^11-13, antimicrobial^14-16, anticonvulsant¹⁷,antiHIV¹⁸, anti-inflammatory and antitumor activities.

 

EXPERIMENTAL:

Material and Methods:

All chemicals and solvents used were of AR grade. All metal(II) salts were used as chlorides. IR spectra were recorded on a Jasco FTIR Spectrophotometer. UV-Visible spectra were obtained in DMF on a Shimadazu model-UV-Visible Spectrophotometer. The proton magnetic spectra were recorded on a Bruker AMX-5000 Spectrometer.

 

Synthesis of 4-Methyl 7-hydroxy coumarin:

4-Methyl 7-hydroxy coumarin was prepared by the reported method^[19].

Concentrated H₂SO₄ (500 ml) was cooled to 0⁰ C in ice bath. Mixture of ethylacetoacetate (65 ml) and meta-Cresol (55 ml) was added in concentrated H₂SO₄ under vigorous stirring at 0-5 ⁰C over a period of 1-1.5 hrs . Stirring was continued at 5⁰C for 2 hrs. Temperature of reaction mixture was then raised slowly to 30⁰C and allowed to stand for 24 hrs. The solution was then poured in ice bath and water . The product precipitated was filtered. The crude product was dissolved in 5% NaOH solution and the solution was then clarified with activated charcoal and filtered. Filtrate was acidified with conc. HCl to give 4- Methyl 7 –hydroxyl coumarin. The yield of the product was around 95%.

 

Synthesis of 4-methyl-7-hydroxy 8-formyl coumarin:

4-Methyl 7-hydroxy coumarin (30g, 0.170 moles ) was dissolved in 300 ml glacial acetic acid. Hexamine(60 g, 0.428 moles) was added and heated to 85-90^oC for 5 hours. Reaction was monitored for its progress by TLC ( 30% Ethyl acetate in hexane). After reaction was completed as indicated by TLC, Reaction mixture was quenched in 20% HCl and heated to 60-80^oC for 20 minutes. Reaction mixture was cooled to room temperature and product was extracted in methylene chloride( 100 ml x 3 times). Combined MDC extract was washed with distilled water and dried over anhydrous Na₂SO₄. MDC extract was concentrated and crude product was purified by Silica gel column chromatography to get pure 4-Methyl-7-hydroxy-8-formyl coumarin. The yield of the product was around 20%.

 

Synthesis of Schiff base:

The Schiff base i.e. the ligand 8-[(Z)-{[3-(dimethylamino)propyl]imino}methyl]-7-hydroxy-4-methyl-2H-chromen-2-one] [DMAPIMHMC] was synthesized by the condensation of 8-Formyl-7-Hydroxy-4-Methylcoumarin with N,N-dimethylpropane-1,3-diamine in (1:1) molar proportion in ethanol in the presence of traces of concentrated hydrochloric acid. The reaction mixture was refluxed for an hour.

On cooling, the product was isolated to obtain yellowish brown oily mass of the schiff base.

As the schiff base was an oily mass and unstable in nature, it was difficult to characterize the compound. Therefore, its oxalate salt was prepared for spectral characterization.

The Schiff base 8-[(Z)-{[3-(dimethylamino)propyl]imino}methyl]-7-hydroxy-4-methyl-2H-chromen-2-one] [DMAPIMHMC]  was obtained by the reaction of N,N-dimethylpropane-1,3-diamine  with 4-methyl-7-hydroxy 8-formyl coumarin in (1:1) molar proportion in ethanol in the presence of traces of concentrated hydrochloric acid. The reaction mixture was refluxed for an hour. It was then treated with Oxalic acid (1 mole equivalent) and further refluxed for an hour. On cooling, the product was isolated as oxalate salt which was recrystallized from alcohol. The yield of the product was around 70%. It was characterized by UV, IR, ¹H NMR, Mass and elemental analysis. Melting point was 199°C. [Table 1]

 

Table 1: Characterisation  Data of the Schiff base oxalate salt

Description	Observations
Colour	Yellow
Melting Point	199 oC
IR	γN-H 3468 cm-1  nC=O (Lacton) 1715 cm-1 nC=N 1609 cm-1 nC-O-C 1076 cm-1 Phenolic nC-O 1313 cm-1
Elemental Analysis	C (57.02%), H(5.69%), N(27.22%),O(9.48%)
UV	λ max 225 nm, 313 nm
Mass	[M+H]+ 289.3
1H NMR	DMSO(d6) 1.59-1.60(t, 2H), 2.07(s, 3H)2.11(s, 3H), 2.51(s, 3H), 3.02( t, 2H), 5.24(s, 1H),5.87( d, 2H, J=9.4Hz), 6.84(d, J=9.4Hz) 8.15(s, 1H).

