Document Type : Original Research Article
Authors
Department of Chemistry, College of Science for Women, University of Babylon, Hillah, Iraq
Abstract
In this study, we synthesized a series of new Schiff base derivatives containing adamantane moiety in the skeleton structure using adamantanol as the initial material, the adamantanol undergoes two reaction steps. In the first step, adamantanol reacts with acetanilide to produce 1,3-bis(4-acetamido-1-phenyl)adamantane as a salt. In the second step, the produced salt prepared in first step undergoes de-protection reaction by react with aqueous solution of sodium hydroxide to generate 1,3-bis (4-amino-phenyl)adamantane. This amine derivative reacts with different aromatic aldehydes to synthesis Schiff base derivatives of adamantane, as well as characterization of hybrid compounds by FT-IR, Mass spectroscopy, 1H-NMR, 13C-NMR, and study of antioxidant activity. All synthesized derivatives have good scavenging ability against (2,2 diphenyl-1-picrylhydrazyl) free radical, at the range of 81.4-89.9% at high concentration of 1 mg/mL.
Graphical Abstract
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Keywords
Main Subjects
Introduction
Adamantane (C10H16) are polycyclic hydrocarbon fused chair from cyclohexane rings, it is colorless crystalline compound with an odor like to camphor [1], it has unique chemical, and physical properties [2], such as high lipophilicity [3], rigid structure, and thermodynamically stable molecules [4]. These structural motifs need to demonstrate their value as effective pharmacophore additions as they are utilized rather infrequently in drug design [2]. It has (potential) applications in a number of domains, including chemical synthesis, molecular electronics, medical profession, and astrochemistry [5]. The synthesis and biological activities of adamantane derivatives, which developed into an attractive issue, were investigated by many researchers due to the benefit of the adamantyl group, which gives increased potency in medications in which it was present. As a result, several adamantane derivatives were found to have different biological functions [6], such as antiviral [7], especially influenza viruses [8], medicine catalysis [9], antibacterial, antifungal, anti-inflammatory [10], antidiabetic, carbonic anhydrase inhibitors, and anticancer effects [11].
Schiff base produce by condensation reaction of “ketones or aldehydes with primary amines” Schiff bases that prepared from aromatic amines and aromatic aldehydes are typically those that are stable[12]. Yet, due to steric and electronic factors, aldehydes react more quickly in condensation processes than ketones [13, 14]. These substances can be both found in nature and created in a lab. [15]. They have a wide range of biological functions [16], including antimalarial [17], antiprotozoal [18], antitumor [19], antifungal [20], antibacterial [21], analgesic, anti-inflammatory, antioxidant, cardiovascular, antitubercular, and used as local painkillers [17, 22], as well as they have extensive applications in organometallic chemistry [15, 23-25], catalysis[26], removal dyes[27], foodstuff industrial, diagnostic chemistry, an agricultural chemical such as an insecticide or an herbicide [28]. Due to their widespread applications and simplicity of manufacture, Schiff-based derivatives have drawn a lot of interest [29]. Imines are crucial starting materials and intermediates for numerous reactions, including the production of Mannich bases [30]. Typically, the Schiff bases with aromatic nuclei have strong bioactivities [31]. Several researchers were interested in the biological activities of adamantane derivatives of Schiff base such as Zhu et al. [32] created a series of Schiff base thiosemicarbazone derivatives with an adamantane moiety, that may contribute to the development of novel compounds with intriguing biological properties. Osman et al. [33] synthesize new Schiff bases by the condensation reaction of adamantane-1-carbohydrazide with a suitable isatin derivative. The resulting hybrid molecules should have improved brain penetration and the capacity to influence a variety of targets implicated in the epilepsy pathogenesis. Research on the creation of pharmaceuticals with unique architectures is crucial for therapeutic use [32]. The aim of the work is design hybridization molecules have adamantane moiety and bis azomethine group in the same structure, as well as identification of hybrid compound by FT-IR, 1H-NMR, 13C-NMR, Mass spectroscopy, and evaluation antioxidant activity.
