Synthesis, crystal structure, and antidiabetic property of hydrazine functionalized Schiff base: 1,2-Di(benzylidene)hydrazine European Journal of Chemistry 13 (2) (2022) 234-240 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2022 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.13.2.234-240.2265 European Journal of Chemistry View Journal Online View Article Online Synthesis, crystal structure, and antidiabetic property of hydrazine functionalized Schiff base: 1,2-Di(benzylidene)hydrazine Nilankar Diyali , Meena Chettri , Abhranil De and Bhaskar Biswas * Department of Chemistry, University of North Bengal, Darjeeling, 734013, India * Corresponding author at: Department of Chemistry, University of North Bengal, Darjeeling, 734013, India. e-mail: bhaskarbiswas@nbu.ac.in (B. Biswas). 10.5155/eurjchem.13.2.234-240.2265 Received: 10 March 2022 Received in revised form: 17 April 2022 Accepted: 27 April 2022 Published online: 30 June 2022 Printed: 30 June 2022 Hydrazine functionalized Schiff base, 1,2-di(benzylidene)hydrazine has been synthesized through a condensation between hydrazine and benzaldehyde under reflux, and structurally characterized. The crystal structure analysis reveals that the Schiff base crystallizes in an orthorhombic crystal system with the Pbcn space group. Crystal data for C14H12N2: a = 13.130(2) Å, b = 11.801(2) Å, c = 7.5649(16) Å, V = 1172.1(4) Å3, Z = 4, T = 298.0(2) K, μ(MoKα) = 0.071 mm-1, Dcalc = 1.180 g/cm3, 10252 reflections measured (6.206° ≤ 2Θ ≤ 65.352°), 2027 unique (Rint = 0.0381, Rsigma = 0.0283) which were used in all calculations. The final R1 was 0.0627 (I > 2σ(I)) and wR2 was 0.2462 (all data). It is evident that the imine protons are intramolecularly locked with the imine-N bond, and the phenyl rings exist in anti orientation with respect to the =N-N= bond adopting a nearly planar conformation. The Schiff base grows a one-dimensional framework in the crystalline phase through long- distant C-H···π interaction. Hirshfeld surface and energy framework analyses have also been performed to understand the supramolecular forces and their contributions meticulously. The hydrazine functionalized Schiff base showed an excellent antidiabetic activity through α-amylase inhibitory assay relative to a standard compound, acarbose under an identical condition. Synthesis Hydrazine Schiff base Antidiabetic activity X-ray crystal structure Structural characterization Cite this: Eur. J. Chem. 2022, 13(2), 234-240 Journal website: www.eurjchem.com 1. Introduction Hydrazine-containing compounds have gained the utmost importance as they serve as a fundamental unit in the areas of pharmaceuticals [1], agrochemicals [2], a precursor to poly- merization catalysts [3,4], fuel [5,6], chemosensors [7], etc. The expanding research on the hydrazine-based molecule is evident from the world hydrazine market value which is US$424 million in 2020 as per the report by Future Market Insight (FMI) and in 2021 the value surpassed US$426 million [8]. On the verge of the development of efficient hydrazine-based materials, many functionalizations have been achieved [9-12]. The functiona- lization of hydrazine improves the efficiency of the materials and may create new properties in it. Among various functiona- lizations, one with Schiff base is trending due to the diverse properties of Schiff base including antibacterial [13,14], anti- fungal [15-17], antioxidant [18-20], antiviral [21], antitumor [22], anti-inflammatory [23,24], biomimics [25], luminescence [26] and catalytic activity [27-29]. A brief literature survey shows that Biswas et al. has successfully designed a Schiff base functionalized with hydrazine and employed it for the synthesis of nanoaggregates that showed blue emission properties [30]. Additionally, Roy et al. developed an analogue of hydrazine- functionalized Schiff base and used it for cascade sensing for fluoride and bisulphate [7]. On the other hand, the tremendous rise in the field of pharmaceutical and medicinal chemistry has drawn the attention of researchers toward the formulation of efficient drugs even for the treatment of diseases as complex as diabetes mellitus. Diabetes mellitus, one of the global