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CHEMICAL PROBLEMS 2025 no. 1 (23) ISSN 2221-8688
PREPARATION AND DIAGNOSIS OF NEW DERIVATIVES OF THE TETRAZOLE RING DERIVED FROM 2-BROMOISOPHTHALADEHYDE AND EVALUATION OF
THEIR BIOLOGICAL EFFECTIVENESS
Zahra A. Murad, Ayad S. Hamad
Chemistry Department, Tikrit University, Tikrit, Iraq Email: zg230006pep@st. tu.edu. iq
Received 07.03.2024 Accepted 30.05.2024
Abstract: This study included the preparation of Schiff base derivatives (Z1-Z5) derived from 2-bromoisophthaladehyde with aniline substitutes. By the reaction of prepared compounds with sodium azide using dioxane as a solvent a pentacyclic rings derived from tetrazole (Z6-Z10) were obtained. The prepared compounds (Z6-Z10) were characterized through measurements of fluorescence infrared (FTIR) spectra and proton (1H-NMR) and carbon nuclear magnetic resonance spectroscopy (13C-NMR). The melting points were measured, and the biological efficacy of several compounds prepared for two types of Gram-positive and Gram-negative bacteria was evaluated. Keywords: tetrazole, Schiff bases, biological activity. DOI: 10.32737/2221-8688-2025-1-116-124
1. Introduction
Tetrazole is a heterocyclic pentacyclic [1] contains the following three isomers compound containing one carbon atom and four (Scheme 1): nitrogen atoms. The molecular formula CH2N4
N—N N-N'H N=N
A % . - // 23\ , - H J* 3\
„X» ! —- c 5 . 3N ""*--rs 2 TV
H Si'
g N N
l#-tetrazole 2/7-tetrazole 5^-tetrazole
Scheme 1. Izomers of tetrazole
These compounds are considered among the most vital cyclic compounds. Because it contains four pairs of free electrons, equivalent to four nitrogen atoms, it is one of the electron-pushing compounds [2]. Previous studies have shown that tetrazole compounds and their derivatives are essential in medicine, especially in the biological field and show antibacterial [3] and antifungal [4] activity. In addition, they are an antidote against viral immunodeficiency [5], and the following compounds show good
anticancer activity [6].
Schiff bases are compounds containing an azomethine group (-HC=N-) and are usually yellow. They are named after the chemist Hugo Schiff [7]. Hydrazone compounds and their derivatives have received extensive attention recently, especially after discovering their biological effects. They are widely used in the medical and pharmaceutical fields as antifungal [8], antibacterial [9], and antitumor [10] agents. They are also effective against viruses [11].
CHEMICAL PROBLEMS 2025 no. 1 (23)
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2. Experimental part
2.1. Materials: All compounds used in this research, including 2-bromoisophthaldehyde, which was obtained from Sigma pure, has a molecular weight of 213.03 g/mol, its melting point is 139-144 degrees Celsius, and its boiling point is 298 + 25 degrees Celsius, while the rest of the materials are from BDH, Fluka, and Aldrich without further purification.
2.2. Devices used: A thermoelectric melter 9300 was used to determine melting points. Using KBr disk at a scale of (400-4000) cm-1, Shimadzu FT-IR 8400S spectrophotometer; 1H-NMR and 13C-NMR spectra using Bruker apparatus operating at 400 MHz. Thickness at 0.2 mm, Fluka silica gel plates were employed in thin-layer chromatography (TLC). The plates were activated with fluorescent silica gel G, and visibility was achieved by UV light.
2.3. Preparation of Schiff bases (Z1-Z5)
[12]
Schiff bases were prepared by dissolving an amount of the compound 2-bromozophthaldehyde (0.0004 moles and 0.8 g) in 10 ml of ethanol solvent, adding it to the reaction flask, then adding a few drops (3-5) of
acid glacial acetic as a catalyst with stirring. Then one of the substituted aromatic amine derivatives was dissolved in an amount of (0.0008 mol) in 10 ml of ethanol solvent and then added to the aldehyde with stirring and sublimation for (4-6) hours, and residues of different proportions and colors were obtained. The mixture was cooled, filtered, dried, and recrystallised with ethanol, and the melting points were measured. The completion of the reaction was confirmed using the TLC technique as shown in Table 1.
2.4. Preparation of Tetrazole (Z6-Z10)
[13]
These compounds are prepared as follows: (0.0004 moles) of previously prepared Schiff bases are dissolved in (10 ml) of dioxane solvent and placed in a circular flask, and gradually added (3 drops of triethylamine) (Et3N) and progressively added to a mixture of (0.05 g, 0.0008 mol sodium azide (NaN3), dissolved in (10 ml) dioxane, heated in a water bath (8 hours), added to crushed ice after cooling, the sediment was filtered, dried and repeated with ethanol. The physical properties are shown in Table 1.
Table 1. T ie produced chemicals' physical attributes (Z1-Z10)
Comp. No. R Molecular formula m.p. °C Yield% Color
Z1 OCH3 C22H19N2O2Br 172-174 85% Gray light
Z2 Br C20H13N2Br3 186-188 86% White
Z3 Cl C20H13Cl2N2Br 175-178 75% White
Z4 NO2 C20H13N4O4Br 155-157 74% Yellow
Z5 C6H6N C32H25N4Br 168-170 77% Green
Z6 OCH3 C22H21N8 O2Br 192-194 59% White
Z7 Br C20H15N8Br3 212-214 60% White
Z8 Cl C20H15 Cl2N8Br 220-222 64% White
Z9 NO2 C20H15N10O4Br 174-177 61% Yellow
Z10 C6H6N C32H27 N10Br 230-232 62% Green Light
2.5. Evaluation of the biological activity of (Z1, Z4, Z6, Z7, Z8)
The propagation approach of the Kirby Bauer movement, which involves spreading 0.1 ml of bacterial solution on ager Muller Hinton plates and letting them absorb the fluid for five minutes, has been used to measure biological
activity [14]. A cork plunger and a five mm diameter cork were used to create holes in each dish. Then, 0.1 ml of the produced solutions for the fourth hole, which employed Ciprofloxacin as a reference sample, were incubated at 37 °C for twenty-four hours. Using Prescott's approach
[15], the inhibitory zone widths surrounding each hole have been determined in millimeters.
3. Results and discussion
This study included using 2-bromoisophthaladehyde as a nucleus in preparing Schiff bases (Z1-Z5) and then
3.1. Characterization of Schiff bases
Examining the produced Schiff base compounds' (Z1-Z5) infrared spectra (FTIR), the appearance of an elastic band in the range (1623-1595) cm-1 belongs to the something group (C=N), which is the distinctive band of labial compounds and is evidence of the formation of the product. In addition to these
When studying the proton NMR spectrum of the compound [Z1], A solitary signal was detected
reacting them with sodium azide to form pentagonal heterocyclic rings called tetrazoles (Z6-Z10) as in Scheme 2.
bands, absorption bands related to the stretching of the aromatic bond (C-H) began to develop in the region (3065-3025) cm-1. And the emergence of two absorption bands indicative of the bond's (C=C) aromaticity in the ranges of (1565-1510) cm-1 and (1489-1456) cm-1[16], as shown in Table 2 and Fig. 1.
at the ppm location (8.97), which was identified as the proton of the azomethine group (HC=N).
3000
2000
1500
1000
71
500 1/cm
Fig.1. Infrared spectrum of compound (Z1)
The sole signal that appeared at the ppm spot (3.80) was recognised as the group proton (CH3). Likewise, multiple signals appear in the ppm site (7.02-8.25) attributed to the aromatic
Examining the chemical [Z1's] carbon NMR spectra. A signal was shown to emerge at the ppm locations (159.03), which was linked to the
ring's protons (C=C), and the protons of the solvent (DMSO-d6) are responsible for a signal in the ppm spot (2.51), as in Fig. 2.
azomethine group's carbon (C=N). A signal was detected at the ppm locations (55.85 ppm) related to the group's carbon (CH3).
r
n-
■n
R = och3 , Br , ci ,n02 , -hQ>-nH2
Fig. 2. The 13C-NMR spectrum of the compound (Z1)
Scheme 3. The proposed mechanisms of tetrazole derivatives
Signals linked to the aromatic benzene ring's carbons may be seen at the location (115.08-156.70) ppm; a signal is detected at the ppm location (40.18) that is linked to the solvent's carbon (DMSO-d6). as in Fig. 2.
3.2.Characterization of Tetrazole derivatives [17]:
Scheme 3 below shows the proposed mechanisms of tetrazole derivatives.
By examining the produced compounds' infrared spectra [Z6-Z10], the stretching of the (N-H) group on the tetrazole ring is the cause of the formation of an intermediate band in the range (3264-3195) cm-1. The stretching of the aromatic bond (C-H) is what causes an absorption band to form in the region of (30853038) cm-1. The stretching of the aliphatic (CH)
When examining the compound's 1H-NMR spectra [Z7] using a solvent (DMSO-d6), it was observed that multiple signals appeared in the ppm range (6.98-8.20) attributed to the protons of the aromatic rings, and a single signal after the chemical shift, ppm (5.56). It is attributed to the protonation of two (CH) groups on the tetrazole ring, and the appearance of a single signal after the ppm chemical shift (3.54) is attributed to the protonation of two. Groups (NH) and the appearance of a signal unique to the chemical shift ppm (3.33) are attributed to the protons of water (H2O). When a signal first appears, the solvent's protons (DMSO-d6) are
of the tetrazole ring is responsible for the formation of two symmetrical and asymmetric absorption bands, respectively, in the range of (2963-2931) cm-1 and (2894-2850) cm-1.
