Synthesis, crystal structure with free radical scavenging activity and theoretical studies of Schiff bases derived from 1-naphthylamine, 2,6-diisopropylaniline, and substituted benzaldehyde European Journal of Chemistry 12 (2) (2021) 204-215 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2021 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.12.2.204-215.2088 European Journal of Chemistry View Journal Online View Article Online Synthesis, crystal structure with free radical scavenging activity and theoretical studies of Schiff bases derived from 1-naphthylamine, 2,6-diisopropylaniline, and substituted benzaldehyde Segun Daniel Oladipo 1,2,*, Tunde Lewis Yusuf 1,3,*, Sizwe Joshua Zamisa 1, Gideon Femi Tolufashe 4, Kolawole Ayodapo Olofinsan 5, Zikhona Tywabi-Ngeva 6 and Nonhlangabezo Mabuba 3,* 1 School of Chemistry and Physics, University of KwaZulu-Natal, Westville campus, Private Bag X54001, Durban, 4000, South Africa oladipodanielsegun@gmail.com (S.D.O.), tundey@uj.ac.za (T.L.Y.), zamisas@ukzn.ac.za (S.J.Z.) 2 Department of Chemical Sciences, Olabisi Onabanjo University, P.M.B. 2002, Ago-Iwoye, Nigeria 3 Department of Chemical Sciences, University of Johannesburg, Doornfontein, P.O. BOX 17011, 2028 Johannesburg, South Africa nmabuba@uj.ac.za (N.M.) 4 Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal gideonfemitolufashe@yahoo.co.uk (G.F.T.) 5 Department of Biochemistry, Faculty of Natural and Applied Sciences, Nile University of Nigeria, Abuja, Nigeria kollyck@gmail.com (K.A.O.) 6 Department of Chemistry, Faculty of Sciences, Nelson Mandela University, Port Elizabeth, 6000, South Africa zikhona.tywabi-ngeva@mandela.ac.za (Z.T.N.) * Corresponding author at: School of Chemistry and Physics, Westville Campus, University of KwaZulu-Natal, Private Bag X54001, Durban, 4000, South Africa. e-mail: tundey@uj.ac.za (T.L. Yusuf), nmabuba@uj.ac.za (N. Mabuba) and oladipodanielsegun@gmail.com (S.D. Oladipo). 10.5155/eurjchem.12.2.204-215.2088 Received: 27 January 2021 Received in revised form: 19 March 2021 Accepted: 28 March 2021 Published online: 30 June 2021 Printed: 30 June 2021 Three Schiff bases 1-(4-chlorophenyl)-N-(naphthalen-1-yl)methanimine (1), 1-(4-methoxy phenyl)-N-(naphthalen-1-yl)methanimine (2), and 1-(4-chlorophenyl)-N-(2,6-diisopropyl phenyl)methanimine (3) were synthesized and characterized by elemental analysis, 1H and 13C NMR, FT-IR and UV-Visible spectroscopic techniques. The crystal structure of compound 3 was obtained and it revealed that the compound crystallized in a monoclinic space group P21/n and there exists an intermolecular hydrogen bond in a phenyl-imine form with C- H⋯N. Crystal data for C19H22ClN: a = 7.28280(10) Å, b = 9.94270(10) Å, c = 24.0413(2) Å, β = 97.0120(10)°, V = 1727.83(3) Å3, Z = 4, μ(Mo Kα) = 0.215 mm-1, Dcalc = 1.1526 g/cm3, 14038 reflections measured (12.42° ≤ 2Θ ≤ 52.74°), 3448 unique (Rint = 0.0223, Rsigma = 0.0182) which were used in all calculations. The final R1 was 0.0337 (I≥2u(I)) and wR2 was 0.0927 (all data). The free radical scavenging activities of all three compounds were assayed using DPPH, FRAP, and OH assays. According to results obtained, compound 2 shows effective DPPH- (IC50 = 22.69±0.14 μg/mL), FRAP+ (IC50 = 28.44±0.12 μg/mL), and OH- (IC50 = 27.97±0.16 μg/mL) scavenging activities compared with compounds 1 and 3 but less than standard antioxidant compound Trolox (TRO). Additionally, theoretical calculations for the three complexes were performed by using density functional theory (DFT) calculations at the B3LYP/6-31++G(2d,2p) level in the ground state to obtain an optimized geometrical structure and to perform an electronic, molecular electronic potential surface and natural bond orbital (NBO) analysis. The geometrical calculation obtained was found to be consistent with the experimental geometry. Further analysis was conducted using the in silico technique to predict the drug likeness, molecular and ADME properties of these molecules. Synthesis Schiff bases Drug-likeness Crystal structure Antioxidant properties Density functional theory Cite this: Eur. J. Chem. 2021, 12(2), 204-215 Journal website: www.eurjchem.com 1. Introduction Antioxidants are synthetic or natural compounds that delay or inhibit the oxidation process of significant macromolecules such as proteins, fats, carbohydrates, and DNA [1], and they are of great benefit to human health [2,3]. They are helpful to avert cardiovascular disease, preventing injuries associated with vessel membranes, which aids proper blood circulation in the human body [4] and to protect cells from oxidative damage, which results in ageing as well as diseases [5]. Frequently, antioxidants are suggested at the initial stage in developing new drugs for the treatment of pathological disorders that are caused by free radicals interacting with the protein [6]. Free radicals are molecules or molecular fragments containing one or more unpaired electrons in their atomic or molecular orbitals [7]. Antioxidants help to prevent diseases caused by free radicals, and their mechanism of action has been attributed to their ability to convert free radicals to stable molecules [8,9]. However, in low concentrations, free radicals play physiological roles in cellular responses to noxia, such as enhancing cellular ABSTRACT RESEARCH ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.12.2.204-215.2088 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.12.2.204-215.2088 mailto:oladipodanielsegun@gmail.com mailto:tundey@uj.ac.za mailto:zamisas@ukzn.ac.za mailto:nmabuba@uj.ac.za mailto:gideonfemitolufashe@yahoo.co.uk mailto:kollyck@gmail.com mailto:zikhona.tywabi-ngeva@mandela.ac.za mailto:tundey@uj.ac.za mailto:nmabuba@uj.ac.za mailto:oladipodanielsegun@gmail.com