health issues, is due to irregular insulin production that can lead to a series of other diseases. Recently, functionalized Schiff bases are found to be a promising candidate in this field [31]. In various studies conducted to investigate insulin-mimetic properties, hydrazine derivatives of Schiff base have some interesting results, for example, Szklarzewick's group showed the antidiabetic potentiality of a Schiff base [32]. In this context, we report the synthesis, crystal structure, Hirshfeld surface, and energy framework analysis of novel hydrazine functiona- lized Schiff base. We have also evaluated the antidiabetic activity of the prepared Schiff base by α-amylase inhibitory assay. 2. Experimental 2.1. Instrumentations The percentage contribution of the elements of the Schiff base was determined on a Perkin Elmer 2400 CHN Elemental Analyzer. ABSTRACT RESEARCH ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.13.2.234-240.2265 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.13.2.234-240.2265 mailto:bhaskarbiswas@nbu.ac.in http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.13.2.234-240.2265&domain=pdf&date_stamp=2022-06-30 Diyali et al. / European Journal of Chemistry 13 (2) (2022) 234-240 235 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.234-240.2265 Table 1. Crystal data and structure refinement for the Schiff base. Empirical formula C14H12N2 Formula weight 208.26 Temperature (K) 298.0(2) Crystal system Orthorhombic Space group Pbcn a, (Å) 13.130(2) b, (Å) 11.801(2) c, (Å) 7.5649(16) Volume (Å3) 1172.1(4) Z 4 ρcalc (g/cm3) 1.180 μ (mm-1) 0.071 F(000) 440.0 Crystal size (mm3) 0.5 × 0.14 × 0.09 Radiation MoKα (λ = 0.71073) 2Θ range for data collection (°) 6.206 to 65.352 Index ranges -9 ≤ h ≤ 18, -15 ≤ k ≤ 15, -10 ≤ l ≤ 8 Reflections collected 10252 Independent reflections 2027 [Rint = 0.0381, Rsigma = 0.0283] Data/restraints/parameters 2027/0/73 Goodness-of-fit on F2 1.007 Final R indexes [I≥2σ (I)] R1 = 0.0627, wR2 = 0.1795 Final R indexes [all data] R1 = 0.1270, wR2 = 0.2462 Largest diff. peak/hole (e.Å-3) 0.15/-0.18 N N C C H2N NH2 Ethanol Reflux O H H H + Scheme 1. Synthetic procedure of the compound. An FTIR-8400S Shimadzu spectrophotometer was employed to record the infrared spectrum (KBr) in the range of 400-3600 cm–1. The UV-Vis spectrum of the synthetic compound was measured on a Hitachi U2910 spectrometer. 2.2. Synthesis High purity hydrazine monohydrate (Merck, India) and benzaldehyde (SRL, India) were obtained from commercial sources and used as received. All the reagents and solvents were of analytical grade. Hydrazine monohydrate (0.032 g, 1 mM) was refluxed with benzaldehyde (0.212 g, 2 mM) in a 1:2 stoichiometric ratio in 30 mL of ethanol. The reaction mixture was filtered and upon slow cooling of the reaction, the solution produced suitable colourless crystals. The crystals were collected and washed with n-hexane. Further, the crystals were dried and kept over silica gel indicator for subsequent uses (Scheme 1). Yield: 0.188 g (~90%). Anal. calcd. for C14H12N2: C, 80.74; H, 5.81; N, 13.45. Found: C, 80.71; H, 5.85; N, 13.52. IR (KBr, ν, cm-1): 1614, 1587 (C=N). UV-Vis (λmax, nm): 227, 254. 2.3. Single crystal X-ray diffraction study Single crystal X-ray diffraction data were recorded with a Rigaku XtaLABmini diffractometer on a Mercury375R (2×2 bin mode) CCD detector using a graphite monochromated MoKα radiation (λ = 0.71075 Å) at 293(2) K using ω scans. The data were reduced and the space group was determined by Crystal- clear suite [33] and OLEX2, respectively [34]. The structure was resolved and refined by full-matrix least-squares procedures with SHELXL-97 [35] and OLEX2 suite [34] (Table 1). 2.4. Hirshfeld surface and energy framework analysis Hirshfeld surface and 2D fingerprint plots were generated by Crystal Explorer 17.5 program [36,37]. The energy framework analysis of the synthetic Schiff base was pursued with Crystal Explorer software with B3LYP/6-31G(d,p) basis sets using TONTO software for the cluster environment of 3.8 Å surrounding a particular molecule of interest [38]. The total interaction energy is articulated as Etot = keleE´ele + kpolE´pol + kdispE´disp + krepE´rep, where the k values belong to the scale factors for benchmarked energy models. E´ele represents the electrostatic energy, E´pol represents the polarization energy, E´disp represents the dispersion energy, and E´rep represents the repulsive energy. 