Materials and methods
All of the use’s materials are commercially available and have relative purity about 95%-99%, the measuring devices used involve: Melting point Smp30 Stuart (UK). FT-IR spectrophotometer 8400s Shimadzu (Japan), 1H-NMR, 13C-NMR Bruker at (400 MHz) Switzerland with (DMSO) solvent, Mass spectroscopy Agilent Technology (HP), Model: 5973 Network Mass Selective Detector, at Isfahan University of Technology (IUT) with (DMSO), UV-Visible Spectrophotometry.
Preparation of adamantane salt [1,3 bis(4-acetamido-1-phenyl)adamantane] (A1)
1 eq. from adamantanol (15 g, 0.0985) was mixed with 2eq. of acetanilide (26.6 g, 0.197), 300 mL from H2SO4 as solvent, and oxidation agent was added with drop-wise under vigorously stirring for 24 hours at room temperature. After that, the produced mixture was poured into ice water with stirring for 30 minutes, and then the precipitate was washed for several times after filtration to remove the residue of the acid. Next, dries the product as a white powder with high yield 87%, as shown in Scheme 1. This method was according to Habib et al. [1].
Preparation of adamantane amine [1,3 bis(4-amino phenyl)adamantine] (A2)
1eq of adamantane salt of acetanilide was mixed with 2 eq of sodium hydroxide dissolved in less amount of water, and then added 250 mL of absolute ethanol the reaction occur under reflux conditions for 24 hours, after that the mixture poured into ice water with stirring for 30 minutes, and then the precipitate is washed carefully for several times after filtration to remove the residue of the base, the precipitate is dried as a light brown powder, melting point approximately (120 °C) with good yield 85%, as demonstrated in Scheme 1.
Synthesis of Bis Schiff's base derivatives
The diaminoadamantane derivative were treated with several aromatic aldehyde where, 1eq of prepared amine mixed with 2eq of aromatic aldehyde in 35 mL of absolute ethanol as a solvent and 0.5 mL of pyridine as catalyst, the reaction occurs under reflux condition for 5-6 hours, and then the mixture is filtered and recrystallization by absolute ethanol, general reaction of new Schiff base derivatives synthesized, as shown in Scheme 1.
Synthesis of 4,4'-(adamantane-1,3-diyl)bis(N-benzylideneaniline) (B1)
Off-white solid, Yield: 56%, M.P.: 155-156 °C, FT-IR (KBr) (νmax/cm-1): 3061 (Ar-CH), 1627 (C=N), 1597 (C=C); 1H-NMR (DMSO-d6): δ 1.77-2.2 (m, 14H, C-H cycloaliphatic), 7.2-8.6 (m, 18H, Ar-H), 8-8.6 (s, 2H, N=C-H); 13C-NMR (400 MHz, DMSO-d6): δ 160 (C=N), 121-149 (C-Ar), 37-42 (C-Adamantane); m/z calculated 494.6 g/mol, m/z found 494.3 g/mol.
Synthesis of 4,4'-(adamantane-1,3-diyl)bis(N-(4-methylbenzylidene) aniline) (B2)
Off-white solid, Yield: 68%, M.P.: 142-144 °C, FT-IR (KBr) (νmax/cm-1): 3045 (Ar-CH), 1626 (C=N), 1597 (C=C); 1H-NMR (400 MHz, DMSO-d6): δ 1.75-2.2 (m, 14H, C-H cycloaliphatic); 2.2-2.3 (S, 6H, C-H aliphatic), 7.2-7.8 (m, 16H, Ar-H), 8.5 (s, 2H, N=C-H). 13C-NMR (100 MHz, DMSO-d6): 160 (C=N), 121-149 (C-Ar), 29-42 (C-Adamantane), 21.6 (CH3); m/z calculated 522.7 g/mol, m/z found 522.4 g/mol.
Synthesis of 4,4'-(adamantane-1,3-diyl)bis(N-(4-methoxybenzylidene)aniline) (B3)
Off-white solid, Yield: 72%, M.P.: 130-132 °C, FT-IR (KBr) (νmax/cm-1): 3101 (Ar-CH), 1627 (C=N), 1577 (C=C). 1H-NMR (400 MHz, DMSO-d6): δ 1.75-2.2 (m, 14H, cycloaliphatic), 3.8 (s, 6H, C-H aliphatic), 7-7.9 (m, 16H, Ar-H), 8.54 (s, 2H, N=C-H). 13C-NMR (100 MHz, DMSO-d6): δ 159.6 (C=N), 114-132 (C-Ar), 29-42 (C-Adamantane), 55.8 (C-O). The m/z calculated 554.7 g/mol, m/z found 554.4 g/mol.