http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.12.2.204-215.2088&domain=pdf&date_stamp=2021-06-30 Oladipo et al. / European Journal of Chemistry 12 (2) (2021) 204-215 205 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.2.204-215.2088 O H R NH2 N H R N H R R = Cl, 1 R = OCH3, 2 R = Cl, 3 Ethanol, 6 hrEthanol, 6 hr NH2 Scheme 1. Synthesis of compounds 1-3. signals needed for proper functioning as well as protecting living systems by killing infectious agents [10]. Research is ongoing by scientists in different disciplines to develop compounds, either synthesized or isolated from a natural source that could curb the deleterious effects of free radicals in living systems and most importantly possess antioxidant activities better than the commercially available ones. Schiff bases have been reported to have unique biological properties such as antioxidant [11,12], antibacterial [13,14], antiglycation [15,16], antifungal [17], anticancer [18], diuretic [19] and anticonvulsant [20] activities. Aside from their biological application, they have also been used as corrosion inhibitors [21], ligands in coordination chemistry [22], and sensors [23]. They are synthesized by the condensation reaction between primary amine (R-NH2) and an active carbonyl (aldehyde or ketone) [24], with the ones with aryl substituents relatively stable and easy to prepare than the aliphatic counterparts [25]. Schiff bases have broad-spectrum biological activities, and this could be attributed to the unique role of the imine bond (-C=N-) plays during these biological processes [26]. Recently, Bakir et al. [27] reported the free radical scavenging ability of Schiff bases prepared from thiocarbo- hydrazide, isatin, and substituted aldehydes. Their results showed that the monosubstituted products derived from thiocarbohydrazide displayed better antioxidant activity than their disubstituted counterparts which have a moiety of isatin molecule. In their report, compounds with electron-donating methoxy substituents showed better activity than others, however, none of the reported compounds displayed better antioxidant activity than the standard, gallic acid. Herein, we report the synthesis, characterization, crystal structure, DFT calculation, and free radical scavenging properties of Schiff bases derived from 1-napthylamine, 2,6- diisopropyaniline, and substituted aromatic aldehydes. The synthesized compounds were characterized by UV-Visible, FT- IR, and NMR spectrometry, and the purity affirmed by elemental analysis. The in vitro antioxidant activities were evaluated using 2,2-diphenyl-1-picrylhydrazyl, ferric reducing antioxidant power, and hydroxyl assay. 2. Experimental 2.1. Materials All solvents (ACS reagent grade, ≥99.5 %) were obtained from Sigma-Aldrich and used as obtained without further purification. Reagents: 2,6-diisopropylaniline (97%), 1-napthyl amine (≥99%), 4-chlorobenzaldehyde (97%), and 4-methoxy benzaldehyde (98%) were obtained from Sigma Aldrich while acetic acid (≥99%) was obtained from Promark Chemicals South Africa. 2.2. Instrumentation The melting point of the compounds was recorded using electrothermal (9100). 1H and 13C NMR spectra were recorded at 25 °C on a Bruker Avance-III 400 MHz spectrometer. Both 1H NMR and 13C NMR data were recorded in either CDCl3 referenced to the residual CDCl3 peaks at δ 7.26 and δ 77.00 ppm. Elemental analyses were recorded on a Vario elemental EL cube CHNS analyzer. IR spectra were obtained on a PerkinElmer Universal ATR spectrum 100 FT-IR spectrometer and UV-Vis absorption spectra were recorded on Shimadzu UV- vis-NIR spectrophotometer. 2.3. Synthesis of the Schiff base ligands To a stirring ethanolic solution of amine in a flask was added the appropriate aldehyde. To the resulting solution, 2 or 3 drops of acetic acid were added dropwise and stirring continued for 6 hr at room temperature to afford off-white precipitates. The crude product was washed with hexane three times to remove unreacted anilines, to give air-stable products and stored in a desiccator for further use. 2.3.1. Synthesis of 1-(4-chlorophenyl)-N-(naphthalen-1- yl)methanimine (1) The reaction of 1-naphthylamine (1.00 g, 7 mmol) and 4- chlorobenzaldehyde (0.98 g, 7 mmol) in 20 mL of ethanol furnished Schiff base 1 as an off-white powder (Scheme 1). Color: Off white. Yield: 89 %, 1.76 g. M.p: 149-151 °C. FT-IR (ATR, ν, cm-1): 3059 (w), 2878 (w), 1620 (s), 1595 (m), 1568 (m), 1264 (s), 1206 (s), 1040 (s), 801 (m), 775 (s), 501 (m). 1H NMR (CDCl3, 400 MHz, δ, ppm): 7.06 (d, 1H, JHH = 7.24 Hz, Ar-H), 7.50 (m, 5H, JHH = 7.96 Hz, Ar-H), 7.72 (d, 1H, JHH = 8.24 Hz, Ar- H), 7.84 (d, 1H, JHH = 6.76 Hz, Ar-H), 7.94 (d, 2H, JHH = 8.32 Hz, Ar-H), 8.32 (d, 1H, JHH = 9.04 Hz, Ar-H), 8.50 (s, 1H, -C=N(H)). 13C NMR (CDCl3, 100 MHz, δ, ppm): 123.89, 125.84, 126.02, 126.50, 127.69, 128.81, 129.52, 130.13, 133.97, 134.93, 137.50, 148.94, 158.84. Anal. calcd for C17ClH12N: C, 76.84; H, 4.55; N, 5.27. Found: C, 76.25; H, 4.31; N, 5.13%. UV-Vis (CHCl3, λmax, nm): 233, 267. 2.3.2. Synthesis of 1-(4-methoxyphenyl)-N-(naphthalen-1- yl)methanimine (2) The reaction of 1-naphthylamine (1.00 g, 7 mmol) and 4- methoxybenzaldehyde (0.95 g, 7 mmol) in 20 mL of ethanol furnished Schiff base 2 as an off-white powder (Scheme 1). Color: Off white. Yield: 91 %, 1.78 g. M.p: 145-146 °C. FT-IR (ATR, ν, cm-1): 3003 (w), 2964 (w), 1600 (s), 1571 (m), 1504 (m), 1248 (s), 1248 (s), 1171 (s), 1031 (s), 837 (s), 770 (s), 516 (m). 1H NMR (CDCl3, 400 MHz, δ, ppm): 3.89 (s, 3H, OCH3), 7.02 (d, 3H, JHH = 8.72 Hz, Ar-H), 7.45 (t, 1H, JHH = 7.80 Hz, Ar-H), 7.49 (m, 2H, Ar-H), 7.69 (d, 1H, JHH = 8.24 Hz, Ar-H), 7.85 (t, 1H, JHH = 6.80 Hz, Ar-H), 7.96 (d, 2H, JHH = 8.68 Hz, Ar-H), 8.34 (t, 1H, JHH = 6.88 Hz, Ar-H), 8.47 (s, 1H, -C=N(H)). 