Catalyst- and solvent-free synthesis, characterization, biological activity of Schiff bases and their metal (II) complexes derived from ferrocene

doi:10.21203/rs.3.rs-2317280/v1

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Catalyst- and solvent-free synthesis, characterization, biological activity of Schiff bases and their metal (II) complexes derived from ferrocene

https://doi.org/10.21203/rs.3.rs-2317280/v1

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A novel efficient method for synthesizing ferrocene-based schiff bases and their metal (II) complexes was developed. The compounds were characterized by XRD and various spectroscopic techniques. In addition, their physicochemical studies were carried out using TGA-DTA analysis. The biological activities of ligands and their metal (II) complexes have been screened for in vitro antibacterial (such as S. aureus, B. cereus and E. coli), antifungal properties (such as A. niger and A. fumigatus). The results of these studies have revealed that Zn (II) complexes B11 was the most active against all bacterial strains, and antifungal activity was overall enhanced after complexation of the ligands.

ferrocene

Schiff base

catalyst- and solvent-free

metal (II) complexes

synthesis

Ferrocene is a classic organometallic compound ^[1]. For the special structure of ferrocene, it exhibits many unique and superior properties in various fields, such as antimicrobial, anticancer, cytotoxicity, antitumor and, antimalarial etc ^[2–9]. Schiff base is a important organic compound having a special imine structure (-RC = N-) ^[10] with hybrid orbitals and the lone pair electron. The lone pair electron of Schiff base can be coordinated with the metal ions to form the metal complexes ^[11] which applied in biology ^[12–14], material application and so on ^{[15, 16]}. Among the organometallic compounds, ferrocene is one of the most well-known compounds in many areas of science, especially in medicinal chemistry ^[17–20]. It attracted great attention on account of the high stability, lipophilicity, low toxicity, easy functionalization and mild reversible redox property ^[21]. In addition, Ferrocene metal organic compounds have unique electrochemical and optical properties, and probable potential applications in optical ^[22–23] and other high-tech fields ^[24].

With the development of the organic chemistry, the solvent-free method had gradually appeared in synthesis of polypeptides, hormones, proteins and so on ^[25]. And the solvent-free synthesis could be found in many reactions such as Mannich reaction ^[26], Petasis reaction ^[27], Suzuki reaction ^[22–29], the Adol reaction, Claisen-Schmidt reaction and so on. At present, the solvent-free method having the advantages of simple operation, mild conditions, short reaction time, low costs, high yield and purity, which is regarded as an important part of green chemistry.

In recent years, our group has been working on simple, efficient and green synthesis of ferrocene-based schiff bases and their metal complexes ^[30–32]. In this paper, ferrocene was used as raw material to obtain the ferrocene-based schiff bases and their metal (II) complexes (Fig. 1). We synthesized the target compounds by liquid-phase and catalyst- and solvent-free. The biological activity of the target compounds was also studied.

2.1 Materials and methods

All chemicals were analytical grade and used without further purification. All reagents were provided from Aldrich and Sigma chemicals companies. The melting points were determined in an open glass capillary and uncorrected. Infrared spectra (400–4000 cm^− 1) were recorded on Bruker Vector-22 FT-IR with samples prepared as KBr pellets. The NMR tests were run on Bruker Avance-400 MHz in DMSO-d6 solution with TMS as an internal standard. The molar conductance of the complexes were measured with 1×10^− 3 M DMSO solutions at 25 ± 1 ℃ using a systronic conductivity bridge type 305. The XRD was tested by D8 QUEST.

The acyl ferrocene were prepared as reported ^[33].The S-dithiocarbazate were prepared as reported ^[34–35].

2.2 Synthesis of Ligands L1-L6

A mixture of acyl ferrocene (0.01mol), hydrazyl dithioformate ester (0.011 mol), TsOH and 20 mL ethanol was finely pestled 15 min in a mortar at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was filtered, washed and dried. Crudes were recrystallized from ethanol to get the pure products.

2.3. General procedure for synthesis of B1-B12

Liquid-phase method

Ligand (2 mmol) and metal salt (1 mmol) were dissolved in ethanol (20 mL) in a 100 mL three-necked flask. Then the reaction was run for 8 h at reflux temperature, whereupon the complexes were precipitated. Products B1-B12 were recrystallized from acetone.(Fig. 1, Table 3)

Catalyst- and solvent-free method

A mixture of Ligand (2 mmol) and metal (II) salts (1mmol) was ground for 30 min until reaction completed at room temperature in the mortar. And then it was incubated for 1 h. The mixture was filtered, washed by 95% ethanoland dried to obtain the B1-B12.(Fig. 1, Table 3)

2.4. Biological activity

2.4.1. Antibacterial activity (in vitro)

To assess the biological potential of the synthesized compounds, they were tested by different species of bacteria. The organisms used in the present investigations included three bacterium (S. aureus, B. cereus and E. coli). The antimicrobial activities were evaluated at a concentration of 3 g/L. The bacterial inoculum was coated on the surface of the nutrient agar with the sterile cotton swab. Tetracycline was set as the standard antibacterial drug, DMSO as a control solvent and the plates were incubated overnight at 37 ℃. The results of the antimicrobial activities were showed in Table 6, Fig. 7.