Synthesis of 4,4'-(adamantane-1,3-diyl)bis(4,1-phenylene)bis(azanylylidene) bis(methanylylidene)bis(N,N-dimethylaniline) (B4)
Pale yellow solid, Yield: 67%, M.P.: 158-160 °C, FT-IR (KBr) (νmax/cm-1): 3050 (Ar-CH), 1608 (C=N), 1599 (C=C), 1H-NMR (400 MHz, DMSO-d6) δ 1.76-2.27 (m, 14H, C-H cycloaliphatic), 3.02 (s, 12H, C-H aliphatic), 6.7-7.76 (m, 16H, Ar-H), 8.43 (s, 2H, N=C-H). 13C-NMR (100 MHz, DMSO-d6): 159.7 (C=N), 111-152 (C-Ar), 29-37 (C-Adamantane), 40-42 (C-N). Calculated 580.8 g/mol, m/z, found 580.4 g/mol.
Synthesis of 4,4'-(adamantane-1,3-diyl)bis(N-(furan-2-ylmethylene) aniline) (B5)
Light brown solid, Yield: 43%, M.P.: 164-166 °C, FT-IR (KBr) (νmax/cm-1): Above 3000 (Ar-CH), 1622 (C=N), 1516 (C=C). 1H-NMR (400 MHz, DMSO-d6): δ 1.7-2.9 (m, 14H, C-H cycloaliphatic), 6.3-7.1 (m, 8H, Ar-H), 7.1-7.9 (m, 6H, Ar-H heterocyclic), 8.4 (s, 2H, N=C-H). 13C NMR (100 MHz, DMSO-d6): δ 152 (C=N), 112-126 (C-Ar), 146-149 (C-Aromatic heterocyclic), 29-42 (C-Adamantane); m/z calculated 474.59 g/mol, m/z found 474.3 g/mol.
Synthesis of 4,4'-(adamantane-1,3-diyl)bis(N-(2-nitrobenzylidene)aniline) (B6)
Dark yellow solid, Yield: 54.5%, M.P.: 137-139 °C, FT-IR (KBr) (νmax/cm-1): Above 3000 (Ar-CH), 1616 (C=N), 1570 (C=C), 1519 (NO2). 1H-NMR (400 MHz, DMSO-d6): δ 1.74-2.25 (m, 14H, C-H cycloaliphatic), 7.2-8.1 (m, 16H, Ar-H), 8.8 (s, 2H, N=C-H). 13C NMR (100 MHz, DMSO-d6): δ 156 (C=N), 121-134 (C-Ar), 29-42 (C-Adamantane), 148-149 (C=C-NO2). m/z calculated 584.66 g/mol, m/z found 584.4 g/mol.
Synthesis of 2,2'-(adamantane-1,3-diylbis(4,1-phenylene))bis (azanylylidene))bis(methanylylidene))diphenol (B7)
Light yellow solid, Yield: 58.7%, M.P.: 111-112 °C, FT-IR (KBr) (νmax/cm-1): Above 3000 (Ar-CH), 1618 (C=N), 1599 (C=C), 3400 (OH). 1H-NMR (400 MHz, DMSO-d6): δ 1.76-2.2 (m, 14H, C-H cycloaliphatic), 7.6 (s, 2H, N=C-H), 4.8 (s, 2H, O-H). 13C-NMR (100 MHz, DMSO-d6): δ 160 (C=N), 117-133 (C-Ar), 29-42 (C-Adamantane), 149-145 (C=C-O); m/z calculated 526.6 g/mol, m/z found 526.3 g/mol.
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Antioxidant activity of Schiff base derivatives
Free radical highly reactive species are able to damage physiologically important components including DNA, carbohydrates, proteins, and lipids in the cell nucleus and cell membranes [34]. A number of illnesses and degenerative processes, including as inflammation, cancer, dementia, and physiological aging, have been linked to metabolic oxidative stress, either directly or indirectly, moreover, oxidative stress is a major factor in liver diseases [35]. As a result, antioxidants that can scavenge free radicals are crucial for the treatment and prevention of various disorders [22]. The DPPH (2,2 diphenyl-1-picrylhydrazyl) radical is an extremely stable commercial nitrogen-centered free radical due to the steric hindrance and conjugation [36]. In this report, all the produced compounds were evaluated for their in vitro antioxidant activity by scavenging DPPH free radicals. 0.05 mg/ml prepared from DPPH in methanol and kept away from light as well as prepared different concentrations of 1 mg, 0.5 mg, 0.25 mg, and 0.125 mg from all compounds in methanol .0.1 ml of all concentrations of sample were mixed with 0.1 ml of DPPH solution, control solution was used from DPPH with methanol. All of the samples' absorbance were measured using a UV-Visible spectrophotometer at a maximum wavelength of 517 nm. The percentage inhibition of free radical was calculated by the following formula:
Percent inhibition % = [(Ao -A)/Ao) ×100] Where: Ao = Absorbance of solution control.
A = Absorbance of sample [37]
Results and discussion
The FT-IR spectrum(cm-1): of Schiff bases derivatives shows a strong-moderate intensity absorption band at 1608-1627 cm-1 indicate to C=N stretching vibrations[38, 39]. Stretching vibrations of aromatic rings can be found in regions between 1410-1599 cm-1. The absence of bands specific to the primary amine (N-H) and appearance (C=N) band indicates the formation of Schiff base derivatives. Other fundamental bands of Schiff base derivatives are listed in Table 1.
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1H-NMR spectrum (DMSO): For new Schiff base showed specific signals such as a singlet peak at the region of δ 8-8.6 ppm indicating to proton imine group [40, 41], multi- peaks at the region of δ 1.75-2.9 ppm indicate to protons of adamantane structure and multi-peaks at the region of δ 6.5-8 ppm refer to the aromatic ring. 13C-NMR spectrum (DMSO): The presence of carbon of imine group (C=N) observed at the range of 152-
160 ppm[42]. The chemical shift between 29 and 42 indicate to carbons of adamantane, while the chemical shift at the range of 110-150 indicated the aromatic carbons. Mass spectrometry: is based on a rather straightforward idea: A substance is ionized using the "ionization method," the ions are separated based on their mass/charge ratio using the "ion separation method," and the number of ions representing each mass/charge unit is then recorded as a spectrum. The intensity of molecular ion peak depends on the stability of molecular ion[43]. All Schiff base derivatives (B1, B2, B3, B4, B5, B6, and B7), listed in Table 2, have parent ion and base peak in the same value except B5, which indicate the stability of these compound.
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Antioxidant Activity: According to Table 3, Schiff base derivatives synthesized compounds (B1-B7) exhibited high inhibition percentage against DPPH free radical from less value of 81.4% in compound B4 to a higher value of 89.9% in compound B3 at a high concentration of 1 mg/mL, as well as the percent inhibition decreased with decreased concentration in all compounds. Figure 1 illustrated the change in color of all compounds in different concentrations. These changes prove the radical scavenging ability of all compounds. Likewise, the substituent on aromatic ring and their position make an influence on scavenging ability.
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In this report, a new series of Schiff base derivatives containing adamantane moiety in their structure have been successfully synthesized, as well as characterized by using FT-IR, 1H-NMR, 13C-NMR, Mass spectroscopy, with yield percent from 43%-72%, and evaluation of the antioxidant activity of all synthesized compounds against DPPH free radical. All synthesized compounds have high scavenging ability against DPPH free radical, at a range from 81.4% to 89.9% at a high concentration of 1 mg/mL. The different substituent and their position on aromatic ring make an influence on the antioxidant activity. Further research is required to better understand the connection between structure and activity.
Acknowledgements
The authors acknowledge with gratitude the help of the Chemistry Department in carrying out this study.
Conflict of Interest
The authors declare that there is no conflict of interest
Orcid:
Ansam A. Al-Ajili: https://orcid.org/0009-0002-2548-0672
Sadiq A. Karim: https://orcid.org/0000-0002-6750-9405
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How to cite this article: Ansam A. Al-Ajili, Sadiq A. Karim. Synthesis and characterization of new (Bis) Schiff base derivatives based on adamantane and evaluation antioxidant activity. Eurasian Chemical Communications, 2023, 5(8), 748-757. Link: https://www.echemcom.com/issue_21448_23693.html
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