13C NMR (CDCl3, 100 MHz, δ, ppm): 55.49, 112.74, 114.25, 124.04, 125.40, 125.61, 126.10, 126.34, 127.62, 128.89, 129.57, 130.69, 133.96, 149.66, 159.67, 162.35. Anal. calcd for C18H15NO: C, 82.73; H, 5.79; N, 5.36. Found: C, 82.51; H, 5.61; N, 5.16%. UV-Vis (CHCl3, λmax, nm): 232, 269. 206 Oladipo et al. / European Journal of Chemistry 12 (2) (2021) 204-215 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.2.204-215.2088 Table 1. The summary of X-ray crystal data collection and structure refinement parameters for compound 3. Empirical formula C19H22ClN Formula weight 299.85 Temperature (K) 150.0 Crystal system Monoclinic Space group P21/n a (Å) 7.28280(10) b (Å) 9.94270(10) c (Å) 24.0413(2) β (°) 97.0120(10) Volume (Å3) 1727.83(3) Z 4 ρcalc (g/cm ) 1.1526 μ (mm-1) 0.215 F(000) 640.8 Crystal size (mm3) 0.31 × 0.19 × 0.14 Radiation Mo Kα (λ = 0.71073) 2Θ range for data collection (°) 12.42 to 52.74 Index ranges -9 ≤ h ≤ 7, -12 ≤ k ≤ 12, -30 ≤ l ≤ 30 Reflections collected 14038 Independent reflections 3448 [Rint = 0.0223, Rsigma = 0.0182] Data/restraints/parameters 3448/0/194 Goodness-of-fit on F2 1.050 Final R indexes [I≥2σ (I)] R1 = 0.0337, wR2 = 0.0856 Final R indexes [all data] R1 = 0.0411, wR2 = 0.0927 Largest diff. peak/hole (e Å-3) 0.24/-0.24 Figure 1. ORTEP diagram of compound 3 drawn at 50 % thermal ellipsoid probability. 2.3.3. Synthesis of 1-(4-chlorophenyl)-N-(2,6-diisopropyl phenyl)methanimine (3) The reaction of 2,6-diisopropylaniline (0.71 g, 4 mmol) and 4-chlorobenzaldehyde (0.54 g, 4 mmol) in 20 mL of ethanol furnished Schiff base 3 as an off-white powder (Scheme 1). Color: White. Yield: 84 %, 0.95 g. M.p: 120 - 121 °C. FT-IR (ATR, ν, cm-1): 3056 (m), 2963 (m), 1619 (s), 1594 (m), 1487 (m), 1264 (m), 1206 (s), 1087 (s), 800 (m), 774 (s). 1H NMR (CDCl3, 400 MHz, δ, ppm): 1.16 (d, 12H, JH,H = 6.88, CH3-CH), 2.93 (m, 2H, JH,H = 6.88, CH-CH3), 7.13 (m, 3H, Ar-H), 7.47 (d, 2H, JH,H = 8.36, Ar-H), 7.45 (d, 2H, JH,H = 8.40, Ar-H), 8.15 (s, 1H, -CH=N). 13C NMR (CDCl3, 100 MHz, δ, ppm): 23.44, 27.99, 123.07, 124.27, 129.15, 129.73, 134.48, 137.51, 137.53, 148.98, 160.63. Anal. calcd for C19ClH22N: C, 76.11; H, 7.40; N, 4.67. Found: C, 75.91; H, 7.32; N, 4.49%. UV-Vis (CHCl3, λmax, nm): 235, 271. 2.4. Single-crystal X-ray diffraction The crystallographic data collection of compound 3 was done on a Bruker Smart APEXII diffractometer with MoKα radiation (λ = 0.71073 Å) equipped with an Oxford Cryostream low-temperature apparatus operating at 100 K for all samples. Reflections were collected at different starting angles, and the APEXII program suite was used to index the reflections [28]. Data reduction was performed using the SAINT [29] software, and the scaling and absorption corrections were applied using the SADABS [30] multi-scan technique. The structures were solved by the direct method using the SHELXS program and refined using SHELXL program (Figure 1) [31]. Graphics of the crystal structures were drawn using Mercury software [32]. Non-hydrogen atoms were first refined isotropically and then by anisotropic refinement with the full-matrix least square method based on F2 using SHELXL. All hydrogen atoms were positioned geometrically, allowed to ride on their parent atoms, and refined isotropically. The crystallographic data and structure refinement parameters for compound 3 are given in Table 1. 2.5. Density functional theory calculation All calculations were performed using the DFT/B3LYP level of theory [33] on Gaussian 16 package [34]. The coordinates of the compounds (Figure 1) were used for geometry optimi- zations, using a medium-sized basis set, 6-31G(d,p). Frequency calculation revealed the compounds were fully optimized with no negative imaginary value. More accurate energies of the optimized geometries for compounds 1-3 were calculated with a double-ζ quality basis set, 6-31++G(2d,2p). Gas-phase IR spectra and TD-DFT calculation at the B3LYP/6-31++g(2d,2p) level in Chloroform was performed to retrieve the UV-vis spectrum. 1H and 13C-NMR chemical shifts of the molecules in dichloromethane were computed using GIAO-SCF level [35]. HOMO and LUMO orbitals in the gas phase were also obtained from the TDDFT calculation [36]. Oladipo et al. / European Journal of Chemistry 12 (2) (2021) 204-215 207 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.2.204-215.2088 2.6. In vitro antioxidant studies 2.6.1. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay The antioxidant capacity of the samples was evaluated from their ability to scavenge 2,2′-diphenyl-1-picrylhydrazyl (DPPH), in a modified method described by Turkoglu et al. [37]. Briefly, 2 mL of each sample and standard (Trolox) was added to 2 mL 0.2 mM DPPH prepared in ethanol. The mixture was vortexed and kept under pitch-dark conditions at 25 °C for 30 min. Then, the absorbance was measured at 517 nm, and the DPPH radical mapping activity was calculated as follows: % DPPH Scavenging activity = AControl−ASample AControl × 100 (1) where A control is the absorbance of the blank solution and A sample is the absorbance of the sample or standard. 2.6.2. Ferric reducing antioxidant power The ferric reducing antioxidant properties of the chemical compounds was evaluated by adopting the method by Oyaizu [38]. 1mL of varying concentrations of the compounds or Trolox (10-50 mM) was added to 500 µL distilled water, 100 μL 0.2 M phosphate buffer (pH = 6.6), and 100 µL 1% potassium ferricyanide [K3Fe(CN)6]. The mixture was incubated at 50 °C for 20 min, followed by acidification with 100 µL trichloroacetic acid (10%). After centrifugation at 2,500 rpm for 15 min, 200 µL of the supernatant was transferred into another test tube containing 200 µL distilled water and 0.8 mL of FeCl3 (0.1%). Finally, absorbance was measured at 700 nm in a spectro- photometer. The reductive antioxidant power was calculated thus: Ferric reducing antioxidant power % = Absorbance of sample Absorbance of Trolox (50 mM) × 100 (2) 2.6.3. Hydroxyl radical (OH•) scavenging activity The Hydroxyl radical scavenging ability of the samples was measured using a slightly modified method of Smirnoff and Cumbes [39]. Briefly,1 mL of varying concentrations of the samples (10-50 mM) was added to 0.3 mL ferrous sulfate (8 mM), 0. 