 

Table 2: Infrared Spectral Data (cm^-1) of the Schiff base Ligand (DMAPIMHMC)

Schiff base Ligand	nN-H	nC=N	nC=O Lactonyl	Phenolic c-o
DMAPIMHMC	3468	1609	1715	1313

Synthesis of Metal Complexes of Schiff base:

As the Schiff base [DMAPIMHMC] was an oily product, it was freshly prepared in situ by mixing N,N-dimethylpropane-1,3-diamine with 4-methyl-7-hydroxy 8-formyl coumarin in (1:1) molar proportion in ethanol. Then equimolar quantities of divalent metal chloride were mixed and the reaction mixture was heated on water bath for about five hours. It was then cooled and pH was adjusted to about 8.5 by 25% aq. ammonia when coloured solid separated out which was filtered and washed with ethanol, recrystallized in ethanol  and dried in oven at 80-100^oC. This is the general method for the synthesis of metal complexes of ligand with divalent metal chlorides MCl₂.2H₂O Where M= Co(II),  Ni(II),  Cu(II), Zn(II). Since  Zn (DMAPIMHMC)₂.2H₂O Complex was diamagnetic in nature, it was possible to scan for ¹H NMR  As it was non-ionic, it was not possible to detect fragments  in Mass spectrometer. ¹H NMR of Zn (DMAPIMHMC)₂.2H₂O Complex in DMSO-d6 : 1.82(t, 2H, J=6.5Hz), 2.40(s, 3H), 2.45(s, 3H), 2.63(s, 3H), 2.93(t, 2H, J=6.4Hz)), 3.84( t, 2H, J 7.8Hz), 6.09(s, 1H), 6.67( d, 2H, J=8.8Hz), 7.67(d, J=9.2Hz) 8.93(s, 1H).

 

RESULTS AND DISCUSSION:

Physical properties:

The Schiff base [DMAPIMHMC] (Fig. 1) was freshly prepared by refluxing N,N-dimethylpropane-1,3-diamine with 4-methyl-7-hydroxy 8-formyl coumarin in (1:1) molar proportion in ethanol in the presence of traces of concentrated hydrochloric acid.

 

Infrared spectra:

IR spectra of the Schiff base showed the absence of bands at 1725 and 3300 cm^-1 due to carbonyl n(C=O) and n(NH₂) stretching vibrations and, instead, appearance of a strong new band at ~ 1610 cm^-1 assigned^[20] to the azomethine, n(C=N) linkage. It suggested that amino and aldehyde moieties of the starting reagents are absent and have been converted into the azomethine moiety (Fig.1). The comparison of the IR spectra of the Schiff base and their metal complexes (Table 2 and 3 ) indicated that the Schiff base was principally coordinated to the metal atom

a)      The band appearing at 1610 cm^-1 due to the azomethine was shifted to lower frequency by ~ 10-15 cm^-1 indicating^[21] participation of the azomethine nitrogen in the complexation.

b)      A band appearing at 3414-3449 cm^-1 in metal complexes which have significantly different characteristic of n_OH stretching vibration due to stretching modes of coordinated water molecule.

c)      Further conclusive evidence of the coordination of these Schiff base compounds with the metals, was shown by the appearance of weak low frequency new bands at 565-640 and 435-522 cm^-1. These were assigned^[22,23] to the metal-nitrogen  (M-N) and metal-oxygen  (M-O) respectively. These new bands were observed   in the spectra of the metal complexes and not in the spectra of its Schiff base compounds thus confirming participation of these hetero groups (O or N) in the coordination.

Fig. 1

 

Table 3: FT-IR Bands for Metal Complexes of (DMAPIMHMC) and their Assignments

Complex	Lattice water n (OH) cm-1	Lactonyl n C=O cm-1	n C=N cm-1	Phenolic C-O cm-1	n M-N cm-1	n M-O cm-1
Co[(DMAPIMHMC)2].2H2O Ni[(DMAPIMHMC)2].2H2O Cu (DMAPIMHMC)2.2H2O Zn (DMAPIMHMC)2.2H2O	3314 3414 3435 3439	1717 1719 1721 1711	1620 1624 1620 1630	1398 1336 1342 1371	555 559 552 554	449 453 461 455

 

Figure 2

 

 

¹H NMR spectra:

The proton magnetic resonance spectrum of Schiff base (DMAPIMHMC) in DMSO solution shows a NH=C-H protons of Schiff base (DMAPIMHMC) resonating at d 8.15 and methyl protons of 8-Formyl-7-Hydroxy-4-Methylcoumarin at  d 2.63 in metal complex. The PMR spectra values of metal complex of Zn is shown in (Figure 2)

 

Due to paramagnetic nature of Complexes with Cu[II], Ni[II] and Co[II], it was not possible to take ¹H NMR spectrum and the signals obtained were very broad in nature and could not be interpreted properly.

 

Due to its diamagnetic nature, ¹H NMR spectrum was scanned for Zinc complex in DMSO-d6. It was observed that the aldehyde proton at 10.59 ppm in 8-Formyl-7-Hydroxy-4-Methylcoumarin was appearing at 8.15 ppm in schiff’s base. After complexation with  Zinc metal it was shifted downfield to 8.93 ppm due to deshielding effect of Metal atom. This was the significant observation from ¹H NMR spectra which is in line with observations reported by available literature so far. Apart from the downfield shift of azomethine, following other interesting observations were also made. Aromatic protons of coumarin ring appearing at 5.87 ppm and 6.84 ppm in schiff’s base were shifted to 6.67ppm and 7.67 ppm respectively due to the electron withdrawing mesomeric  effect exerted by Zinc metal atom. Olefinic proton of coumarin ring appearing at 5.24 ppm was also shifted down field to 6.09 ppm due to electron withdrawing mesomeric effect operating through the conjugation across the aromatic ring over the α,β-unsaturated double bond of coumarin ring. The methyl protons and phenyl protons of Schiff base ligand of the divalent Zinc metal ion complex are showing shift in d values (Table 4)

 

Table 4: Proton Magnetic Resonance Shifts (d values) of Metal Complexes and their Assignments

Zn (DMAPIMHMC)2.2H2O	Assignments
8.93 ppm 6.09 ppm 6.67-7.67 ppm 2.63 ppm	N = C-H azomethine proton C=C-H proton of  coumarin Aromatic protons of coumarin CH3 group at 4 position of coumarin

 

UV-visible spectra:

The electronic absorption spectral data of all the transition metal complexes are recorded in the range 200-800 nm in DMSO solution. The spectra show two intra-ligand transitions in the ultra-violet region in the range 27247-32841cm^-1, which may be attributed to p-p* transitions within the ligand molecular orbitals. (Table 5, 6) shows that p-p* transitions in the metal complexes are observed at different positions as compared to their positions in the spectra of the ligands, suggesting that the p-electron system of the ligands is involved in the coordination to the metal ion As all the metal complexes are fairly soluble in DMSO solution, the solution spectra show d-d transitions at relatively low concentrations.

 

The Co(II) complexes show three bands at 10821, 18761 and 30156 cm^-1  assigned to ⁴ T_1g (F) → ⁴T_2g (F) , ⁴T_1g(F) → ³A_2g (F) and ⁴T_1g→ ⁴T_1g (P)    respectively and are indicative^[4-6] of a typical octahedral geometry for Co(II) complexes.

 

The electronic spectra of Ni(II) complexes show three spin-allowed bands at 13286, 18208 and 27247 cm^-1 assignable^[8] which indicates three transitions ³A_2g(F) → ³T_2g(F)(v₁), ³A_2g(F) → ³T_1g(F)(v₂) and ³A_2g(F) → ³T_2g(P)(v₂) respectively, expected for an octahedral geometry.

 

The electronic spectra of the Cu(II) complexes show bands between 10Dq band for a distorted octahedral geometry⁷ corresponding to the transition ²E_g → ²T_2g . The bands at 29282 and 32841 cm^-1 may be due to intra ligand change transfer transition.

 

The diamagnetic Zn(II) complexes did not show any d-d bands and their spectra are dominated only by charge transfer bands. The charge transfer band at    29112 cm^-1 assignable^9-10 due to the ²E_g→ ²T_2g which suggested octahedral geometry around the metal ion.