2.5. Antidiabetic study The antidiabetic study of the synthetic Schiff base was carried out following a review of the literature [39]. The reaction mixture was prepared by adding 25 mL of sample solution (100-400 µg/mL), 50 μL of α-amylase (10 µ/mL) solution in phosphate buffer (pH = 6.9) and 50 µL of starch solution (0.05%). The reaction was stopped by adding 25 μL of 1 M HCl followed by adding up 100 mL of iodine-potassium iodide solution. The solution mixture was incubated for 10 min at 37 °C followed by measuring the absorbance at 630 nm. Acarbose was used as a positive control. The following formula was used to calculate the α-amylase inhibitory activity. % Inhibitory activity = [(A0 - A1)/A0]×100 (1) A0 = Absorbance of the control and A1 = Absorbance of the test samples. After determining the α-amylase inhibitory activity of the different concentrations, the IC50 values were determined for the acarbose and samples. 3. Results and discussion 3.1. Synthesis The hydrazine functionalized compound was synthesized by condensing hydrazine with benzaldehyde under reflux in ethanol. 236 Diyali et al. / European Journal of Chemistry 13 (2) (2022) 234-240 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.234-240.2265 Table 2. Bond distances, bond angles and torsion angles for the Schiff base. Bond distances Atom Atom Length (Å) Atom Atom Length (Å) N1 N11 1.419(3) C7 C6 1.376(3) N1 C1 1.265(2) C3 C4 1.382(3) C2 C1 1.464(2) C6 C5 1.368(3) C2 C7 1.388(2) C4 C5 1.375(3) C2 C3 1.391(2) Bond angles Atom Atom Atom Angle (°) Atom Atom Atom Angle (°) C1 N1 N11 112.93(17) C6 C7 C2 120.22(18) C7 C2 C1 121.72(16) C4 C3 C2 120.58(18) C7 C2 C3 118.58(17) C5 C6 C7 120.83(18) C3 C2 C1 119.69(15) C5 C4 C3 119.90(19) N1 C1 C2 122.51(16) C6 C5 C4 119.9(2) Torsion angles Atom Atom Atom Atom Angle (°) Atom Atom Atom Atom Angle (°) N1 i N1 C1 C2 179.43(14) C1 C2 C7 C6 -179.07(17) C1 N1 N1 i C1 i 180.00(15) C3 C2 C7 C6 -0.4(2) N1 C1 C2 C3 178.99(16) C2 C3 C4 C5 0.6(3) N1 C1 C2 C7 -2.3(3) C3 C4 C5 C6 -0.9(3) C1 C2 C3 C4 178.79(17) C4 C5 C6 C7 0.6(3) C7 C2 C3 C4 0.0(3) C5 C6 C7 C2 0.1(3) i Symmetry code: 1-x, 1-y, 1-z. Table 3. Geometrical parameters of C-H···π interactions (Å, °) are involved in the supramolecular construction. D = Donor, A = Acceptor (Å, °). D–H···A (Å) d(D-H) d(H···A ) d(D···A ) ∠ D–H···A Symmetry C(3)-H(3)···Cg(1) 0.95 2.96 3.91 143 3/2-x, 1/2-y, -1/2+z Figure 1. ORTEP diagram of the Schiff base (1) i: 1-x, 1-y, 1-z. Upon slow cooling of the hot ethanolic reaction mixture, suitable crystals were obtained. The crystals were diffracted with the X-ray diffraction technique. The composition was established by spectral analysis and X-ray crystallography. The synthetic scheme is given by Scheme 1. 3.2. Crystal structure and supramolecular interactions The crystal structure analysis of the Schiff base reveals that the synthetic compound exists in an orthorhombic crystal lattice with the Pbcn space group. An ORTEP diagram of the asymmetric unit is shown in Figure 1. The crystallographic refinement parameters for the Schiff base are summarized in Table 1 and the bond angles and distances are presented in Table 2. The crystal structure analysis shows that the hydrazine functionalized Schiff bases exist in a locked state with strong intramolecular H-bonded interactions and adopt anti- conformation (Figure 1). In the asymmetric unit, the azomethine bond distance between C1 and N1 atoms was found to be 1.265(2) Å while the N1-N11 bond distance value was marked as 1.419(3) Å. The bond distance values corroborate a pure double and single bond character for C1-N1 and N1-N1a bonds, respectively (Table 2) [40]. Further, the bond angles C2- C1-N1 and C1-N1-N1i (i: 1-x, 1-y, 1-z) are estimated as 122.51(16) and 112.93(17)° attributing to the planarity of the asymmetric unit in the crystalline phase [41]. The measure- ment of torsion angles further supports the planar geometry of the molecule (Table 2). The role of supramolecular interactions is also assessed for the construction of a long-range architecture. It is revealed that the Schiff base functionalized with hydrazine develops a one-dimensional supramolecular framework through long-distant C–H···π interactions [42] (Figure 2, Table 3). In the formation of the long-range supramolecular architecture, the azomethine-N of the synthetic Schiff base involves very little interaction in the intermolecular hydrogen bonding as it is intramolecularly locked with imine- proton while the phenyl-H contributes to a great extent through C–H···π interactions. Figure 2. Stacking of asymmetric units through weak C-H···π interactions. Diyali et al. / European Journal of Chemistry 13 (2) (2022) 234-240 237 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.234-240.2265 All, 100% H···H, 50.1% C···H/H···C, 38.6% N···H/H···N, 9.2% Figure 3. 2-Dimensional fingerprint plot of the main intermolecular interactions in the crystal structure of the title compound. Dispersive energy Coulombic energy Total energy Figure 4. Energy framework diagrams for title compound, showing their respective type of energies. The role of C-H···π interaction in the supramolecular framework was also confirmed by Hirshfeld surface analysis (Figure 3). It is observed that N···H hydrogen bonding only makes 9.2% and C-H···π interactions cover 22.1% of the total surface area in the long-range architecture for the synthetic Schiff base. Other non-classical interactions were not significant as evidenced by the Hirshfeld 2D fingerprint plots (Figure 3). Further, the energy framework analysis suggests that the dispersive force (-92.0 kJ/mol) made a significant contribution to the overall framework energy diagram of the Schiff base (Figure 4). C-H···π interactions remain the origin to cause the dispersive force in the supramolecular framework (Table 4). 238 Diyali et al. / European Journal of Chemistry 13 (2) (2022) 234-240 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.234-240.2265 Table 4. Energy framework detail of interaction with symmetry operations (symop) and distances between molecular centroids (R). Color N Symop R Electron density Eele Epol Edis Erep Etot 4 x+1/2, -y+1/2, -z 8.83 B3LYP/6-31G(d,p) -2.7 -0.8 -15.6 8.9 -11.5 2 x, y, z 13.13 B3LYP/6-31G(d,p) 0.2 -0.2 -8.8 0.0 -7.6 2 -x, y, -z+1/2 13.66 B3LYP/6-31G(d,p) -0.4 -0.2 -6.0 0.0 -5.8 2 -x, y, -z+1/2 13.66 B3LYP/6-31G(d,p) 0.8 -0.1 -3.2 0.0 -2.0 4 -x+1/2, -y+1/2, -z+1/2 9.60 B3LYP/6-31G(d,p) -3.8 -0.5 -15.3 6.2 -13.9 2 -x, y, -z+1/2 3.78 B3LYP/6-31G(d,p) -5.8 -2.0 -43.1 28.3 -27.6 Total -11.7 -3.8 -92.0 43.4 -68.4 * Interaction energies (kJ/mol), R is the distance between molecular centroids (mean atomic position) in Å., Total energies, only reported for two benchmarked energy models, are the sum of the four energy components. Table 5. α-Amylase inhibitory activity of acarbose and Schiff base. Sample Concentration (µg/mL) % Inhibition Acarbose 100 79.98 ±2.29 200 83.87±0.29 300 85.78±0.37 400 94.24±1.74 Schiff base 100 66.98±1.37 200 70.40±0.45 300 78.70±2.29 400 85.12±0.44 3.3. Antidiabetic study The antidiabetic activity of the synthetic compound was evaluated in a dose-dependent manner. For the treatment of diabetes mellitus, inhibitory action on carbohydrate digesting enzymes like α-amylase and α-glucosidase is preliminary. Conventionally used starch iodine method for α-amylase inhibitory activity making use of the synthetic Schiff base has some intriguing results. The dose-dependent α-amylase inhibition assay (Table 5) reveals that on an average ~75% inhibition activity is found for the synthetic Schiff base. Acarbose is used as a standard antidiabetic agent which showed a slightly higher ~86% inhibition activity [43-45]. The IC50 values for the synthetic Schiff base and acarbose are also determined to be 74.67 and 62.05 µg/mL, respectively. The IC50 values are comparable and express the potential capacity of the synthetic Schiff base to turn out as an excellent anti-diabetic agent. 4. Conclusions We have reported a straightforward synthesis of a hydrazine-functionalized Schiff base and its structural characterization with spectroscopy and X-ray crystallography. Crystal structure analysis suggested that the Schiff base adopts a nearly planar structure with an anti-orientation of phenyl rings with respect to =N-N= linkage. More interestingly, the imine-Hs are locked with the N-atom of the azomethine group attributing a hindrance to the excited state electron transfer phenomenon. Moreover, the asymmetric unit of the Schiff base displays the formation of a 1D supramolecular framework through long-distant C-H···π interactions in crystallizing phase. The significant contribution of C-H···π interactions for the long- range crystalline framework of the synthetic Schiff base was evidenced by the 22.1% coverage of the Hirshfeld surface and the estimated dispersive force, -92.0 kJ/mol to the overall energy of the Schiff base (-68.4 kJ/mol). The synthetic Schiff- based showed an excellent α-amylase inhibition activity. The comparable IC50 value of the Schiff base relative to the standard antidiabetic agent, acarbose holds a great promise for designing a cost-effective antidiabetic agent. Supporting information CCDC-2157622 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/, 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 interest: The authors declare that they have no conflict of interest. Ethical approval: All ethical guidelines have adhered to. Sample availability: Samples of the compounds are available from the author. CRediT authorship contribution statement Conceptualization: Bhaskar Biswas Methodology: Nilankar Diyali, Meena Chettri Software: Nilankar Diyali; Validation: Bhaskar Biswas Formal Analysis: Nilankar Diyali, Meena Chettri, Abhranil De Investigation: Bhaskar Biswas, Nilankar Diyali, Meena Chettri Resources: Abhranil De, Bhaskar Biswas; Data Curation: Bhaskar Biswas Writing - Original Draft: Bhaskar Biswas Writing - Review and Editing: Bhaskar Biswas; Visualization: Bhaskar Biswas. https://www.ccdc.cam.ac.uk/structures/ mailto:data_request@ccdc.cam.ac.uk mailto:data_request@ccdc.cam.ac.uk Diyali et al. / European Journal of Chemistry 13 (2) (2022) 234-240 239 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.234-240.2265 ORCID and Email Nilankar Diyali nilankardiyali02@gmail.com https://orcid.org/0000-0002-1064-8308 Meena Chettri chettrimeena78@gmail.com https://orcid.org/0000-0003-2821-8880 Abhranil De abhranilde@gmail.com https://orcid.org/0000-0002-6131-2548 Bhaskar Biswas bhaskarbiswas@nbu.ac.in icbbiswas@gmail.com https://orcid.org/0000-0002-5447-9729 References [1]. 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Basic principles of organic chemistry; 2nd ed.; Benjamin-Cummings Publishing Co., Subs. of Addison Wesley Longman: Reading, PA, 1977. mailto:nilankardiyali02@gmail.com https://orcid.org/0000-0002-1064-8308 mailto:chettrimeena78@gmail.com https://orcid.org/0000-0003-2821-8880 mailto:abhranilde@gmail.com https://orcid.org/0000-0002-6131-2548 mailto:bhaskarbiswas@nbu.ac.in mailto:icbbiswas@gmail.com https://orcid.org/0000-0002-5447-9729 https://finance.yahoo.com/%20news/hydrazine-hydrate-market-worth-us-180000622.html https://finance.yahoo.com/%20news/hydrazine-hydrate-market-worth-us-180000622.html https://www.researchgate.net/%20publication/346728834_synthesis_and_anti-inflammatory_activity_study_of_schiff_bases_complexes https://www.researchgate.net/%20publication/346728834_synthesis_and_anti-inflammatory_activity_study_of_schiff_bases_complexes https://www.researchgate.net/%20publication/346728834_synthesis_and_anti-inflammatory_activity_study_of_schiff_bases_complexes 240 Diyali et al. / European Journal of Chemistry 13 (2) (2022) 234-240 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.234-240.2265 [41]. 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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. Instrumentations 2.2. Synthesis 2.3. Single crystal X-ray diffraction study 2.4. Hirshfeld surface and energy framework analysis 2.5. Antidiabetic study 3. Results and discussion 3.1. Synthesis 3.2. Crystal structure and supramolecular interactions 3.3. Antidiabetic study 4. Conclusions Supporting information Disclosure statement CRediT authorship contribution statement ORCID and Email References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: