Reaction of p-chlorobenzaldehyde derived ligand Complexes possessing an azomethine and oximino functions with Lanthanide (III) ions and its biological activity.

doi:10.21203/rs.3.rs-2565335/v1

The synthesis of benzilmonoximethiocarbohydrazide-p-chlorobenzaldehyde (HBMTpCB) ligand possessing one of oxime functions that is associated to a second functions such as azomethine or thiocarbohydrazide function in the first described. This prepared ligand, which possesses an inner N₂S coordination site, allows formation of neutral lanthanide (III) metal-ligand complexes under their mono deprotonated form. The ligand was characterized by elemental analysis, FT (IR), ¹H NMR and electronic spectra. The La (III), Nd (III), Gd (III), Tb (III) and Dy (III) complexes of the HBMTpCB were prepared and characterized by the analytical and spectroscopic methods. In addition, the magnetic susceptibility and molar conductance measurements have been made. Seven coordinated geometrical structure were proposed for La (III), Nd (III), Gd (III), Tb (III) and Dy (III) complexes. These prepared novel complexes complete our work dealing with the oxime function complexing ability towards lanthanides (III) ions.

Oxime functions

benzilmonoximethiocarbohydrazide

p-chlorobenzaldehyde

Hugo Schiff first identified Schiff base compounds as those containing an azomethine group that come from a reversible acid-catalyzed condensation reaction between primary amine and carbonyl compounds in 1864^1–2. Because of the wide range of biological applications, simplicity of synthesis, chelating properties, and stability of Schiff base compounds, this class is significant and has been widely studied^3–5. Depending on the type of bacteria and lanthanide, there are numerous different types of lanthanides (Ln-L) that respond differently to bacteria⁶. Additionally, (Ln-L) has numerous advantageous uses in physics, such as luminescence and solar cells^{7, 8}. There are various ways to make the chemical 3-(2-fluoro) acrolein, including Witting⁹, Heck¹⁰, and Stille reactions¹¹. The chelating ligand benzilmonoxime is well recognized and frequently used as a Schiff base derivative in organic and inorganic chemistry^12–13. The researchers have for the first time shown that benzilmonoxime is a well-known analytical extracting agent for molybdenum, tungsten, and vanadium¹⁴. Cobalt was extracted and its microgram amount was determined using benzilmonoxime¹⁵. Utilizing sodium dodecylsulfate micellar medium and benzilmonoxime, cobalt has been detected spectrophotometrically¹⁶. Analytical and biological considerations make benzilmonoxime important. In view of these, our aim is directed towards the preparation of lanthanide (III) metal complexes of HBMTpCB ligand.

The free HBMTpCB ligand can be synthesized by equimolar amount of benzilmonoximethiocarbohydrazide and p-chlorobenzaldehyde in ethanol. The La (III), Nd (III), Gd (III), Tb (III) and Dy (III) metal complexes are prepared by 1:3 (ML₃) molar ratio in ethanol solvent, under refluxed condition¹⁷. This prepared HBMTpCB ligand and its lanthanide (III) complexes are easily characterized by NMR, FT (IR), electronic absorption spectra, magnetic moment and molar conductivity measurements. The molar conductivity data of the all prepared complexes, suggested that they are 1:1 electrolyte in nature¹⁸. The physical and analytical data for the HBMTpCB ligand and its metal complexes are listed in Table-1.

Table-1: Analytical and physical data of the ligand and its lanthanide (III) metal complexes

Compound

Color

Yield

%

M.P. / Dec. pointºC

Elemental Analysis

Magnetic

Moments

(B.M.)