Besides the emergence of two bands in the intervals of (1533-1487) and (1579-1553) cm-1 is caused by the aromatic bond's vibration (C=C). The center bands that emerge in the region of (1449-1488) cm-1 are part of the group (N=N) that is linked to the formation of the tetrazole ring., and the appearance of other bands in the range (1230-1271) cm-1 due to synergistic stretching (C-N), in addition to the appearance of absorption bands in the range (1071-1012) cm-1 due to synergistic stretching (N-N ) [18]. IR data is in Table 3 in Fig. 3.
the cause of the chemical shift ppm (2.48), as shown in Fig. 4.
When examining the compound's 13C-NMR spectra [Z7] using a solvent (DMSO-d6), multiple signals were observed in the ppm chemical shift (115.05-153.73) attributed to the carbons of the aromatic ring, and the appearance of a signal at the ppm chemical shift (87.50) is attributed to the carbon group (CH) on the tetrazole ring, and the solvent's carbon (DMSO-d6) is responsible for the signal that appears at the ppm chemical shift (39.12-40.79). The spectrum is shown in Fig. 5.
100
%T
80
60
Cl 40
3000
2000
1500
1000
Z23
500 1 /cm
Fig. 3. The compound's infrared spectrum (Z8)
Fig. 4. The H-NMR spectrum of the compound (Z7)
;io im i*» i«n in» iimi j4o no i*o no joo w«om«»or»o«o®kiio tt u*oti)
Fig. 5. The 13C-NMR spectrum of the compound (Z7) Table 2. The synthesised compounds' FT-IR data (Z1-Z5) cm-1
Compound No IR (KBr) cm-1
R v(C-H) Arom. v(C=N) v(C=C) Arom. Others
Z1 4-OCH3 3058 1595 1510 1460 v (C-O) 1251
Z2 4-Br 3039 1600 1527 1467 v (C-Br) 597
Z3 4-Cl 3065 1612 1516 1478 v (C-Cl) 614
Z4 4-NO2 3025 1623 1565 1489 v (NO2).asy.(1524) sym.(1318)
Z5 4-C6H6N 3051 1598 1534 1456 v (NH2) asy.3271 sym.3230
Ta le 3. The synt hesised compounds' FT-I R data (Z6-Z10) cm-1
Comp. No. R IR (KBr) cm-1
v(NH) v(C-H) Arom. V (N=N) v(C=C) Arom. v(C-N) v(N-N) v(C-H) Aliph. Others
Z6 4-OCH3 3195 3081 1468 1553 1492 1223 1045 2954 2871 v (C-O) 1306
Z7 4-Br 3252 3085 1449 1579 1487 1238 1071 2963 2886 v (C-Br) 567
Z8 4-Cl 3249 3045 1456 1560 1502 1245 1027 2945 2894 v (C-Cl) 675
Z9 4-NO2 3264 3038 1473 1575 1495 1230 1034 2931 2850 v(NO2).asy(1541) sym.(1330)
Z10 4-C6H6N 3211 3074 1488 1564 1533 1271 1012 2935 2864 v (NH2) asy.3442 sym.3361
3.4. Evaluation of Biological activity of (Z1, Z4, Z6, Z7, Z8)
At first, the agar diffusion method carried out the biological activity against two types of pathogenic bacteria, namely the gram-positive bacteria Staphylococcus aureus and the second bacteria, the gram-negative coliform bacteria E.coli [19]. The compounds (Z4, Z8, and Z6)
were biologically effective, while compound Z4 showed activity only against positive bacteria and showed no activity against harmful bacteria [20], while both compounds Z8 and were 100% efficient against the two varieties of the chosen bacterial species, as shown in the following Table 4.
Table 4. Antibiotics and other generated chemicals can prevent the growth
Comp. Inhibition diameter of the compounds (potency) measured in millimeters
Escherichia coli Staphylococcus aureus
Conc. 25% 50% 100% 25% 50% 100%
Z4 0 0 0 0 0 12
Z6 0 0 13 0 0 13
Z8 0 0 20 0 0 31
N.A N.A
Conclusion
The authenticity and effectiveness of the prepared compounds were verified through spectroscopic and physical tests. The effectiveness of the obtained composition was verified by carbon nuclear magnetic resonance, proton and infrared spectroscopy, and some of the compounds produced had an inhibitory
effect on Gram-positive and Gram-negative bacteria, where compound Z8 showed an activity comparable to the antibiotic. Ciprofloxacin was used as a control sample, while the others were inactive. The results were compared with antibiotic control samples.
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