2.4.2. Antifungal activity (in vitro)

The antifungal activities of compounds were tested against two fungal strains (A. niger and A. fumigatus) in vitro. And it was cultured on malt medium about 48 h, with filtering of the culture through a thin layer of sterile sintered glass G2 to remove mycelia fragments before the solution containing the spores was used for inoculation. For preparation of plates and inoculation, 1.0 mL of inoculum was added to 50 mL agar medium (50 ℃) and mixed. The agar was poured into the 120 mm Petri dish and allowed to cool to room temperature. Wells (6 mm in diameter) were cut in the agar plates using a proper sterile tube. Then, fill wells were filled up to the surface of agar with 0.1mL of the tested compounds dissolved in DMSO (200 µmol/mL). The plates were left on a leveled surface, and incubated at 30 ℃ for 48 h. The results were recorded as the diameter of the inhibition zones and compared with the standard drug Fluconazole.

3.1 The mechanism of synthesizing Schiff base

The proposed general mechanism (nucleophilic addition-elimination) of synthesis Schiff bases was given in Fig. 2. Amino group with lone pairs electrons attacked carbonyl carbon, resulting in nucleophilic addition reaction. Simultaneously, proton transfer and intramolecular dehydration got the target product.

Table 1

Crystal data and structure refinement.
Identification code	L4 (SUST_2107_0ma)
Empirical formula	C₁₄H₁₆FeN₂S₂
Formula weight	332.26
Temperature	107(2) K
Wavelength	0.71073 A
Crystal system, space group	Monoclinic, P2(1)/c
Unit cell dimensions	a = 17.4794(9) A alpha = 90 deg.
	b = 9.8393(5) A beta = 99.121(4) deg.
	c = 8.7867(5) A gamma = 90 deg.
Volume	1492.07(14) A^3
Z, Calculated density	4, 1.479 Mg/m^3
Absorption coefficient	1.277 mm^-1
F(000)	688
Crystal size	0.150 x 0.140 x 0.130 mm
Theta range for data collection	3.130 to 28.328 deg.
Limiting indices	-23 < = h<=21, -13 < = k<=13, -11 < = l<=8
Reflections collected / unique	15715 / 3705 [R(int) = 0.1118]
Completeness to theta = 25.242	99.9%
Absorption correction	None
Refinement method	Full-matrix least-squares on F^2
Data / restraints / parameters	3705 / 0 / 174
Goodness-of-fit on F^2	1.015
Final R indices [I > 2sigma(I)]	R1 = 0.0592, wR2 = 0.0930
R indices (all data)	R1 = 0.1676, wR2 = 0.1168
Extinction coefficient	n/a
Largest diff. peak and hole	0.295 and − 0.301 e.A^-3

Table 2

Bond lengths [A] and angles [deg] for L4.
C(1)-C(2)	1.492(5)	H(4A)-C(4)-H(4B)	109.5	Fe(1)-C(13)-H(13)	125.7
C(1)-H(1A)	0.9800	S(1)-C(4)-H(4C)	109.5	C(13)-C(14)-C(10)	107.6(4)
C(1)-H(1B)	0.9800	H(4A)-C(4)-H(4C)	109.5	C(13)-C(14)-Fe(1)	69.8(2)
C(1)-H(1C)	0.9800	H(4B)-C(4)-H(4C)	109.5	C(10)-C(14)-Fe(1)	69.3(2)
C(2)-N(1)	1.286(4)	C(6)-C(5)-C(9)	107.8(4)	C(13)-C(14)-H(14)	126.2
C(2)-C(10)	1.471(5)	C(6)-C(5)-Fe(1)	69.6(2)	C(10)-C(14)-H(14)	126.2
C(3)-N(2)	1.351(4)	C(9)-C(5)-Fe(1)	69.7(2)	Fe(1)-C(14)-H(14)	126.2
C(3)-S(2)	1.645(4)	C(6)-C(5)-H(5)	126.1	C(6)-Fe(1)-C(8)	67.77(18)
C(3)-S(1)	1.738(4)	C(9)-C(5)-H(5)	126.1	C(6)-Fe(1)-C(11)	106.86(18)
C(4)-S(1)	1.788(4)	Fe(1)-C(5)-H(5)	126.1	C(8)-Fe(1)-C(11)	161.95(19)
C(4)-H(4A)	0.9800	C(5)-C(6)-C(7)	107.8(4)	C(6)-Fe(1)-C(9)	67.58(17)
C(4)-H(4B)	0.9800	C(5)-C(6)-Fe(1)	70.3(2)	C(8)-Fe(1)-C(9)	40.15(16)
C(4)-H(4C)	0.9800	C(7)-C(6)-Fe(1)	70.0(2)	C(11)-Fe(1)-C(9)	155.60(18)
C(5)-C(6)	1.394(6)	C(5)-C(6)-H(6)	126.1	C(6)-Fe(1)-C(12)	121.0(2)
C(5)-C(9)	1.407(5)	C(7)-C(6)-H(6)	126.1	C(8)-Fe(1)-C(12)	126.01(19)
C(5)-Fe(1)	2.040(4)	Fe(1)-C(6)-H(6)	126.1	C(11)-Fe(1)-C(12)	40.62(15)
C(6)-C(7)	1.415(6)	C(8)-C(7)-C(6)	108.0(4)	C(9)-Fe(1)-C(12)	162.80(19)
C(6)-Fe(1)	2.031(4)	C(8)-C(7)-Fe(1)	69.8(2)	C(6)-Fe(1)-C(7)	40.68(16)
C(6)-H(6)	1.0000	C(6)-C(7)-Fe(1)	69.4(2)	C(8)-Fe(1)-C(7)	39.80(16)
C(7)-C(8)	1.386(6)	C(8)-C(7)-H(7)	126.0	C(11)-Fe(1)-C(7)	125.05(19)
C(7)-Fe(1)	2.039(4)	C(6)-C(7)-H(7)	126.0	C(9)-Fe(1)-C(7)	67.22(17)
C(7)-H(7)	1.0000	Fe(1)-C(7)-H(7)	126.0	C(12)-Fe(1)-C(7)	108.57(19)
C(8)-C(9)	1.397(6)	C(7)-C(8)-C(9)	108.4(4)	C(6)-Fe(1)-C(10)	124.50(19)
C(8)-Fe(1)	2.032(4)	C(7)-C(8)-Fe(1)	70.4(2)	C(8)-Fe(1)-C(10)	156.38(19)
C(8)-H(8)	1.0000	C(9)-C(8)-Fe(1)	70.1(2)	C(11)-Fe(1)-C(10)	40.87(14)
C(9)-Fe(1)	2.038(4)	C(7)-C(8)-H(8)	125.8	C(9)-Fe(1)-C(10)	121.23(17)
C(9)-H(9)	1.0000	C(9)-C(8)-H(8)	125.8	C(12)-Fe(1)-C(10)	68.08(16)
C(10)-C(11)	1.423(5)	Fe(1)-C(8)-H(8)	125.8	C(7)-Fe(1)-C(10)	161.94(19)
C(10)-C(14)	1.433(5)	C(8)-C(9)-C(5)	108.0(4)	C(6)-Fe(1)-C(5)	40.03(16)
C(10)-Fe(1)	2.040(4)	C(8)-C(9)-Fe(1)	69.7(2)	C(8)-Fe(1)-C(5)	67.72(19)
C(11)-C(12)	1.414(5)	C(5)-C(9)-Fe(1)	69.9(2)	C(11)-Fe(1)-C(5)	120.06(18)
C(11)-Fe(1)	2.036(4)	C(8)-C(9)-H(9)	126.0	C(9)-Fe(1)-C(5)	40.37(15)
C(11)-H(11)	1.0000	C(5)-C(9)-H(9)	126.0	C(12)-Fe(1)-C(5)	155.3(2)
C(12)-C(13)	1.406(6)	Fe(1)-C(9)-H(9)	126.0	C(7)-Fe(1)-C(5)	67.61(18)
C(12)-Fe(1)	2.039(4)	C(11)-C(10)-C(14)	107.8(4)	C(10)-Fe(1)-C(5)	107.56(18)
C(12)-H(12)	1.0000	C(11)-C(10)-C(2)	126.0(4)	C(6)-Fe(1)-C(13)	156.2(2)
C(13)-C(14)	1.401(5)	C(14)-C(10)-C(2)	126.0(4)	C(8)-Fe(1)-C(13)	109.03(18)
C(13)-Fe(1)	2.041(4)	C(11)-C(10)-Fe(1)	69.4(2)	C(11)-Fe(1)-C(13)	68.47(17)
C(13)-H(13)	1.0000	C(14)-C(10)-Fe(1)	69.6(2)	C(9)-Fe(1)-C(13)	126.28(19)
C(14)-Fe(1)	2.044(4)	C(2)-C(10)-Fe(1)	123.2(3)	C(12)-Fe(1)-C(13)	40.33(16)
C(14)-H(14)	1.0000	C(12)-C(11)-C(10)	107.2(4)	C(7)-Fe(1)-C(13)	121.6(2)
N(1)-N(2)	1.377(4)	C(12)-C(11)-Fe(1)	69.8(2)	C(10)-Fe(1)-C(13)	68.19(16)
N(2)-H(2)	0.8800	C(10)-C(11)-Fe(1)	69.7(2)	C(5)-Fe(1)-C(13)	162.7(2)
C(2)-C(1)-H(1A)	109.5	C(12)-C(11)-H(11)	126.4	C(6)-Fe(1)-C(14)	162.1(2)
C(2)-C(1)-H(1B)	109.5	C(10)-C(11)-H(11)	126.4	C(8)-Fe(1)-C(14)	121.50(18)
H(1A)-C(1)-H(1B)	109.5	Fe(1)-C(11)-H(11)	126.4	C(11)-Fe(1)-C(14)	68.92(16)
C(2)-C(1)-H(1C)	109.5	C(13)-C(12)-C(11)	108.8(4)	C(9)-Fe(1)-C(14)	108.65(17)
H(1A)-C(1)-H(1C)	109.5	C(13)-C(12)-Fe(1)	69.9(2)	C(12)-Fe(1)-C(14)	67.89(18)
H(1B)-C(1)-H(1C)	109.5	C(11)-C(12)-Fe(1)	69.6(2)	C(7)-Fe(1)-C(14)	155.8(2)
N(1)-C(2)-C(10)	115.6(3)	C(13)-C(12)-H(12)	125.6	C(10)-Fe(1)-C(14)	41.10(14)
N(1)-C(2)-C(1)	125.8(4)	C(11)-C(12)-H(12)	125.6	C(5)-Fe(1)-C(14)	125.81(19)
C(10)-C(2)-C(1)	118.6(3)	Fe(1)-C(12)-H(12)	125.6	C(13)-Fe(1)-C(14)	40.12(15)
N(2)-C(3)-S(2)	120.9(3)	C(14)-C(13)-C(12)	108.6(4)	C(2)-N(1)-N(2)	117.4(3)
N(2)-C(3)-S(1)	112.9(3)	C(14)-C(13)-Fe(1)	70.1(2)	C(3)-N(2)-N(1)	119.5(3)
S(2)-C(3)-S(1)	126.2(2)	C(12)-C(13)-Fe(1)	69.7(2)	C(3)-N(2)-H(2)	120.3
S(1)-C(4)-H(4A)	109.5	C(14)-C(13)-H(13)	125.7	N(1)-N(2)-H(2)	120.3
S(1)-C(4)-H(4B)	109.5	C(12)-C(13)-H(13)	125.7	C(3)-S(1)-C(4)	101.90(19)