Electrical Conductance

10^-3M(in nitrobenzene)

mhos

% M

Found

(Calcd)

% C

Found

(Calcd)

% H

Found

(Calcd)

% N

Found

(Calcd)

% O

Found

(Calcd)

% Cl

Found

(Calcd)

HBMTpCB

Yellow

81.61

209

-

60.61

(59.92)

4.16

(4.98)

16.07

(16.02)

3.67

(3.65)

8.13

(8.00)

-

[Tb(BMTpCB)₃]NO₃

Brown

80.69

239

10.42

(10.29)

51.91

(51.00)

3.34

(3.21)

14.68

(14.50)

6.29

(6.20)

6.29

(6.20)

9.52

26.15

[La(BMTpCB)₃]NO₃

Green

81.26

244

10.70

(10.21)

50.86

(50.80)

3.66

(3.61)

15.08

(15.07)

6.89

(6.83)

7.65

(7.63)

Dia

22.33

[Dy(BMTpCB)₃]NO₃

Orange

73.06

238

10.81

(10.33)

52.70

(52.33)

3.39

(3.20)

13.97

(13.50)

6.38

(6.58)

9.40

(6.58)

10.48

26.24

[Gd(BMTpCB)₃]NO₃

Brown

78.62

243

10.50

(10.05)

52.89

(52.52)

3.41

(3.21)

14.02

(13.92)

6.41

(6.36)

9.48

(9.66)

7.79

21.69

[Nd(BMTpCB)₃]NO₃

Green

79.96

241

9.54

(9.48)

52.41

(52.29)

3.38

(3.30)

14.82

(14.78)

6.35

(6.23)

7.00

(6.88)

3.60

30.45

FT (IR) spectroscopy:

The FT(IR) spectrum of the HBMTpCB ligand showed a sharp band at 1613 cm^-1 and 1588 cm^-1, which due to azomethine and oximino linkages which was shifted to higher frequencies in the lanthanide (III) metal complexes, indicating coordination of the lanthanide (III) metal ions through the azomethine and oximino linkages^19-20. For broadband shown in the HBMTpCB ligand at 3641 cm^-1 due to -OH of the oximino group, this band disappeared in the lanthanide (III) metal complexes spectra, indicating involvement of this group in the complex formation and deprotonation²¹.

The appearances of new bands at the region 525-535 and 428-440 cm^-1 due to n(M-N) and n(M-S) groups, respectively²². The FT (IR) spectral data and their tentative assessment are listed in Table-2.

Table-2: IR spectral bands of the ligand (HBMTpCB) and its metal complexes (cm⁻¹)

Assignments	HBMHpCB	Nd(III)	Tb(III)	La(III)	Dy(III)	Gd(III)
ν(OH)	3641	-	-	-	-	-
ν(N-H)	3297	3187	3301	3295	3297	3287
νC=C Ar.	3046	2915	3047	3023	3080	3191
νC=NN	1613	1633	1629	1614	1645	1599
νC=NO	1588	1570	1593	1577	1588	1590
νN-N	974	1054	1021	1049	1056	1014
νN→O	-	985	957	965	922	9666
νM-N	-	541	593	559	557	606
νM→ N	-	503	507	540	508	523

Electronic spectra:

Electronic absorption spectra of the HBMTpCB ligand and its lanthanide (III) complexes were carried out in methanol and chloroform solvents respectively. The HBMTpCB ligand electronic spectra had a strong band at 353and 274 nm assigned as p→ p^* transition of azomethine and oximino linkages.

The [La(BMTpCB)₃]NO₃ complex exhibited only a broad band around 323 nm it was assigned to the metal to ligand charge transfer transition. The absorption bands are of a gadolinium(III), lanthanum(III), neodymium(III), terbium(III) and dysprosium(III) in the near infrared and visible region appear due to transitions from ⁴I_9/2, ⁸S_7/2, ⁶H_5/2, ³H₄ and ⁶H_15/2 ground levels to the J-level excited of the 4f-configuration respectively. Some nephelauxetic effect or red shift is observed in the chloroform solutions of these complexes. This nephelauxetic effect is usually accepted²³ as a higher degree of covalency evidence than the aqua compounds presence. In all prepared lanthanide (III) complexes, marked intensity enhancement of the observed band and this nephelauxetic effect (b) utilizes hypersensitive bands to calculate this effect. From the b values, the Sinha parameters (d%), covalence factor (b^1/2) and the covalency angular overlap parameter (h) have been calculated using the expression below;

h = [(1-b)^1/2/b^1/2] -------------eq-1

b^1/2 = 1/2[(1-b)^1/2] -------------eq-2

d% = [(1-b)/b]x100 -------------eq-3

The d% and values (1-b) are positive in these coordination compounds (Table-3), suggesting that the bonding between the ligand and metal ion is covalent compared to the bonding between the aqua ion and metal ion. The angular overlap (h) and bonding parameter (b^1/2) values are found to be positive, indicating that the covalent bonding.

Table-3: Electronic absorption spectral data of HBMTpCB ligand and its Ln (III) metal complexes

Compound	l (nm)	e (dm³/mol/cm)	Transition
HBMTpCB	353	7740	π→ π^*
	274	10730	π→ π^*
	225	12756	π→ π^*
[Nd(BMTpCB)₃]NO₃	874	103	⁴I_9/2 → ⁴F_3/2	b_ave = 0.9925 b^1/2 = 0.0591 δ% = 0.7587 h = 0.00387
	800	127	⁴I_9/2 → ⁴F_5/2
	745	56	⁴I_9/2 → ⁴F_7/2
	584	3879	⁴I_9/2 → ⁴G_5/2,²G_7/2
	524	4568	⁴I_9/2 → ⁴G_7/2
	518	5789	⁴I_9/2 → ⁴G_9/2
[Tb(BMTpCB)₃]NO₃	623	1170	⁵D₄ → ⁴F₃	b_ave = 0.9933, h = 0.00336, b^1/2 = 0.0527, δ% = 0.6737
	587	3257	⁵D₄ → ⁷F₄
	546	7568	⁵D₄→ ⁷F₅
	490	9291	⁵D₄→ ⁷F₆
[La(BMTpCB)₃]NO₃	392	110	MLCT
[La(BMTpCB)₃]NO₃	243	13541	MLCT
[Dy(BMTpCB)₃]NO₃	740	89	⁴H_15/2→ ⁴I_15/2	b_ave = 0.9971, h = 0.00272, b^1/2 = 0.0505, δ% = 0.545
[Dy(BMTpCB)₃]NO₃	450	4952	⁴H_15/2→ ⁴I_15/2	b_ave = 0.9971, h = 0.00272, b^1/2 = 0.0505, δ% = 0.545
[Gd(BMTpCB)₃]NO₃	564	9365	⁸S_7/2 → ⁶P_5/2	b_ave = 0.9978, h = 0.0049, b^1/2 = 0.0629, δ% = 0.975
[Gd(BMTpCB)₃]NO₃	410	11590	⁸S_7/2 → ⁶P_5/2	b_ave = 0.9978, h = 0.0049, b^1/2 = 0.0629, δ% = 0.975

Biological activity:

All the synthesized ligands and their lanthanide complexes have been studied for antibacterial activities against two gram positive species, S. aureus, and C. diptheriae and two gram negative species, P. aeruginosa and E. coli, as well as in vitro antifungal activities against Aspergillus Niger, Candida albicans, and Aspergillus clavatus. Broth dilution methods have been employed for the evaluation of the antibacterial activity. It is one of the manual in vitro assays for bacterial susceptibility. The amount of antimicrobial agents required to stop the growth of particular microbes can be quantified using this traditional method. It is conducted in tubes.

Table 4. Antibacterial activity of the ligand (HBMTpCB) and its metal complexes

Minimal Inhibition Concentration [Microgram/ml]
Sr No.	Comp Name	*E. coli*	*P. aeruginosa*	*S. aureus*	*C. diptheria*
Sr No.	Comp Name	MTCC 443	MTCC 1688	MTCC 96	MTCC 116
1	HBMTpCB	100	50	62.5	50
2	[La(BMTpCB)₃]NO₃	100	25	62.5	50
3	[Nd(BMTpCB)₃]NO₃	125	100	250	125
4	[Gd(BMTpCB)₃]NO₃	125	100	125	25
5	[Tb(BMTpCB)₃]NO₃	125	50	125	62.5
6	[Dy(BMTpCB)₃]NO₃	100	250	250	250