25 mL hydrogen peroxide (20 mM), and 1 mL salicylic acid (3 mM). The mixture was vortexed and incubated at 37 °C for 30 min. Then, 0.45 mL of distilled water was added to each test before the solution was centrifuged at 10,000 rpm for 10 min. After that, the absorbance was read at 510 nm. The percentage hydroxyl radical scavenging activity of the samples has calculated the expression below: Percentage OH• · scavenging (% OH•) = AControl– (ATest – ASample) AControl × 100 (3) where A control is the absorbance of the mixture without the test sample, A test is the absorbance of the mixture with the test sample and A sample is the absorbance of the sample only. 3. Results and discussion 3.1. General synthesis The synthesis route for compounds 1-3 is shown in Scheme 1, and it was achieved by the condensation reaction between benzaldehyde derivatives (Cl and OCH3 derivatives) and primary amines (1-naphthylamine and 2,6-diisopropylaniline) in the presence of 2 or 3 drops of acetic acid to control the pH of the reaction. The off-white product formed is in good yield (84-91 %) and melts between 120-151 °C. The synthesized compounds showed good solubility in dichloromethane, chloroform, and toluene but were only partially soluble in other polar solvents. The spectra data, together with analytical results, conform to the structure of the synthesized compounds. 3.2. Spectroscopy studies 3.2.1. Nuclear magnetic resonance The 1H NMR data for compounds 1-3 were obtained in CDCl3 and peak assignments are done using 2D NMR. The signals of methyl and diisopropyl protons for compound 3 appeared at δ 1.16 and 2.93 ppm, while the methyl protons for methoxy group (-OCH3) for compound 2 appeared as a singlet at δ 3.89 ppm. The azomethine proton (NC(H)=N) for compounds 1-3 appeared as singlet between δ 8.15-8.47 ppm. The aromatic protons of the benzene and naphthalene rings appeared as multiplets, majorly duplets and triplets in the range of δ 7.01-8.34 ppm. The 13C NMR spectra of compounds 1-3 showed signals ascribed to the protons of benzene and naphthalene rings between δ 112.74-149.69 ppm, and these peaks were similar to those reported in the literature [40]. The peak due to imine carbon (-C=N) appeared downfield at δ 158.84-160.63, and it is not exceptional to those reported in the literature [40,41] while the peak at δ 162.35 ppm in compound 2 is assigned to the carbon atom of the benzene ring attached to the methoxy group. This appeared in a far downfield region compared to other carbon atoms of the benzene ring due to the electronegative effect of the methoxy group deshielding the carbon atom [40]. The signal at δ 55.49 ppm in compound 2 is attributed to the methoxy protons (-OCH3), while the ones for methyl (CH3-CH) and (CH-CH3) appeared at δ 23.44 and 27.99 ppm, respectively. 3.2.2. Fourier transform infra-red and electronic absorption spectroscopy Three major vibrational bands were observed in the IR spectra of Schiff bases containing an aromatic ring. These are stretching vibrational bands of sp2 C-H, sp3 C-H, and ν(C=N). For compounds 1-3, the sp3 C-H, sp3 C-H, and ν(C=N) vibrational bands appeared at 3003-3059, 2959-2964 and 1600-1620 cm- 1, respectively, and these are similar to those reported in the literature [42-44]. Other peaks such as the ones around 1504- 1596 cm-1 could be attributed to -C=C- stretching vibrational bands while the ones around 745-837 cm-1 may be due to out- of-plane C-H bending vibrations [40]. The electronic absorption spectra of compounds 1-3 in dichloromethane solution are given in Figure 2. The spectra of compounds 1-3 showed two major bands, one less intense absorption band on the higher energy side around 232-235 nm, and this can be assigned to the π→π* transition due to the excitation of π-electrons in the aromatic ring. The second band appeared at 267-271 nm and can be assigned to the π→π* transition of the imine functional group (-C=N) [45]. 3.3. X-ray crystal structure Suitable crystal for single-crystal X-ray diffraction analysis was obtained for compound 3 by slow evaporation of concentrated ethanol solution. The compound crystallizes in a monoclinic P21/n space group. The asymmetric unit contains one whole of the compound (Figure 1) and it has one imine group (C7=N1) with the bond distance of 1.265(2) Å. There exists a non-classical hydrogen bond in a phenyl-imine form with C-H⋯N. All intramolecular bond parameters are comparable with closely related compounds in the literature [46-50]. 208 Oladipo et al. / European Journal of Chemistry 12 (2) (2021) 204-215 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.2.204-215.2088 Figure 2. Electronic absorption spectra of compounds 1-3. dnorm Shape index Curvedness Figure 3. Hirshfeld surfaces mapped with dnorm (left), shape index (middle), and curvedness (right) for compound 3. Figure 4. Fingerprint plot, where the areas of different intermolecular contacts are clearly shown. The imine plane is significantly planar as indicated by the dihedral angle of -4.3(2)° for N1-C7-C6-C1 and makes an angle of 65.18° to the plane of o,o’-diisopropylphenyl group. there exists an intermolecular hydrogen bond in a phenyl-imine form with C-H⋯N. 3.4. Hirshfeld surface analysis The Hirshfeld surface is defined by the points where the contribution to electron density from the molecule inside the surface is equal to the contribution