3.2 Synthesis of Schiff base and their metal (II) complexes

Comparing the yields of Schiff bases and (II) metal complexes under the optimum conditions, they were synthesized by liquid-phase method and solvent-free method, respectively (Fig. 3, Fig. 4). For different Schiff bases and metal complexes, the yields of the solvent-free method were higher than the liquid-phase method. In short, the solvent-free method has the advantages of short time, high yield, simple and environmental protection.

3.3 Structural analysis

3.3.1 Single crystal X-ray structure of L4

The single crystal of L4 was cultured in ethyl acetate/n-hexane. After about one week, the single crystal of yellow needle shape were grown from the solution and its structure was determined by X-ray crystallography.

Crystal was chosen using a polarizing microscope and was mounted on a glass fiber which was used for data collection. Cell constants and orientation matrices for data collection were obtained by least-squares refinement of diffraction data from unique reflections. The data were corrected for Lorentz and Polarizing effects.

ORTEP drawing of L4 with the atom-numbering scheme was shown in the Fig. 5. The single crystal XRD studies of L4 showed that the molecule was crystallized as a single asymmetric and the corresponding unit cell parameters are given as, a = 17.4794(9) A alpha = 90 deg, b = 9.8393(5) A beta = 99.121(4) deg, c = 8.7867(5) A gamma = 90 deg. Detailed information of the single crystal, method of data collection including instruments and refinements were presented in the Table 1. The structural parameters viz. Bond lengths/angles obtained from the single crystal X-ray analysis were presented in the Table 2.