The standard drugs

DRUGS	*E. coli*	*P. aeruginosa*	*S. aureus*	*C. diptheria*
-	MTCC 443	MTCC 1688	MTCC 96	MTCC 116
	Minimal Inhibition Concentration [microgram/ml]
Gentamycin	0.05	1	0.25	0.5
Ampicillin	32	-	40	25
Chloramphenicol	50	50	50	50
Ciprofloxacin	25	25	50	50
Norfloxacin	10	10	10	10

Table 5: Antifungal activity of the HBMTpCB ligand and its complexes.

Minimal Fungicidal Concentration [microgram/ml]
Sr No.	Comp Name	C. albicans	A. niger	A. clavatus
Sr No.	Comp Name	MTCC 227	MTCC 282	MTCC 1323
1	HBMTpCB	500	1000	>1000
2	[La(BMTpCB)₃]NO₃	500	1000	>1000
3	[Nd(BMTpCB)₃]NO₃	500	500	1000
4	[Gd(BMTpCB)₃]NO₃	250	500	500
5	[Tb(BMTpCB)₃]NO₃	500	1000	>1000
6	[Dy(BMTpCB)₃]NO₃	500	500	500

The standard drugs

Drugs	C.albicans	A.niger	A.clavatus
-	MTCC 227	MTCC 282	MTCC 1323
	Minimal Fungicidal Concentration [microgram/ml]
Nystatin	100	100	100
Greseofulvin	500	100	100

From the obtained data, the following inferences can be concluded:

Ligand shows medium antibacterial activity against S. aureus but quietly strong activity against C. diptheria. The La (III) and Gd (III) complexes show promising antibacterial activity against P. aeruginosa and C. diptheria. Tb (III) complex are also moderately active against C. diptheria. While Tb (III) and Dy (III) complexes do not show any antibacterial activity against any of the bacteria. The enhancement of the activity against the bacteria after the formation of the complexes may be due to the chelation of the ligands with the central metal ion, which may produce partial polarization of the complexes^25-27. The prepared complexes were subjected to antifungal activity against the mentioned fungi. From the obtained data, the following result can be evaluated:

Gd(III) complex show antifungal activity to some extent against the bacteria C. albicans²⁸,
For the fungal species A. niger and A. clavatus, no any complexes show antibacterial activities, i.e., these complexes are inactive against A. niger and A. clavatus.

Chemicals:

All required solvents and reagents were purchased from Sigma-Aldrich chemical and used as a received. The HBMTpCB ligand was prepared by a reported method²⁹ (Scheme-I). HMOTCH was synthesised by combining a hot aqueous solution of thiocarbohydrazide (20.000 g, 0.188 mol) with an ethanolic solution of benzilmonoxime (10.000 g, 0.044 mol) in the presence of sodium acetate (20.000 g), then refluxing the mixture for seven hours on a water bath and storing it overnight at room temperature. The solid was filtered, washed with hot water, and dried at 100^oC.

Preparation of Lanthanide complexes:

All Ln (III) complexes are prepared by refluxing a mixture of lanthanide (III) nitrate (1mmol) in distilled water and HBMTpCB ligand (2 mmol) in ethanol, at 70 °C for 5-9 h to from a clear color solution. Cool these reaction mixtures to 25-30 ^oC, filtered and hot distilled water (Scheme-II).

In summary five new lanthanide (III) complexes of HBMTpCB ligand with structures [La(BMTpCB)₃]NO₃ where Ln = La, Nd, Tb, Gd and Dy, have been successfully prepared and all the prepared Ln (III) complexes are magnetically and structurally characterized. All the complexes exhibited a 3:1 molar ratio based on their stoichiometry (ligand: lanthanide ion) in a neutral state. It was discovered that the recently synthesized Schiff base molecule and its complexes had strong antifungal and antibacterial activities. The antibacterial result proves that metal complexes are more effective against microbes than free ligands.

Ethical Approval: Not applicable

Competing interests: The authors declare that they have no conflict of interest.

Authors' contributions: The authors confirm contribution to the paper as follows:

1) Author 1: Study conception and design.

2) Author 2: Data collection

3) Author 2: Analysis and interpretation of results.

4) Author 1 and Author 2: Draft manuscript preparation.

All authors reviewed the results and approved the final version of the manuscript.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Availability of data and materials: The data that support this study are available from the corresponding author upon reasonable request.

Xavier A and Srividhya N; Synthesis and study of Schiff base ligands; IOSR J. Appl. Chem; 7, 6–15 (2014).
Badihian S, Shaygannejad V, Soleimani P, Mirmosayyeb O, Samee Z, Manouchehri N and Esmaeil N; Decreased serum levels of interleukin-35 among multiple sclerosis patients may be related to disease progression; J. Biol. Regul. Homeost. Agents; 32, 1249–1253 (2018).
Buldurun K, Turan N, Savcı A and Colak N; Synthesis, structural characterization and biological activities of metal (II) complexes with Schiff bases derived from 5-bromosalicylaldehyde: Ru (II) complexes transfer hydrogenation; J. Saudi Chem. Soc; 23, 205–214 (2019).
Shaygan S, Pasdar H, Foroughifar N, Davallo M and Motiee F; Cobalt (II) complexes with Schiff base ligands derived from terephthalaldehyde and ortho-substituted anilines: Synthesis, characterization and antibacterial activity; Appl. Sci; 8, 385 (2018).
Cotton S A; Establishing coordination numbers for the lanthanides in simple complexes; Comptes Rendus Chim; 8, 129-145 (2005).
Al-Momani W M, Taha Z A, Ajlouni A M, Shaqra Q M A and Al-Zouby M; A study of in vitro antibacterial activity of lanthanides complexes with a tetradentate Schiff base ligand; Asian Pac. J. Trop. Biomed; 3, 367–370 (2013).
Sagar Babu S V, Krishna Rao K and Ill Lee Y; Synthesis, characterization, luminescence and DNA binding properties of Ln (III)-Schiff base family; J. Chil. Chem. Soc; 62, 3447–3453 (2017).
Wang X, Yang Y L, Wang P, Li L, Fan R Q, Cao W W, Yang B, Wang H and Liu J Y; High efficiency co-sensitized solar cell based on luminescent lanthanide complexes with pyridine-2,6-dicarboxylic acid ligands; Dalton Trans; 41, 10619–10625 (2012).
Wittig G and Schöllkopf U; Triphenyl-phosphin-methylene als olefinbildende Reagenzien I. Mitteil; Chem. Ber; 87, 1318–1330 (1954).
Heck R F and Nolley J P Jr; Palladium-catalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halides; J. Org. Chem; 37, 2320–2322 (1972).
Milstein D and Stille J; Palladium-catalyzed coupling of tetraorganotin compounds with aryl and benzyl halides. Synthetic utility and mechanism; J. Am. Chem. Soc; 101, 4992–4998 (1979).
Bhagwat R, Badekar R, Patankar-Jain K and Lokhande R; Synthesis and characterization of schiff base 3-[2-(hydroperoxyimino)-1, 2-diphenylethylidene] hydrazinylidene} methyl] phenol metal (II) complexes; Journal of Advanced Scientific Research; 12(02) Suppl-1, 230-234 (2021).
Bhagwat R, Badekar R, Patankar-Jain K and Lokhande R; Synthesis and spectroscopic analyses of Co(II), Ni(II), and Fe(II) complexes with salicylaldehyde derivatives of benzilmonoximehydrazide; Journal of Advanced Scientific Research; 12(02) Suppl-1, 225-229 (2021).
Boutamine S., Hank S., Meklati M. and Benali-Baitich O.; J. Radioanaly. Nucl. Chem.; 185, 347 (1994).
Yadav P, Badekar R, Nag P, and Lokhande R; Synthesis, complexation and spectral study of novel 2-bromobenzaldehyde derived benzilmonoximehydrazone; Journal of Advanced Scientific Research; 12(01), 231-234 (2021).
Eskandari H. and Karkaragh G. I.; Analyt. Sci.; 19, 1549 (2013).
Nguyen, Thuy-Ai D., Jacqueline M. Veauthier, David E. Chavez, Bryce C. Tappan, Alexander H. Mueller, Brian L. Scott, and Damon A. Parrish; Lanthanide Complexes of Bis (tetrazolato) amine: A Route to Lanthanide Nitride Foams; Inorganic Chemistry; 59(22), 16109-16116 (2020).
Sharma A and Shah M; Synthesis and characterization of some transition metal complexes derived from bidentate Schiff base ligand; J of Appl Chem; 3(5), 62-66 (2013).
Thakkar N and Bootwala S; Synthesis and characterization of binuclear metal complexes derived from isonitrosoactophenone and benzidine; Ind J of Chem; 34A, 37-374 (1995).
Raman N, Johnson S, Joseph J, Sakt Hivel A and Dhaveethu J; Synthesis and characterization of ZnO microcrystal tubes; J Chil Chem Soc; 53(3), 1599-1604 (2008).
Park S, Choi Y, Has S and Lee K; Sharp line electronic spectroscopy and ligand analysis of Cr(II) complexes with amino acid ligands; Bull Korean Chem Soc; 20(12), 1475-1478 (1999).
Alomar K, Khan M, Allain M and Bout G; Polyhedron; 28, 1273-1280 (2009).
Reisfeld R, Jorgensen C K; Chemical bonding and lanthanide spectra; Lasers and Excited States of Rare Earths; 123-156 (1977).
Sankhe S and Kamble P; Synthesis and characterization of Pd (II), Zn (II), Cd (II) and Hg(II) metal coordination compounds of (4-(dimethylaminobenzylidene) hydrazono)butane-2-one oxime; JETIR; 5(8),677-682 (2018).
Thiravidamani C, Arunadevi A and Raman N; Synthesis, spectral characterization, DNA-binding and antimicrobial profile of biological active mixed ligand Schiff base metal (II) complexes incorporating 1, 8-diaminonaphthalene; Journal of Coordination Chemistry; 74(4-6), 804-822 (2021).
Abdel-Kader N S, Abdel-Latif S A, El-Ansary A L and Sayed A G; Spectroscopic studies, density functional theory calculations, non-linear optical properties, biological activity of 1-hydroxy-4-((4-(N-(pyrimidin-2-yl) sulfamoyl) phenyl) diazenyl)-2-naphthoic acid and its chelates with Nickel (II), Copper (II), Zinc (II) and Palladium (II) metal ions; Journal of Molecular Structure; 1223, 129203 (2021).
Zheng R, Junru G, Xinyi C, Lianjie B, Chengyu L, Singh A, Trivedi M, Kumar A and Jianqiang L; Manganese complexes and manganese-based metal-organic frameworks as contrast agents in MRI and chemotherapeutics agents: Applications and prospects; Colloids and Surfaces B: Biointerfaces; 112432 (2022).
Artur A, Ożarowski M and Karpiński A; Antibacterial activity of some flavonoids and organic acids widely distributed in plants; Journal of clinical medicine; 9(1), 109 (2019).
Singh V, Badekar R and Mane R; International J. of Adv& Innovative Res; 5-3(II), 89-92 (2018).

Scheme I and II are available in the Supplementary Files section.

No competing interests reported.

Scheme1.png
Scheme-I: Preparation of HBMTpCB ligand
Scheme2.png
Scheme-II: Preparation of metal complexes of HBMTpCBligand

Reaction of p-chlorobenzaldehyde derived ligand Complexes possessing an azomethine and oximino functions with Lanthanide (III) ions and its biological activity.

Status:

Version 1

Abstract

Figures

Introduction

Result

Experimental

Conclusion

Declarations

References

Scheme

Additional Declarations

Supplementary Files

Status:

Version 1