from all other molecules in a crystal [51]. Hirshfeld surface analysis is used to designate the surface characteristics of molecules as well as revealing the molecular interactions involved in their packing system. Information about existing interactions, either strong or weak, in crystal systems of molecules is described by performing Hirshfeld surface analysis [52]. Hirshfeld surfaces mapped with dnorm, shape index, curvedness, and 2D fingerprint plots were generated using Crystal Explorer 17.5 [53] and given in Figure 3. In the Hirshfeld surface mapped with dnorm for compound 3, the red region which is visible on the surface of the compound indicates hydrogen bond contacts (i.e., close contact, distance shorter than the sum of Van der Waal radii). The white region indicates the distance of contacts exactly comparable to the van der Waals separation and the blue region represents longer contacts. The full fingerprint plot depicting all the inter- molecular interactions is shown in Figure 4. The major and minor intermolecular interactions with percentage contri- bution to total Hirshfeld surface area for compound 3 are shown in Figure 5. In the fingerprint plot, the H∙∙∙H hydrogen bonding interactions cover 60.0 % of the whole intermolecular interactions and this indicates that they play a major part in the molecular packing of the studied system. Other substantial interactions are C∙∙∙H (13.1 %) and H∙∙∙C (10.7 %) which appear as two wings in the fingerprint plot together with Cl∙∙∙H (8.2 %) and H∙∙∙Cl (5.3 %). The two short narrow spikes pointing towards the bottom left of the plot (Figure 4) correspond to the N∙∙∙H (1.0 %) and H∙∙∙N (0.8 %). Oladipo et al. / European Journal of Chemistry 12 (2) (2021) 204-215 209 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.2.204-215.2088 Figure 5. Relative contributions to Hirshfeld surface area for various intermolecular contacts (H∙∙∙H, H∙∙∙Cl, H∙∙∙C, H∙∙∙N, C∙∙∙H, Cl∙∙∙H, Cl∙∙∙Cl and N∙∙∙H). (1) (2) (3) Figure 6. Optimized structures of compounds 1-3. 3.5. Density functional theory calculation 3.5.1. Frontier molecular orbital (FMO) analysis Before the FMO, a geometry optimization of the 3D structures of compounds 1-3 (Figure 6) was optimized to obtain a stable model energy suitable for reliable further DFT analysis. The orbitals crucial to reactivity are the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), they are simply called frontier orbitals [54]. Most often, the filled molecular orbital having the highest energy, HOMO and to the unoccupied orbital of the lowest energy, LUMO (Table 2 and Figure 7). Reactivity of compounds 1-3 revolves between the aromatic groups surrounding the nitrogen atom. The energy gaps are 3.47, 3.78 and 4.07 eV for compounds 1, 2, and 3, respectively. This suggests that compound 1 (small ΔE) depicts an easy transition while compounds 2 and 3 (larger ΔE) are more thermodynamically stable. Although it has been reported that electron donor groups elevate the energy value of both HOMO and LUMO levels as noticeable for compound 3 with substituted isopropyl [55]. Thus, causing the reduction of ΔE as a result of the destabilization of the HOMO orbital. Also, the HOMO orbital energy is a frozen orbital approximation according to Koopman’s theorem [56] as the minus of the ionization energy (IP) and the LUMO orbital energy is a Koopmans approximation to minus the electron affinity (EA) [57]. 3.5.2. Natural bond orbitals (NBO) analysis The NBO analysis results are presented in Table 3 with the calculated stabilization energies (E2) resulting from the interactions between donor and acceptor atoms [donor (𝑖𝑖) → acceptor (𝑗𝑗)]. This interaction can occur between occupied [for example, the lone-pair (LP)] and antibonding (BD*) orbitals, which represents the deviation of the molecule from the Lewis structure [58]. 210 Oladipo et al. / European Journal of Chemistry 12 (2) (2021) 204-215 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.2.204-215.2088 Table 2. Quantum descriptors of compounds 1-3. Parameters 1 2 3 HOMO -5.831 -5.578 -6.082 LUMO -2.364 -1.803 -2.009 Energy gap (ΔE) 3.467 3.775 4.073 Ionization potential (Ip) 5.831 5.578 6.082 Electron affinity (EA) 2.364 1.803 2.009 Dipole moment (Debye) 1.86 2.42 1.30 Table 3. NBO values of the contributing species in compounds 1-3 obtained from the second-order perturbation energies 𝐸𝐸2 [donor (𝑖𝑖) → acceptor (𝑗𝑗)]. Compound Donor (i) Acceptor (j) E2 (kcal/mol) 1 LP (1) N18 BD*(1) C19 - H20 15.18 LP (1)Cl31 BD*(1) C26 - C28 40.88 BD (2) C24 - C28 BD*(2) C23 - C26 33.14 BD (1) C5 - C6 BD*(1) C10 - C14 25.34 BD (1) C5 - C6 BD*(2) C1 - C2 17.88 2 LP (1) N18 BD*(1) C19 - H20 12.68 LP (2) O31 BD*(2) C26 - C28 26.42 BD (2) C1 - C2 BD*(2) C5 - C6 16.12 BD (1) C32 - H35 BD*(1) C32 - H35 171.31 BD (2) C26 - C28 BD*(2) C21 - C23 23.65 3 LP (1) N30 BD*(1) C31 - H32 13.40 LP (3)Cl43 BD*(2) C38 - C40 12.67 BD (2) C1 - C6 BD*(2) C4 - C5 20.96 BD (2) C38 - C40 BD*(2) C34 - C36 16.96 HOMO LUMO Figure 7. FMO (HOMO-LUMO) surfaces of compounds 1-3. The molecules under study comprise delocalized double, single bonds and electronegative atoms (O and N) capable of donating their lone pair of electrons for chemical bonding. Common to all, the nitrogen atom form hydrogen bonding with neighbouring atoms with significant perturbation energies of 15.18, 12.68, and 13.4 kcal/mol for compounds 1 and 2 (LP (1)N18 → σ*C19–H20) and 3 (LP (1)N30 → σ*C31–H32), respectively. In addition, intramolecular interactions resulting from π conjugation occurred in the aromatic rings. The contribution of a substituted methoxy at the para position of the phenyl of compound 2 donated more electron to the ring with E2 of 171.31 kcal/mol between (σ(1)C32-H35 → σ*C32–H35). 3.5.3. Molecular electrostatic potential surface Molecular electrostatic potential (MEP) is an approach used to visualize the charge distributions within compounds and charge related properties of compounds [59]. The most positive electrostatic potential regions are depicted in blue, red shows the areas with a smaller positive charge [60]. Besides, the regions with lone pairs atoms (N and aromatic rings) in all molecules showed negative electrostatic potential indicative of proton attraction by the concentrated electron density (red colour). However, the regions with blue color depict the positive electrostatic potential corresponds to the repulsion of the proton by the atomic nuclei in regions where low electron density (Figure 8) [61]. 3.5.4. Electronic spectra Compounds 1-3 in the study comprise several aromatic rings with conjugated double bonds. Thus, we expect strong π- π* transitions in the UV-Vis region having a high expansion coefficient. The electronic transitions spectra data and absorption maxima as generated in chloroform are presented in Table 4. The visible band is only seen for compound 1 around 402.21 nm (first excited state) and may be attributed to the high delocalization of π-electrons and the substituted chloride. The bands in the UV region around 381.91 and 373.61 nm for compounds 2 and 3, respectively. 3.5.5. 1H and 13C NMR chemical shifts The 1H and 13C NMR spectra for compounds 1-3 determined by B3LYP/ 6–31+G(d,p) in CDCl3 are presented in Table 5. The computational results obtained showed good agreement with the experimental. The 1H NMR theoretical chemical shift showed a linear correlation with the experimental. Oladipo et al. / European Journal of Chemistry 12 (2) (2021) 204-215 211 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.2.204-215.2088 Table 4. Calculated electronic transitions for compounds 1-3. Compound Excitations CI expansion coefficient Wavelength (nm) Oscillator strength (f) 1 Excited State 1 69 -> 70 0.70357 402.21 0.6336 Excited State 2 66 -> 70 0.70125 329.83 0.0002 Excited State 3 68 -> 70 0.5955 314.83 0.0298 2 Excited State 1 69 -> 70 0.69371 381.91 0.5453 Excited State 2 68 -> 70 0.49249 311.41 0.2619 Excited State 3 67 -> 70 0.52451 300.04 0.003 3 Excited State 1 80 -> 81 0.68878 373.61 0.1425 Excited State 2 79 -> 81 0.69976 312.16 0.0064 Excited State 3 78 -> 81 0.65192 277.75 0.7051 Table 5. Experimental and theoretical data (DFT/B3LYP) for the 1H and 13C NMR chemical shifts (ppm) for compounds 1, 2 and 3. 1H NMR Experimental (Theoretical), ppm 13C NMR Experimental (Theoretical), ppm 1 2 3 1 2 3 7.06 (6.96) 3.90 (3.96) 1.16 (0.93) 123.89 (120.10) 55.49 (23.22) 23.44 (22.98) 7.50 (7.05) 7.02 (7.22) 2.93 (2.56) 125.84 (122.10) 112.74 (110.11) 27.99 (28.32) 7.72 (7.53) 7.49 (7.69) 7.13 (7.23) 126.02 (124.32) 114.25 (111.13) 123.07 (122.03) 7.84 (7.77) 7.69 (7.79) 7.45 (7.56) 126.50 (124.33) 124.40 (119.69) 124.27 (122.21) 7.94 (7.79) 7.85 (7.93) 7.47 (7.61) 127.69 (126.90) 126.10 (124.86) 129.15 (126.23) 8.32 (8.02) 7.96 (8.06) 8.15 (8.30) 128.81 (126.96) 126.34 (125.20) 129.73 (128.60) 8.50 (8.22) 8.34 (8.44) 129.52 (127.20) 127.62 (125.99) 134.48 (135.19) 8.47 (8.70) 130.13 (128.42) 128.89 (126.58) 137.51 (136.00) 133.97 (130.92) 129.57 (126.86) 137.53 (136.42) 134.93 (132.48) 130.69 (128.68) 148.98 (149.23) 137.50 (134.36) 133.96 (130.99) 160.63 (159.99) 148.94 (141.93) 146.66 (144.42) 158.84 (151.02) 159.67 (158.63) 162.35 (160.60) Table 6. Antioxidant potential of tested compounds 1-3 at different concentrations using DPPH, ·OH, and FRAP assays. Compounds DPPH assay FRAP assay ·OH assay IC50 (mM) IC50 (mM) IC50 (mM) 1 141.32 35.55 27.96 2 89.17 28.44 27.97 3 130.24 48.28 38.84 Trolox 22.69 24.31 20.77 Figure 8. Contours of the molecular electrostatic potential of compounds 1-3. The correlation values R2 for compounds 1, 2 and 3 are 0.8359, 0.8566, and 0.7800, respectively, while for 13C the linear correlation values R2 are 0.934, 0.9010, and 0.9400. The deviation ranged from 0.01-0.78 ppm. The observed deviation is consistent with similar reports. 3.6. Antioxidant studies In this study, the antioxidant activity of the synthesized Schiff bases was evaluated in vitro by DPPH, Hydroxyl, and FRAP assay. 3.6.1. DPPH scavenging radical assay DPPH assay has been used extensively to determine the antioxidant activity of compounds by quantifying their free radical scavenging or hydrogen donor abilities [62]. DPPH has a stable free radical with an odd electron in its structure, and in the presence of antioxidants, the odd electron in DPPH paired up with proton radicals or an electron from antioxidants to form a stable diamagnetic compound [63]. During this process, the purple color of DPPH changed to yellow due to the formation of reduced DPP-H [63]. The IC50 values were used to evaluate the antioxidant activity of the compounds, and they were calculated from the % DPPH free radical scavenging ability i.e., a low IC50 value is proportional to good antioxidant activity. The results are summarized in Table 6 and were compared with the antioxidant activity of Trolox (22.69 mM) which were used as standard. The IC50 values of compounds 1- 3 are high when compared to the ones of Trolox (Table 6), and this indicates their poor free radical scavenging ability. 212 Oladipo et al. / European Journal of Chemistry 12 (2) (2021) 204-215 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.2.204-215.2088 Figure 9. % Free radical scavenging vs concentration (mM) of compounds 1-3. Figure 10. % Hydroxyl radical scavenging vs concentration (mM) of compounds 1-3. Figure 11. % Ferric reducing antioxidant power vs concentration (mM) of compounds 1-3. Compound 2 showed the highest antioxidant activity when compared to compounds 3 and 1, and this could be attributed to the presence of electron-donating methoxy substituent in compound 2, which has been previously reported to enhance the stability of radicals, and hence antioxidant property [64]. The antioxidant activity of compounds 1-3 increases as their concentration increase, as illustrated in Figure 9. The result presented here are the mean values from three independent experiments. 