3.3.2 IR

The IR spectra of the Schiff base was compared with its complexes. We found that the complex was composed of ligand and metal in a molar ratio of 2:1, so the complex had the similar functional group to the ligand. Such as C = N, C-S, ferrocene ring and the like. However, the structure of the ligand and complex was different, the peak of -NH- disappeared in the infrared spectrum, and the peak of -C = N-N = C- and -OH appeared after the coordination.

The results showed that there was no absorption peak of -NH- in the complex, and the peak of -OH appeared near 3446 cm^− 1, indicating that the N atom participated in the coordination. The IR absorption peaks between 1548 and 1608 cm^− 1 could be assigned to the C = N stretching vibration. In addition, the absorption peak of the ring of the ring appeared at about 1050 cm^− 1, 820 cm^− 1, and the absorption peak of the C-S single bond appeared at around 650 cm^− 1. All the changes indicated that Schiff base existed tautomeric forms during the complexes formation. The N atom and the S atom were coordinated with the metal (II) ions after the proton was lost, indicating the formation of complexes.(Table 4)

3.3.3 ¹H NMR

Taking the [Fe(L2)₂]·2H₂O as an example, there were six different proton hydrogens in this structure. It could be seen from the ¹H NMR spectrum that 2.42 ppm was the four proton hydrogens of the S atom-bonded group. And the integral 10:4:4 peak at 4.23 ppm, 4.53 ppm, and 4.80 ppm indicated the presence of two ferrocenes. The peak at 6.29 ppm was the two proton hydrogens attached to the ferrocene ring. In comparison with the spectrum of the ligand L2, it was found that the peak at 12.31 ppm of -NH disappeared. The results showed that the hydrogen number of the complex was doubled compared to the ligand. It indicated that the N atom participated in the coordination. From the above information, the metal and the ligand were coordinated in a ratio of 1:2.(Table 5)

Table 3

Molar conductivity, molar weight and melting point of the metal (II) complexes.
Compounds	R¹	R²	Formula, molar weight	Color	M.P. (℃)			Λm (Ω⁻¹mol⁻¹cm²)
Compounds	R¹	R²	Formula, molar weight	Color	Found	Reported	Ref.	Λm (Ω⁻¹mol⁻¹cm²)
L2	H	Et	C₁₄H₁₆FeN₂S₂, 332.3	Orange	126–128	--	--	--
B1	H	Et	C₂₈H₃₄Fe₃N₄S₂O₂, [Fe(L2)₂]·2H₂O, 690.3	Brown	>300	--	--	6.39
B2	H	Et	C₂₈H₃₄NiFe₂N₄S₂O₂, [Ni(L2)₂]·2H₂O, 693.1	Brown	243–245	--	--	6.62
B3	H	Et	C₂₈H₃₄ZnFe₂N₄S₂O₂, [Zn(L2)₂]·2H₂O, 699.8	Brown	212–214	--	--	6.53
B4	H	Et	C₂₈H₃₄PbFe₂N₄S₂O₂, [Pb(L2)₂]·2H₂O, 841.6	Brown	282–284	--	--	6.43
L4	CH₃	CH₃	C₁₄H₁₆FeN₂S₂, 332.3	Orange	125–129	123	[36]	--
B5	CH₃	CH₃	C₂₈H₃₄Fe₃N₄S₂O₂, [Fe(L4)₂]·2H₂O, 690.3	Brown	>300	--	--	6.24
B6	CH₃	CH₃	C₂₈H₃₄NiFe₂N₄S₂O₂, [Ni(L4)₂]·2H₂O, 693.1	Brown	234–236	--	--	6.93
B7	CH₃	CH₃	C₂₈H₃₄ZnFe₂N₄S₂O₂, [Zn(L4)₂]·2H₂O, 699.8	Brown	192–194	--	--	6.67
B8	CH₃	CH₃	C₂₈H₃₄PbFe₂N₄S₂O₂, [Pb(L4)₂]·2H₂O, 841.6	Brown	>300	--	--	6.75
L6	CH₃	CH₂Ph	C₂₀H₂₀FeN₂S₂, 408.4	Orange	150–152	148	[36]	--
B9	CH₃	CH₂Ph	C₄₀H₄₂Fe₃N₄S₂O₂, [Fe(L6)₂]·2H₂O, 842.5	Brown	>300	--	--	6.61
B10	CH₃	CH₂Ph	C₄₀H₄₂NiFe₂N₄S₂O₂, [Ni(L6)₂]·2H₂O, 845.3	Brown	245–247	241	[37]	6.53
B11	CH₃	CH₂Ph	C₄₀H₄₂ZnFe₂N₄S₂O₂, [Zn(L6)₂]·2H₂O, 852.0	Brown	232–234	--	--	6.56
B12	CH₃	CH₂Ph	C₄₀H₄₂PbFe₂N₄S₂O₂, [Pb(L6)₂]·2H₂O, 993.8	Brown	>300	--	--	6.81

^a Isolated yield. ^b The yield of liquid-phase method. ^c The yield of catalyst- and solvent-free method.

Table 4

Characteristic IR bands(4000 − 250 cm^− 1) of the Schiff base and their metal (II) complexes.
Compounds	_{ν (−OH)}	_{ν (−NH−)}	_{ν (=C−H)}	_{ν (−C−H)}	_{ν (−C=N−)}	_ν(Ph)	_{ν (−CH3)}	_{ν (Fc−ring)}	_{ν (C−S)}
L2	--	3115	--	2927	1599	--	1388	1081, 826	--
B1	3445	--	--	2800	1594	--	1448, 1353	1013	750
B2	3446	--	--	2913	1589	--	1382	1007, 823	673
B3	3439	--	--	2833	1589	--	1381	1026, 822	668
B4	3437	--	--	2925	1548	--	1373	1005, 822	608
L4	--	3182	3081	2911	1582	--	1412,1387	1071, 826	--
B5	3422	--	--	2920	1595	--	1383	1107, 843	619
B6	3405	--	--	2817	1592	--	1438,1328	1047, 807	749
B7	3417	--	--	2930	1582	--	1382	1017	628
B8	3688	--	--	2928	1586	--	1350	1005	708
L6	--	3182	3014	2918	1600	1507, 1450	1381	1050, 818	--
B9	3421	--	--	2815	1591	1492	1351	1103	689
B10	3419	--	--	2923	1583	1491	1382	1106	700
B11	3441	--	--	2922	1586	1494	1358	1104	701
B12	3429	--	--	2918	1608	1558, 1455	1383	807	690

Table 5

¹H NMR spectral data of the Schiff base and their metal (II) complexes.
Compounds	Proposed assignment of the protons (ppm)
L2	¹H NMR (400 MHz, DMSO) δ: 2.02 (s, 3H, -CH₃), 2.76 (s, 2H, -SCH₂-), 4.18 (s, 5H, Fc-H), 4.31 (s, 2H, Fc-H), 4.63 (s, 2H, Fc-H), 12.31 (s, H, -NH-);
B1	¹H NMR (400 MHz, DMSO) δ: 2.12 (m, 6H, -CH₃), 2.42 (s, 4H, -SCH₂-), 4.23 (s, 10H, Fc-H), 4.53 (s, 4H, Fc-H), 4.80 (s, 4H, Fc-H), 6.29 (s, 2H, H-C=)
B2	¹H NMR (400 MHz, DMSO) δ: 2.17 (m, 6H, -CH₃), 2.48 (s, 4H, -SCH₂-), 4.22 (s, 10H, Fc-H), 4.49 (s, 4H, Fc-H), 4.81 (s, 4H, Fc-H), 6.32 (s, 2H, H-C=)
B3	¹H NMR (400 MHz, DMSO) δ: 2.14 (m, 6H, -CH₃), 2.44 (s, 4H, -SCH₂-), 4.31 (s, 10H, Fc-H), 4.54 (s, 4H, Fc-H), 4.86 (s, 4H, Fc-H), 6.36 (s, 2H, H-C=)
B4	¹H NMR (400 MHz, DMSO) δ: 2.16 (m, 6H, -CH₃), 2.53 (s, 4H, -SCH₂-), 4.31 (s, 10H, Fc-H), 4.42 (s, 4H, Fc-H), 4.98(s,4H,Fc-H),6.42(s,2H,H-C=)
L4	¹H NMR (400 MHz, DMSO) δ: 2.26 (s, 3H, -CH₃), 2.47(s, 3H, -SCH₃), 4.20 (s,5H, Fc-H), 4.44 (s, 2H, Fc-H), 4.71 (s, 2H, Fc-H), 12.20 (s, H, -NH-)
B5	¹H NMR (400 MHz, DMSO) δ: 1.76 (s, 6H, -CH₃), 2.53 (s, 6H, -SCH₃), 4.23 (s, 10H, Fc-H), 4.52 (s, 4H, Fc-H), 4.76 (s, 4H, Fc-H)
B6	¹H NMR (400 MHz, DMSO) δ: 1.28 (s, 6H, -CH₃), 2.09 (s, 6H, -SCH₃), 4.15 (s, 10H, Fc-H), 4.27(s,4H,Fc-H),4.37(s,4H,Fc-H)
B7	¹H NMR (400 MHz, DMSO) δ: 2.06(s,6H,-CH₃),2.37(s,6H,-SCH₃), 4.23(s,10H,Fc-H), 4.45 (s, 4H, Fc-H), 4.82 (s, 4H, Fc-H)
B8	¹H NMR (400 MHz, DMSO) δ: 1.88 (s, 6H, -CH₃), 2.55 (s, 6H, -SCH₃), 4.25 (s, 10H, Fc-H), 4.44 (s, 4H, Fc-H), 4.72 (s, 4H, Fc-H)
L6	¹H NMR (400 MHz, DMSO) δ: 2.16 (s, 3H, -CH₃), 2.68 (s, 2H, -SCH₂-), 4.24 (s, 5H, Fc-H), 4.61 (s, 2H, Fc-H), 4.92 (s, 2H, Fc-H), 7.13–7.42 (m, 5H, Ar-H), 12.23 (s,H,-NH-)
B9	¹H NMR (400 MHz, DMSO) δ: 1.76 (s, 6H, -CH₃), 2.52 (s, 4H, -SCH₂-), 4.34 (s, 10H, Fc-H), 4.53 (s, 4H, Fc-H), 4.71 (s, 4H, Fc-H), 6.66 (s, 2H, H-C=), 7.14–7.53 (m, 5H, Ar-H)
B10	¹H NMR (400 MHz, DMSO) δ: 2.11 (s, 6H, -CH₃), 2.35 (s, 4H, -SCH₂-), 4.26 (s, 10H, Fc-H), 4.54 (s, 4H, Fc-H), 4.78 (s, 4H, Fc-H), 7.09–7.45 (m, 5H, Ar-H)
B11	¹H NMR (400 MHz, DMSO) δ: 1.94 (s, 6H, -CH₃), 2.45 (s, 4H, -SCH₂-), 4.32 (s, 10H, Fc-H), 4.53 (s, 4H, Fc-H), 4.72 (s, 4H, Fc-H), 7.18–7.53 (m, 5H, Ar-H)
B12	¹H NMR (400 MHz, DMSO) δ: 1.59 (s, 6H, -CH₃), 2.06 (s, 4H, -SCH₂-), 4.16 (s, 10H, Fc-H), 4.46 (s, 4H, Fc-H), 5.09 (s, 4H, Fc-H), 7.30–7.48 (m, 5H, Ar-H)

3.4 Solubility of Schiff bases and their metal (II) complexes

The obtained Schiff bases were all stable in air, soluble in solvents such as chloroform, DMF, DMSO, acetone and slightly soluble in methanol, ethanol but insoluble in water. The obtained complexes were stable in air, insoluble in solvents such as methanol, ethanol, diethylether, isopropanol, water, but soluble in, chloroform, DMF, DMSO and acetone.

3.5 Molar conductance measurements

The molar conductivity of Schiff bases and their metal (II) complexes were measured at room temperature in a concentration of 1 × 10^− 3 M DMSO. The results were listed in Table 3, ranging from 6.24 to 6.93 Ω⁻¹ mol^− 1 cm². It showed that Schiff bases had not the molar conductivity, and their metal complexes had the lower molar conductivity (Λm < 50), indicating nonelectrolytic nature of the complexes.

3.6 Thermo gravimetric analysis of complexes

TGA-DTA analysis of complex B12 ([Pb(L6)₂]·2H₂O) was carried out in nitrogen atmosphere at a heating of 10℃/min over a temperature range of 600℃ (Fig. 6). It could be found from the TGA curve that weight loss occured at around 100 ℃, which was the loss of crystal water of the complex. Subsequently, the main skeleton of the metal complex began to decompose. It was due to unstable and decomposed cyclopentadienyl ring. The thermal behavior of other complexes was similar to B12 and experienced a series of weightlessness process.

3.7 Biological activity

The mode of action of the compounds might involve formation of a hydrogen bond through the azomethine group (> C = N-) with the active centers of various cellular constituents, resulting in interference with normal cellular processes ^[38]. It had been suggested that the ligands with nitrogen and oxygen donor systems, inhibiting enzyme activity. The enzymes required these activity groups which appeared to be especially more susceptible to deactivation by metal ions on coordination. Moreover, coordination reduced the polarity of the metal ion mainly because of the partial sharing of its positive charge with the donor groups ^[39] within the chelate ring system formed during coordination. Conversely, this process increased the lipophilic nature of the central metal atom, which favored its permeation more efficiently through the lipid layer of the microorganism ^[40], destroying them more aggressively. Metal ions were essential for the growth-inhibitory effects ^[41] by disturbing the respiration processes of the cells and thus blocking the protein synthesis, which was required for further growth of the organisms. The lipid membrane that surrounds the cell favors the passage of only lipid-soluble materials, lipophilicity is an important factor controlling the antifungal activity.

3.7.1 Antibacterial activity (in vitro)

Table 6

Antibacterial and antifungal activity (concentration used 1mg/mL of DMSO) of the ligands and their metal (II) complexes [zone of inhibition (mm)].
Compounds	Bacteria			Fungus
Compounds	S. aureus	B. cereus	E. coli	A. niger	A. fumigatus
L2	11	12	16	14	15
B1	17	18	19	19	20
B2	14	15	15	16	16
B3	21	20	23	22	21
B4	15	16	20	16	18
L4	11	11	15	14	13
B5	17	17	15	19	18
B6	13	15	14	15	15
B7	20	19	22	21	20
B8	15	15	18	16	18
L6	12	13	17	15	17
B9	18	19	20	20	21
B10	15	16	16	18	16
B11	22	21	24	23	22
B12	17	17	21	19	19
DMSO	--	--	--	--	--
Tetracycline	25	24	25	--	--
Fluconazole	--	--	--	24	23

< 15, weak; 15–20, moderate; >20, significant.

In summary, a series of ferrocene-based schiff bases and their metal (II) complexes were synthesized by catalyst- and solvent-free method and characterized by several physicochemical and spectral analyses. Comparing with the liquid-phase method, the catalyst- and solvent-free method is a cost-effective synthetic method which avoids the use of organic solvents and catalyst, mild conditions, shorter time, higher yield. The molar conductivity measurements indicated that all complexes were nonelectrolytes. Moreover, most metal (II) complexes possessed biological activity against the bacteria or fungi more than the free ligands. The bacterial screening results revealed that the Zn (II) complexes B11 had significant activity against all bacterial and antifungal strains.

Ethical Approval

This declaration is “not applicable”.

Competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Authors' contributions

Yuting Liu: Supervision, Project management, Conceptualization, Methodology, Formal analysis, Writing-first draft, Survey, Formal analysis. Longrui Wang: Survey, data management, Writing-review and Editing, Mthodology. Dawei Yin: Conception, Writing, Review and Editing, Resources, Funding acquisition.

Funding

We are grateful for the financial support from 973 preliminary projects (2014CB260411). The authors gratefully acknowledge the financial supports from Key R & D Program in Shaanxi Province of China (2021GY-162).

Availability of data and materials

CCDC 1890873 contains the supplementary crystallographic data for compound L4. These data can be obtained free of charge via http: // www. ccdc. cam. ac. uk / conts/ retrieving. html, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK (e-mail: deposit @ ccdc. cam. ac. uk).

Author Agreement

All authors have reviewed the manuscript and approved to submit to materials.

Acknowledgments

The authors are thankful to the Instrument analysis center of the Shaanxi University of Science & Technology for FT-IR, 1H NMR. The authors are indebted to Dr. Kang Yifan for his XRD analysis.

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No competing interests reported.

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Catalyst- and solvent-free synthesis, characterization, biological activity of Schiff bases and their metal (II) complexes derived from ferrocene

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Version 1

Abstract

Figures

1. Introduction

2. Experimental

2.1 Materials and methods

2.2 Synthesis of Ligands L1-L6

2.3. General procedure for synthesis of B1-B12

2.4. Biological activity

2.4.1. Antibacterial activity (in vitro)

2.4.2. Antifungal activity (in vitro)

3. Results And Discussion

3.1 The mechanism of synthesizing Schiff base

3.2 Synthesis of Schiff base and their metal (II) complexes

3.3 Structural analysis

3.3.1 Single crystal X-ray structure of L4

3.3.2 IR

3.3.3 ¹H NMR

3.4 Solubility of Schiff bases and their metal (II) complexes

3.5 Molar conductance measurements

3.6 Thermo gravimetric analysis of complexes

3.7 Biological activity

3.7.1 Antibacterial activity (in vitro)

4. Conclusions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1

Catalyst- and solvent-free synthesis, characterization, biological activity of Schiff bases and their metal (II) complexes derived from ferrocene

Status:

Version 1

Abstract

Figures

1. Introduction

2. Experimental

2.1 Materials and methods

2.2 Synthesis of Ligands L1-L6

2.3. General procedure for synthesis of B1-B12

2.4. Biological activity

2.4.1. Antibacterial activity (in vitro)

2.4.2. Antifungal activity (in vitro)

3. Results And Discussion

3.1 The mechanism of synthesizing Schiff base

3.2 Synthesis of Schiff base and their metal (II) complexes

3.3 Structural analysis

3.3.1 Single crystal X-ray structure of L4

3.3.2 IR

3.3.3 1H NMR

3.4 Solubility of Schiff bases and their metal (II) complexes

3.5 Molar conductance measurements

3.6 Thermo gravimetric analysis of complexes

3.7 Biological activity

3.7.1 Antibacterial activity (in vitro)

4. Conclusions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1

3.3.3 ¹H NMR