 

Table  5: U.Vspectral Data of the Schiff base (DMAPIMHMC)

Schiff base	λmax in nm
DMAPIMHMC	225 nm
	313 nm

 

 

Table  6: Electronic Spectral Data for the Metal Complexes of (DMAPIMHMC)

Complex	Transitions Band Position in cm-1
Co(DMAPIMHMC)2.2H2O Ni(DMAPIMHMC)2.2H2O Cu(DMAPIMHMC)2.2H2O Zn(DMAPIMHMC)2.2H2O	10821, 18761 and 30156 13286, 18208 and 27247 29282 and 32841 29112

 

 

From the discussion of the results of various physico-chemical studies presented above, it may be concluded that the proposed geometry for the transition metal complexes with general formula ML₂.2H₂O is octahedral for Co(II),Ni(II), Zn(II) complexes and for  ML₂ is square planer for Cu(II) complexes and the bonding in the complexes can be represented as follows:[Fig. 3]

 

Where M is divalent metal atom like Cu, Co, Ni and Zn

(Fig. 3) Proposed structure of the metal(II) complex

 

Antibacterial properties:

The title Schiff base and their metal chelates were evaluated for their antibacterial activity against the strains Gram-negative bacteria viz .Escherichia coli and antifungal activity against strain Aspergillus niger by the tube dilution technique.

 

The lowest concentration which showed no visible growth was taken as an end point known as minimum inhibitory concentration (MIC).

 

A comparison of the antimicrobial activity of the Schiff base and their metal complexes shows that the antimicrobial activity of the Schiff base was enhanced due to the complexation with metal ion. The results of the studies of minimum inhibitory concentration of the Schiff base and their metal complexes are summarized in (Table 8).

 

 

Table 7: Physical and analytical data of the metal (II) chelates

Complex	Colour	Decomposi-tion Temp. ° C	Observed/(Calculated)
			%C	%N	%H	%O		%M
Co(DMAPIMHMC)2.2H2O   Ni (DMAPIMHMC)2.2H2O   Cu (DMAPIMHMC)2.2H2O   Zn (DMAPIMHMC)2.2H2O	Brown   Light Green   Green   Yellow	255   250   230   245	57.66 (57.75) 57.71 (57.77) 57.32 (57.35) 57.15 (57.17)	8.40 (8.42) 8.39 (8.42) 8.41 (8.36) 8.31 (8.34)	5.70 (5.71) 5.73 (5.72) 5.66 (5.68) 5.65 (5.66)		19.24 (19.25) 19.22 (19.26) 19.11 (19.12) 19.04 (19.06)	8.81 (8.86) 8.80 (8.83) 9.48 (9.49) 9.75 (9.78)

 

Table 8: Antimicrobial Activity (MIC, µg ml^-1) of Schiff base [DMAPIMHMC] and its Metal Complexes

Compound	Escherichia coli	Aspergillus niger
[DMAPIMHMC]	<200	<200
Co[DMAPIMHMC]2.2H2O	<20	<20
Ni[DMAPIMHMC]2.2H2O	<20	<20
Cu[DMAPIMHMC]2.2H2O	<20	<20
Zn[DMAPIMHMC]2.2H2O	<20	<20

 

CONCLUSION:

Novel Schiff base 8-[(Z)-{[3-(dimethylamino)propyl]imino}methyl]-7-hydroxy-4-methyl-2H-chromen-2-one] [DMAPIMHMC]  was obtained by the reaction of N,N-dimethylpropane-1,3-diamine  with 4-methyl-7-hydroxy 8-formyl coumarin and its novel transition metal complexes with Co(II), Ni(II), Cu(II) and Zn(II) were prepared and their antibacterial and antifungal activity was screened.

 

In the antibacterial screening against bacteria Escherichia coli it was found that  the ligands  show MIC values greater than 200 μg/ml, whereas transition metal complexes of ligands showed MIC values less than 20 μg/ml. Hence it can be concluded that Metal complexes of transition metals of the ligand showed that they have better activity against Escherichia coli.

 

Antifungal screening was done against organism such as Aspergillus niger, the ligands show MIC values less than 200 μg/ml. whereas transition metal complexes of ligands showed  MIC values less than 20 μg/ml. Hence it can be concluded that Metal complexes of transition metals of the ligand showed that they have better activity against Aspergillus niger.

 

The results of the screening of the Schiff base and their metal complexes for antimicrobial activity indicate that the antimicrobial activity of the Schiff base was enhanced   on complex formation with metal in all cases studied.

 

ACKNOWLEDGEMENTS:

The authors gratefully acknowledge to Dr. Dileep Khandekar for helping in NMR facility, Mr. Shirish Janrao for providing mass spectra, Mr. Ajay Patil and Dr. Rajan Das of TIFR, Mumbai for ESR spectra and Ms. Swati Bisht for screening antimicrobial activity. We are also grateful to the Principal of Patkar-Varde College, Goregaon Mumbai and Principal of Ismail Yusuf College, Jogeshwari, Mumbai for guidance, constant encouragement and support to carry out this research work.

 

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Received on 05.05.2011        Modified on 09.06.2011

Accepted on 23.06.2011        © AJRC All right reserved