3.6.2. Hydroxyl scavenging radical assay The most reactive radical among the relative oxygen species (ROS) is the hydroxyl radical [63]. In an aqueous solution, it has a half-life less than 1 ns and reacts very close to its site of the formation when produced in vivo [65]. Hydroxyl radical, when produced close to molecules such as sugar, DNA bases, amino acids, phospholipids, etc. found in living systems, cells could react with them and might change their normal physiological function [3]. The results of the OH• radical stabilizing potential are summarized in Table 6 and followed the order of Trolox > 2 > 1 > 3. Compound 2 displayed moderate activity, whereas compounds 1 and 3 displayed weak antioxidant activity. None of the compounds was active when compared to Trolox (standard), and their activity increases as the concentrations also increase, Figure 10. 0 25 50 75 100 10 20 30 40 50 DD PH F re e ra di ca l s ca ve ng in g (% F RS ) Concentration (mM) 1 2 3 Trolox 0 25 50 75 100 10 20 30 40 50 Hy dr ox yl r ad ic al s ca ve ng in g (% H RS ) Concentration (mM) 1 2 3 Trolox 0 10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 Fe rr ic re du ci ng a nt io xi da nt p ow er (% F RA P) Concentration (mM) 1 2 3 Trolox Oladipo et al. / European Journal of Chemistry 12 (2) (2021) 204-215 213 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.2.204-215.2088 Table 7. Predicted physicochemical and pharmacokinetic properties of compounds 1-3. Properties / Compounds 1 2 3 Acceptable threshold (Ro5) Physicochemical properties Molecular weight (Da) 265.74 261.32 299.84 ˂500Da Log P 4.68 4.08 5.65 ˂5 Log S (mol/L) -5.05 -4.51 -5.70 0 → -6 TPSA (A2) 12.36 21.59 12.36 ≤140 HBA 1 2 1 ≤10 HBD 0 0 0 ≤5 Rotatable bonds 2 3 4 ˂10 Pharmacokinetics properties GI absorption High High Low BBB Permeant Yes Yes No P-gp Substrate No No No Log Kp (skin permeation) -4.46 -4.90 -3.80 Oral toxicity prediction LD50 (mol/kg) 2.051 2.111 2.613 AMES toxicity Yes Yes No 3.6.3. Ferric reducing antioxidant power assay The data obtained for the FRAP assay showed that all compounds exhibited ferric reducing antioxidant power. Compounds 1 and 2 showed almost the same antioxidant activity, while compound 3 showed the least activity (Table 6), and none of the compounds displayed better activity than Trolox. Similarly, the antioxidant activity is concentration- dependent; it increases as the concentration increases in Figure 11. 3.7. Analysis of drug likeness and pharmacokinetics of compounds 1-3 This study predicted the pharmacokinetics and pharma- cological properties of compounds 1-3 using web-based analytical tools, SwissADME and pKCSM to predetermine their drug-likeness and oral bioavailability. The predicted values for significant parameters are presented in Table 7. Lipinski’s Ro5 is used as a yardstick to know the violations of potential medicinal compounds from the standard and is expected to have minimal violations [66]. Parameters such as molecular weight (MW), lipophilicity (logP), tendency to be hydrogen bond acceptor (HBA) and donor (HBD), topological polar surface area (TPSA), rotatable bonds (Rots), skin permeation (Logkp), and lethal dose 50 % (LD50) were estimated and they are used to predict the extent of toxicity of these compounds when administered orally. Selected pharmacokinetic proper- ties such as blood-brain barrier (BBB), permeant P-glyco- protein (P-gp), and gastrointestinal (GI) absorption and substrate were also predicted. The molecular weight of compounds highly affects the rate at which drugs are absorbed into the body system. The smaller the MW of the drug, the easier they can access target bio- molecules, increasing concentration at the intestinal epithelium surface, thus enhancing absorption [67]. According to Lipinski’s Ro5, the acceptable MW of the active compound is ≤ 500 g/mol. The estimated values for all the compounds are within the threshold, indicating that they are bioavailable and orally active. The predicted LogP values for compounds 1 and 2 complied with Lipinski’s Ro5 (< 5), while compound 3 violated it. All compounds had estimated LogS values within the standard (0 – -6 mol/L). These findings revealed that the compounds are lipophilic, thus permeate easily through the intestinal epithelium surface. These inherent attributes further established their bioavailable as well as their potential use as future drugs. The TPSA could also be used to predict the bioavailability of compounds in terms of their transportation across a lipid bilayer membrane that is closely packed, such as the gastrointestinal tract (GT) and the blood-brain barrier (BBB) [68]. TPSA considers polar atoms on the surface of compounds, such as nitrogen and oxygen, together with their added hydrogens [69]. Compounds with lower TPSA values permeate easily through the cells when compared with those with high TPSA. The estimated TPSA values for all the compounds fall within the accepted value (≤ 140), indicating their ease to permeate through the cells, especially if they are subjected to further optimization [62]. Considering the estimations of HBAs, HBDs, and RotBs, we could predictively say compounds 1-3 are bioavailable and orally active. Rotatable bonds are single bonds, not in a ring, bound to a nonterminal heavy atom [70], and they give information about the molecular flexibility of potential drug compounds. All the compounds did not violate Lipinski’s Ro5 as the estimated RotBs values fell within the acceptable threshold (RotBs < 10). Lipinski’s Ro5 considers compounds with HBAs and HBDs counts of ≤5 and ≤10 to be orally active. Interestingly, all compounds had HBAs counts ≤10 with no HBDs counts, which correlate with the acceptable threshold. While developing an oral drug product, intestinal absorption must be sufficient to be successful [71]. Compounds 1 and 2 are predicted to exhibit high gastrointestinal absorption while compound 3 is low instead. These further establish compounds 1 and 2 to be bioavailable and orally active. All compounds except from compound 3 have the potential to permeate through the brain-blood barrier. The activity of P-gp in the intestine may reduce the oral bioavailability of P-gp substrate drugs [72]. All compounds are predicted not to displayed P-gp substrate properties, and this affirms their drug-likeness properties. The rate at which the compounds penetrate the skin is in the order of compounds 2 > 1 > 3. 4. Conclusion Schiff bases have been traditionally studied for biological properties for several decades. This study further stretches the limits of the potential application of Schiff bases and their application as antioxidant. The study reports the synthesis of three Schiff base compounds and elucidated using NMR, FT-IR, UV-Visible spectroscopic techniques and single-crystal X-ray diffraction measurements. The free radical scavenging properties of all three compounds were studied using DPPH, FRAP, and OH assays. Compared with the historical experi- mental work on this class of compounds, theoretical studies of correlating structural and spectroscopic properties have just begun to emerge. The DFT calculations employed the B3LYP function with 6-31+G(d,p) basis set for all atoms to obtain an optimized geometrical structure, electronic and natural bond orbital (NBO) analysis. Several theoretical parameters such as frontier molecular orbital, electrostatic potential analysis, nuclear magnetic resonance, Hirshfeld Surface Analysis, drug likeness, and pharmacokinetics analysis of the compounds are reported to further give a theoretical insight into the properties of the compounds. 214 Oladipo et al. / European Journal of Chemistry 12 (2) (2021) 204-215 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.2.204-215.2088 Acknowledgements The authors would like to thank the College of Agriculture, Science, and Engineering, the University of Kwazulu-Natal and the Center for High-Performance Computing (CHPC), South Africa for providing computational resources. Dr. Tunde Lewis Yusuf is grateful to Faculty of Science (FRC/URC) postdoctoral support, University of Johannesburg, South Africa. Supporting information CCDC-2058763 contains the supplementary crystallo- graphic data for this paper. These data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/, or by e- mailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033. Disclosure statement Conflict of interests: The authors declare that they have no conflict of interest. Author contributions: All authors contributed equally to this work. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the author. ORCID Segun Daniel Oladipo https://orcid.org/0000-0003-2489-1752 Tunde Lewis Yusuf https://orcid.org/0000-0003-3419-9516 Sizwe Joshua Zamisa https://orcid.org/0000-0003-1968-381X Gideon Femi Tolufashe https://orcid.org/0000-0002-0852-9756 Kolawole Ayodapo Olofinsan https://orcid.org/0000-0002-2987-0996 Zikhona Tywabi-Ngeva https://orcid.org/0000-0002-5290-6942 Nonhlangabezo Mabuba https://orcid.org/0000-0003-0209-7451 References [1]. Kerr, M. E.; Bender, C. M.; Monti, E. J. Heart Lung 1996, 25 (3), 200– 209. [2]. Oladipo, S. D.; Omondi, B.; Mocktar, C. Polyhedron 2019, 170, 712–722. [3]. Valko, M.; Leibfritz, D.; Moncol, J.; Cronin, M. T. D.; Mazur, M.; Telser, J. Int. J. Biochem. Cell Biol. 2007, 39 (1), 44–84. [4]. Hertog, M. G.; Feskens, E. J.; Hollman, P. C.; Katan, M. B.; Kromhout, D. Lancet 1993, 342 (8878), 1007–1011. [5]. Aziz, A. N.; Taha, M.; Ismail, N. H.; Anouar, E. H.; Yousuf, S.; Jamil, W.; Awang, K.; Ahmat, N.; Khan, K. M.; Kashif, S. M. 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The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. Materials 2.2. Instrumentation 2.3. Synthesis of the Schiff base ligands 2.3.1. Synthesis of 1-(4-chlorophenyl)-N-(naphthalen-1-yl)methanimine (1) 2.3.2. Synthesis of 1-(4-methoxyphenyl)-N-(naphthalen-1-yl)methanimine (2) 2.3.3. Synthesis of 1-(4-chlorophenyl)-N-(2,6-diisopropyl phenyl)methanimine (3) 2.4. Single-crystal X-ray diffraction 2.5. Density functional theory calculation 2.6. In vitro antioxidant studies 2.6.1. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay 2.6.2. Ferric reducing antioxidant power 2.6.3. Hydroxyl radical (OH•) scavenging activity 3. Results and discussion 3.1. General synthesis 3.2. Spectroscopy studies 3.2.1. Nuclear magnetic resonance 3.2.2. Fourier transform infra-red and electronic absorption spectroscopy 3.3. X-ray crystal structure 3.4. Hirshfeld surface analysis 3.5. Density functional theory calculation 3.5.1. Frontier molecular orbital (FMO) analysis 3.5.2. Natural bond orbitals (NBO) analysis 3.5.3. Molecular electrostatic potential surface 3.5.4. Electronic spectra 3.5.5. 1H and 13C NMR chemical shifts 3.6. Antioxidant studies 3.6.1. DPPH scavenging radical assay 3.6.2. Hydroxyl scavenging radical assay 3.6.3. Ferric reducing antioxidant power assay 3.7. Analysis of drug likeness and pharmacokinetics of compounds 1-3 Acknowledgements Supporting information Disclosure statement ORCID References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField18: PrintField19: PrintField110: PrintField111: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: PrintField28: PrintField29: PrintField210: PrintField211: