Surface functionalization of chitosan with 5-nitroisatin

Journal Pre-proof Surface functionalization of chitosan with 5-nitroisatin

Marjan Nasrabadi, S. Ali Beyramabadi, Ali Morsali PII:

S0141-8130(19)37830-4

DOI:

https://doi.org/10.1016/j.ijbiomac.2020.01.070

Reference:

BIOMAC 14374

To appear in:

International Journal of Biological Macromolecules

Received date:

26 September 2019

Revised date:

21 December 2019

Accepted date:

6 January 2020

Please cite this article as: M. Nasrabadi, S.A. Beyramabadi and A. Morsali, Surface functionalization of chitosan with 5-nitroisatin, International Journal of Biological Macromolecules(2018), https://doi.org/10.1016/j.ijbiomac.2020.01.070

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© 2018 Published by Elsevier.

Journal Pre-proof

Surface functionalization of chitosan with 5-nitroisatin

Marjan Nasrabadi a, S. Ali Beyramabadi a,b,*, Ali Morsali a,b Department of Chemistry, Mashhad Branch, Islamic Azad University, Mashhad, Iran

b

Research Center for Animal Development Applied Biology, Mashhad Branch, Islamic Azad

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a

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University, Mashhad 917568, Iran

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na

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*e-mail: [email protected]; [email protected].

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Journal Pre-proof ABSTRACT Several possible configurations (CS/NI1-10) for the surface adsorption of 5-nitroisatin (NI) on the chitosan polymer (CS) were investigated using quantum mechanical methods in the gas and solution phases. The values of the binding energies indicate the energetic stability of these configurations. The solvation energies demonstrate that the solubility of NI and CS increases in the presence of each other. The role of hydrogen bonds in noncovalent surface functionalization

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was determined by AIM analysis. The mechanism of covalent surface functionalization and the

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explicit solvent effects (methanol) in this mechanism were investigated and it was determined

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that the covalent functionalization through Schiff base formation is possible. These findings, in

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addition to the biological applications of the chitosan Schiff bases and their complexes, led us to

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synthesize a new Schiff base from condensation reaction of CS and NI (CSB) together with its Ni(II) and Cu(II) complexes. The synthesized compounds were characterized by the elemental

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analysis, infrared spectroscopy (IR), thermogravimetry analysis (TGA) and differential scanning

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calorimetry (DSC). Also, optimized geometries, assignment of the IR vibrational bands as well as exploring of the frontier orbitals of the synthesized compounds have been calculated using

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density functional levels of theory.

Keywords: Chitosan; Schiff base; 5-nitroisatin; DFT; Surface adsorption; Mechanism

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1. Introduction Chitosan and its derivatives, in the form of films, gel, beads, solutions, fibers and powder, have been widely used in bio- medical, heavy metal removal, drug delivery systems, biosensors and health-care areas because of their properties such as non-toxicity, biocompatibility, renewability, biodegradability, low-allergenicity, high permeability, hydrogen bond formation via -OH and NH2 functional groups, controlled drug release, cationic nature, muco-adhesion and

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antimicrobial activity, many of which are related to the primary amino group [1-6]. Chitosan

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was used as carrier for different therapeutic agents such as cisplatin [7], 5-fluorouracil [8],

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methotrexate [9], doxorubicin [10], melphalan [11], paclitaxel [12], capecitabine [13] and

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gemcitabine [14]. Chitosan was also utilized against bacteria [15, 16], HIV [17], Alzheimer’s

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disease [18] and inflammation [19].

In addition to the noncovalent surface functionalization of chitosan, the covalent surface

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functionalization has also been used in many cases. Due to the amino and hydroxyl groups

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peripherally attached to the chitosan surface, many derivatives of the chitosan were synthesized. Condensation reaction between the amino groups of the chitosan with the aldehydes and ketones

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results in the formation of chitosan Schiff bases [20, 21]. The chitosan Schiff bases and their complexes have shown significant biological activities such as antibacterial [22, 23], antimicrobial [20, 24, 25] antifungal [26], anticancer [21] and anticoagulant [27]. They were also used in drug delivery [21, 28, 29]. The Schiff bases account as significant ligands in coordination chemistry, too. In many cases, coordination to metal ions improves biological properties of the Schiff bases [30-32].

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Journal Pre-proof Various analytical [21, 33] and catalytic [34-37] applications of the chitosan Schiff bases have been reported, important of which are remove of heavy metals from aqueous medium [38], corrosion inhibition of mild steel in acid medium [39, 40], antifogging properties in food packaging [41] and lubricant additive [42]. Surface functionalization can be analyzed by quantum chemical computations [43-51]. In this work, quantum computing was used to study the noncovalent and covalent functionalization of

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chitosan with 5-nitroisatin (NI). NI shows significant biological activities, such as anticancer,

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antimicrobial, anti-HIV, tuberculostatic, cytotoxic, antimalarial, antileishmanial and

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anticonvulsant, making it suitable for pharmaceutical applications [52-59]. NI has several active

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functional groups that can form intermolecular hydrogen bonds with biomaterials and carriers

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such as chitosan (noncovalent functionalization) and, in appropriate conditions, NI may form covalent bonds through chemical reactions (covalent functionalization).

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These theoretical predictions encouraged us to synthesize a new Schiff-base derived from the

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chitosan and NI (CSB) as well as its Ni(II) and Cu(II) complexes. Several experimental and

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theoretical methods were employed for the investigation of optimized geometries, spectral properties and Natural Bond Orbital (NBO) analysis of the synthesized compounds.

2. Computational Details For the evaluation of binding and solvation energies, the geometries of all species in solution and gas phases were optimized at B3LYP/6-31G(d,p) and M06-2X/6-31G(d,p) by GAUSSIAN 09 package [60]. Polarized continuum model (PCM) was utilized to consider the implicit solvent effects (methanol) [61]. For the optimization of geometries, the standard convergence criteria were employed. All degrees of freedom for all configurations were optimized. In addition, zero4

Journal Pre-proof point corrections were taken into account. All species involved in the covalent functionalization mechanism were optimized at B3LYP/6-31G(d,p) in solution phase. The transition states were examined to have only one imaginary frequency of the Hessian. Usually, the DFT-computed vibrational frequencies are higher than the experimental ones, which were improved by using a scale factor of 0.9614 [62]. In order to achieve a balance between computational cost and acceptable accuracy for large systems, double-zeta plus polarization basis set (6-31G(d,p)) was

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used for C, O, N and H atoms [63, 64]. LANL2DZ basis set with effective core potential (ECP)

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functions was used for Ni and Cu atoms because it takes into account relativistic effects [65, 66].

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The quantum theory of atoms in molecules (QTAIM) calculations have been used for the examination of hydrogen bonds. QTAIM calculations were done by the AIMALL software [67].

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QTAIM is based on topological quantities such as electron density ρ(r) [68]. We have used

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electron density parameters such as Vb (potential energy density), Gb (kinetic energy density), Hb

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(total energy density) and ∇2ρ (Laplacian of electron density) at a critical point (BCP) to specify the nature of the bonds in different configurations.

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Quantum molecular descriptors can be utilized to estimate chemical reactivity and stability. The

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global hardness (  ) [69] and the electrophilicity index (  ) [70] have been calculated by Eqs (1) and (2), respectively : -

(1) (2)

where I  E HOMO and A  E LUMO are the ionization potential and the electron affinity, respectively.

3. Experimental Details

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Journal Pre-proof The chitosan and 5-nitroisatin were prepared from the Sigma-Aldrich company. The used metal salts and solvents were prepared from the Merck Company. Melting points of the compounds have been obtained by using a Stuart SMP3 melting point apparatus. The IR spectra have been recorded on a Bruker Tensor 27 spectrophotometer by employing the KBr disks. The CHN elemental analyses have been carried out by using a Heraeus elemental analyzer CHN-O-Rapid. Percentage of the metal ions in structure of the synthesized complex have been determined by

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using a Hitachi 2-2000 atomic absorption spectrophotometer.

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The TG analyses were carried out on a TGA-50 SHIMADZU analyzer. The samples were heated

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from 25 to 950 °C under air atmosphere with 10 °C/min heating rate. A platinum crucible was

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used as sample container. The Differential Scanning Calorimetry (DSC) analysis was carried out using a DSC100-L device of the Nanjing Dazhan Institute of Electrochemical Technology. 13

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mg of the sample was placed into aluminum cup and sealed. The samples were heated in 25-600

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°C range and analyzed under continuous flow of dry N2 gas at a heating rate of 10 °C.min-1. 3.1 Synthesis of the CSB Schiff base

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1 g of chitosan was stirred in 5 mL methanol for 5 hours at reflux condition. Then, a solution of

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0.5 g of 5-nitroisatin in 5 mL methanol was added to the chitosan solution. The mixture was refluxed for 12 hours. The obtained yellow precipitate was filtered off and washed with ethanol to give the CSB Schiff base (Decomposed at 220.1 ℃, yield: 65 %). 3.2 Synthesis of the complexes A mixture of 1 g of the CSB Schiff base in 10 mL methanol has been stirred for 4 hours at 40 ℃. Then, a solution of 0.4 g of the CuCl2.2H2O in 5 mL methanol was added dropwise to solution of the CSB Schiff base. The reaction mixture was stirred for 8 h at 40 ℃ to produce the Cu(II) 6

Journal Pre-proof complex of the CSB Schiff base. The dark-green precipitate of the Cu(II) complex was filtered off and washed with methanol and diethyl ether (Decomposed at 200.8 ℃, yield: 78 %). For preparation of the Ni(II) complex of the CSB Schiff base, a solution of 0.4 g of the NiCl2.6H2O salt in 5 mL DMF methanol was added to solution of 1 g of the CSB Schiff base in 10 mL DMF. The mixture was refluxed for 7 hours. The light-green precipitate of the Ni(II)

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complex was filtered off and washed with DMF (Decomposed at 232.6 ℃, yield: 74 %).

4.1 Noncovalent surface functionalization

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4. Results and discussion

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Various theoretical parameters were used to investigate the noncovalent surface

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functionalization.

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4.1.1 Binding energies

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We used a polymer sequence with 4 monomer units for modeling of chitosan. The optimized structures of 5-nitroisatin (NI) and chitosan (CS) have been shown in Fig. 1 (see the

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Supplementary data for the Cartesian coordinates of the calculated structures in gas and solution

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phases). The interaction of NI (functional groups: -NH, -NO2 and two -CO (-CO1 and -CO2 in Fig. 1)) with chitosan (functional groups: -NH2 and two -OH (-OH1 and -OH2 in Fig. 1)) has been examined in ten different ways (CS/NI1-10). The optimized structures of CS/NI1-10 are shown in Figs. 1-3 (in solution phase at M06-2X / 6-31G **). The binding or interaction energies (ΔEs) for CS/NI1-10 configurations have been evaluated using Eq. (3): (3)

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Journal Pre-proof The ΔE values in solution and gas phases at B3LYP and M06-2X functionals have been represented in Table 1 (see the Supplementary data for the electronic plus zero point energies). The ΔEs of M06-2X density functional level of theory (-77.3 kJ mol-1 on average) are more negative than those of B3LYP (-56.8 kJ mol-1 on average). The dispersion contributions to the ΔE are considered by M06-2X functional [71], therefore these corrections appear as attractive forces. The ΔEs of solution phase are more positive than those of gas phase (-85.1 kJ mol-1 and -

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67.1 kJ mol-1 on average at M06-2X and B3LYP, respectively), because solvent molecules

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compete with the NI molecules for adsorption. However, in both phases, the interaction energies

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are negative indicating that the surface adsorption of NI on CS is suitable.

the most negative

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The ΔEs depend on the orientation of NI relative to CS. According to the Table 1, CS/NI3 has in solution phase (the most stable species) in which the -CO1 and -NH

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functional groups of NI interact with the -OH1 and -OH2 functional groups of CS, respectively

where phases. The

and

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The solvation energies (

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4.1.2 Solvation energies

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(Fig. 2).

) were obtained by (Table 1): (4)

show the sum of electronic and zero-point energies in the gas and solution of NI (-44.2 kJ mol-1 and -44.8 kJ mol-1 at M06-2X and B3LYP, respectively)

and CS (-100.3 kJ mol-1 and -125.4 kJ mol-1 at M06-2X and B3LYP, respectively) becomes more negative in CS/NI1-10 configurations (-136.7 kJ mol-1 and -159.9 kJ mol-1 on average at M062X and B3LYP, respectively), therefor the solubility of NI and CS increases in the presence of each other. The main reason for the increase in solubility and strong interactions is related to the

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Journal Pre-proof formation of hydrogen bonds between NI and CS, which will be discussed in detail in the next section by quantum theory of atoms in molecules (QTAIM). 4.1.3 QTAIM analysis Charge density properties were used to examine the intermolecular hydrogen bonds in detail. The characteristic and strength of an interaction could be presented by ∇ The signs of ∇

and

(∇

) and (∇

indicate the nature of the different interactions. If, (∇

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,

,

),

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/

. For 0.5 < −

/ <1

, partially covalent and noncovalent characters are expected, respectively.

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/

,

), then weak, medium and strong bonds are anticipated,

respectively [72]. The bond character can be determined by − and

and ρ(r), respectively.

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Figs. 4 and 5 display the molecular graphs of CS/NI1-5 and CS/NI6-10 at M06-2X/6-31G(d,p) in

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solution phase, respectively. The atoms participating in the intermolecular interactions were marked in these figures (see the Supplementary data for the complete shapes of all the molecular ,

,

and −

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graphs). The ρ(r), ∇ (r),

/

values have been presented in Table 2 (at M06-

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2X density functional level of theory in aqueous solution). The hydrogen bond energies ( have been obtained by [73]:

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(5)

We begin with the most stable species (CS/NI3), in which the -NH and -CO1 functional groups of NI approach -OH2 and -OH1 functional groups of CS, respectively. The H106 O42 ( ) hydrogen bonds with ∇

and H17 O108 ( 0.5 < −

/ < 1 are medium interactions, the first of which (H106 O42) is the

strongest bond in all species. The H8 O108 and H16 O108 interactions with ∇ and −

,

,

/ > 1 are weak hydrogen bonds. For CS/NI3 species, the sum of hydrogen bond

energies (∑

) is

. 9

Journal Pre-proof In CS/NI8 as the second most stable structure (at M06-2X), -CO2 functional group of NI approach -OH2 and -NH2 functional groups of CS (∑

). This

configuration has 5 weak hydrogen bonds, but, as can be seen in Fig. 5 (CS/NI8), in addition to the bond critical points of the hydrogen bonds, there are 4 other bond critical points between O-C and O-O. CS/NI9 has one medium hydrogen bond, three weak hydrogen bonds (∑ ) and 2 other bond critical points between O-C and O-O. In this configuration, -

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NH and -CO1 groups of NI interact with –OH1 and -NH2 groups of CS, respectively. CS/NI5 ) has one medium hydrogen bond with

, two

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(∑

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weak interactions and one other bond critical point between O-N (Fig. 4), in which -CO1 and -

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NH functional groups of NI approaches -OH2 functional group of CS. Similar conditions are ), in which the -NH and -CO1 functional

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observed for CS/NI10 (∑

groups of NI approach -OH2 and -NH2 functional groups of CS, respectively. ) and CS/NI7 (∑

), with two

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CS/NI6 (∑

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medium and one weak hydrogen bonds, have approximately the same stability. In the former, CO1 and -NH functional groups of NI interact with -OH2 and -NH2 functional groups of CS, and

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in the latter -CO1 and -NH functional groups of NI interact with -OH1 and -O- functional groups of CS (Fig. 5). CS/NI1 (∑ and CS/NI4 (∑

), CS/NI2 (∑

)

) are among the most unstable configurations whose

interactions are presented in Table 2 and Fig. 4. 4.1.4 Quantum molecular descriptors Table S1 (see the Supplementary data) presents

(gap of energy between LUMO and HOMO)

and quantum molecular descriptors (electrophilicity power ( ) and global hardness ( )) for NI, 10

Journal Pre-proof CS and CS/NI1-10 in both phases at M06-2X and B3LYP density functional levels of theory. According to the Table S1, Eg and η of NI are reduced in CS/NI1-10 configurations. Since

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used to predict toxicity, it may be concluded that the toxicity of NI is somewhat reduced in the vicinity of the CS. A decrease in Eg and η indicates an increase in system reactivity. Therefore, in the following, we will investigate the mechanism of covalent functionalization (Schiff base formation).

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4.2 Covalent surface functionalization

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In this section, we first theoretically examine the possibility of covalent functionalization and

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4.2.1 Mechanism of covalent functionalization

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then experimentally test it.

The active primary amino group in chitosan provides the possibility of the covalent

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functionalization by the reaction with carbonyl group of NI (Schiff base). Scheme 1 illustrates

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the generally accepted mechanism for such reaction [74]. This mechanism consists of the addition of the -NH2 group from CS to a C=O group from NI to give a stable carbinolamine

CH2OH

O2N

O

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intermediate (I) that loses H2O molecule to produce the imine or chitosan Schiff base (CSB).

CH2OH O

O

CH2OH

O

O

O

OH

TSI

TSII

+

OH

NH2

CS

n

N H

O O

+ H2O

n

N

O2N

O OH

H H

O2N

n

N

NI

CSB N H

O

carbinolamine (I)

N H

O

Scheme1. Mechanism of the covalent surface functionalization. Fig. 6 shows the optimized structures of the carbinolamine intermediate I and the imine product 11

Journal Pre-proof P (CSB+H2O). Using the reactant R (RCS/NI4: appropriate orientation for the reaction) and the carbinolamine intermediate I, the transition state of the first step was optimized (TSI in Fig. 6). The relative energies have been reported in Table 3 (see the Supplementary data for the electronic plus zero point energies). This table indicates that the carbinolamine intermediate I is a stable intermediate. The transition state of the second step was obtained by the carbinolamine intermediate I and product P (TSII in Fig. 6). The activation energies of the first and second steps

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are 107.7 kJ mol-1 and 174.7 kJ mol-1, respectively, indicating that the both steps have high

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activation energies in this mechanism.

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The solvent molecules play an important role in the imine formation [75]. In many chemical

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reactions, a chain of solvent molecules is involved in proton transfer [76-78]. To reduce computational cost, monomer of chitosan was used in this section. Using one methanol molecule,

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reactant R1 (CS+NI+CH3OH), intermediate I1 (carbinolamine+CH3OH) and product P1

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(CSB+H2O+CH3OH) were optimized (Fig. 7). The transition states of the first (R1-I1) and second (I1-P1) steps were named TSIII and TSIV, respectively (Fig. 7). The activation energies

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related to TSIII and TSIV are 70.2 kJ mol-1 and 121.2 kJ mol-1, respectively indicating that the

respectively.

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activation energies of the first and second steps are reduced by 37.5 kJ mol-1 and 53.4 kJ mol-1,

Similarly, the use of two methanol molecules results in the reactant R2 (CS+NI+2CH3OH), intermediate I2 (carbinolamine+2CH3OH), product P2 (CSB+H2O+2CH3OH), TSV (first step) and TSVI (second step) shown in Fig. 8. The activation energies of the first (R2-I2) and second (I2-P2) steps are 45.0 kJ mol-1 and 71.8 kJ mol-1, respectively, which show a significant decrease compared to the previous case. Therefore, in this reaction, the solvent molecules interfere with the proton transfer and significantly reduce the activation energies. These theoretical findings 12

Journal Pre-proof promoted us to synthesize a new Schiff-base derived from the chitosan and 5-nitroisatin (CSB) and its Cu(II) and Ni(II) complexes. The synthesis of these complexes as examples illustrates the potential biological applications of this new Schiff-base. 4.2.2 Elemental analysis and geometry optimization The CHN elemental analysis of the CSB Schiff base and its Cu(II) and Ni(II) complexes as well as the obtained percentages for the Cu2+ and Ni2+ ions in structure of the complexes are gathered

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in Table 4. Good consistency between the observed and calculated results confirms suitability of

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the proposed formulas for the CSB Schiff base and its complexes. The optimized geometries of

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[Ni(CSB)Cl2] and [Cu(CSB)Cl2] complexes are shown in Fig. 9.

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The CSB Schiff base acts as a bidentate ligand, is coordinated to the metal ions via the

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azomethine nitrogen and oxygen of carbonyl group. This coordination mode increases the C=N bond length of the azomethine group and C=O bond of the carbonyl. The C=N and C=O bond

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lengths are 127.2 and 121.0 pm for the CSB Schiff base, respectively, which are about 129 and

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122 pm for the [M(CSB)Cl2] complexes, respectively.

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4.2.3 Vibrational spectroscopy

The IR vibrational frequencies of the CBS Schiff base and its [Ni(CSB)Cl2] and [Cu(CSB)Cl2] complexes have been identified by comparison of their experimental and theoretical IR vibrational frequencies. A very strong absorption band at 1700-1500 cm-1 region of the IR spectrum of the Schiff bases accounts as an important signal in identification of coordination mode of the Schiff bases to the metal ions [36, 79-84]. A very strong band at 1630-1660 cm-1 region of the IR spectra of the CSB, [Ni(CSB)Cl2] and [Cu(CSB)Cl2] species is attributed to the C=N symmetrical stretching mode of the azomethine group. As seen in Table 5, this vibration 13

Journal Pre-proof overlaps with some other stretching vibrations of the C-O, C-N and C-C bonds. The asymmetric and symmetric stretching vibrations of the N-O bonds of the –NO2 group are appeared as the strong bands at about 1580 and 1330 cm-1 of the IR spectra of the investigated compounds. Overlapping of the O-H, N-H, S-H and C-H stretching vibrations causes to broad bands in 36002000 cm-1 spectral region of the IR spectra [80-86]. Deconvolution of this spectral region of the synthesized compounds are listed in Table 5.

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4.2.4. NBO analysis

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The 3D-maps of HOMO and LUMO of the CBS Schiff base and [Ni(CSB)Cl2] complex are

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shown in Fig. S1 (see the Supplementary data). The HOMO orbital of free CSB is mainly

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localized on the –NH2 amino group, while in the structure of [Ni(CSB)Cl2] complex, the HOMO

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orbital is mainly localized on the Ni and two chloro ligands. In both of the CBS and [Ni(CSB)Cl2] species, the LUMO orbital is mainly localized on the NI moiety. Eg plays

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important role in several properties of chemical compounds such as photochemical reactions,

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electronic transitions, stability and so on. Calculated energy gaps for the CSB and [Ni(CSB)Cl2] species are 3.42 eV and 2.49 eV, respectively. These large energy gaps confirm high stability of

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the synthesized compounds.

In the structure of free CSB ligand, bond orders of the C=N bond of the azomethine group and the C=O bond of the carbonyl group are 1.89524 and 1.97588, respectively. Coordination to the Ni2+ ion decreases these bond orders to 1.58344 and 1.7034, respectively. 4.2.5 TGA analysis The TG curves of CBS Schiff base and [Ni(CSB)Cl2] complex are shown in Fig. 10. Both of the TG curves exhibit three different mass loss steps. The first mass loses of the CBS and 14

Journal Pre-proof [Ni(CSB)Cl2] species are about 10 and 15 %, respectively, which is related to the loss of absorbed water below the 100 °C. In two other steps, thermal degradation of the CSB Schiff base is occurred at 200-400 °C and 400-550 °C. In below 600 °C, the CSB is completely degraded (Fig. 10). For the [Ni(CSB)Cl2] complex, second step occurs at 100 to 400 °C with 38 % mass loss. This step is attributed to thermal degradation of the polymer chain. In the third step at 400 to 600°C with 35 % mass loss, the Ni2+ ion loses its Schiff base as well as two chloride ligands to

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produce the NiO oxide, which involves about 10 % of the mass [36, 87].

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4.2.6. DSC analysis

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The thermograms of the CSB Schiff base and [Ni(CSB)Cl2] complex are shown in Fig. S2 (see

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the Supplementary data). As seen, a broad endothermic peak is appeared in 60-120 °C range of

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the investigated spectra. The onset temperature of this peak is 63.7 and 88.0 °C for the free CSB and [Ni(CSB)Cl2] complex, respectively, where the minimum of these peaks appeared in 77.2

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and 99.0 °C, respectively. This endothermic transition is related to evaporation of the absorbed

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water molecules in the samples [88, 89]. Such as the other polysaccharides, the chitosan and its

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derivatives have a strong affinity to water and hydrated easily. The hydration properties of polysaccharides depend on their primary and supramolecular structures. Difference in position of the endothermic water evaporation peak and its area (Fig. S2) reflects physical and molecular changes by coordination of the CSB species to Ni2+ ion. The Ni(II) complex has higher thermal stability than the free CSB species. On the other hand, the obtained heat of reaction (ΔH) for this endothermic process is 88.64 and 234.78 J.g-1 for the free CSB Schiff base and its Ni(II) complex, respectively. Higher ΔH as well larger peak area demonstrate that the [Ni(CSB)Cl2] complex has higher water holding capacity than the free CSB.

15

Journal Pre-proof 5. Conclusion The noncovalent surface functionalization of 5-nitroisatin (NI) with chitosan (CS) were examined by ten configurations (CS/NI1-10) at B3LYP and M06-2X density functional levels of theory in solution and gas phases. The negative values of solvation and binding energies demonstrated that the noncovalent surface functionalization increases the solubility and stability of the components. Considering quantum molecular descriptors, the reactivity of NI in CS/NI1-

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10 increases. AIM analysis showed that the surface adsorption is mainly related to the hydrogen

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bonds.

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The covalent surface functionalization occurs through the formation of Schiff base between the

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active primary amino group of CS and the carbonyl group of NI. The mechanism of this reaction

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involves an intermediate (carbinolamine) and two transition states. Proton transfer plays an important role in this reaction and can be modeled by a chain of methanol molecules. This model

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predicts that the covalent surface functionalization is possible. Therefore, the Schiff base of

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chitosan and 5-nitroisatin (CSB) as well as its Ni(II) and Cu(II) complexes were newly synthesized and characterized using several spectroscopic methods. Also, the DFT methods were

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used to identify the optimized geometries of the synthesized compounds and assignment of their IR-vibrational modes. The oxygen of carbonyl group and azomethine nitrogen of the CSB Schiff base are coordinated to the bivalent metal ions. The bond orders of the C=N azomethine and C=O carbonyl groups reduce by coordination to Ni2+ ion. Two other coordination positions of the square complexes are occupied by two chloro ligands. The TGA data confirm suitability of the optimized geometries for these compounds. The [Ni(CSB)Cl2] complex absorbs water more than the free CSB. ACKNOWLEDGEMENTS 16

Journal Pre-proof We thank the Research Center for Animal Development Applied Biology for allocation of computer time. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. REFERENCES

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Macromol., 130 (2019) 727-736.

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Figure captions Fig. 1. Optimized structures of NI, CS and CS/NI1-2. Fig. 2. Optimized structures of CS/NI3-6. Fig. 3. Optimized structures of CS/NI7-10. Fig. 4. Molecular graph of CS/ NI1-5. Small green spheres and lines related to the bond critical

of

points (BCP) and the bond paths, respectively.

-p

Fig. 6. Optimized structures of I, P, TSI and TSII.

ro

Fig. 5. Same as Fig. 4 for CS/ NI6-10.

re

Fig. 7. Optimized structures of R1, I1, P1, TSIII and TSIV. Fig. 8. Optimized structures of R2, I2, P2, TSV and TSVI.

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Fig. 9. Optimized geometries of [Ni(CSB)Cl2] and [Cu(CSB)Cl2] complexes.

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ur

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Fig. 10. TG-DTG curves of the CBS Schiff base (a) and [Ni(CSB)Cl2] complex (b).

29

Journal Pre-proof

Table1. Binding (

) energies (kJ mol-1) for optimized geometries.

) and solvation (

-44.2

-44.8

-

-

-

-

CS

-100.3

-125.4

-

-

-

-

CS/NI1

-159.5

-157.2

-40.2

-25.1

-23.4

-36.5

CS/NI2

-137.7

-154.7

-32.9

-39.7

-25.2

-40.8

CS/NI3

-109.0

-153.5

-104.1

-134.4

-89.5

-106.2

CS/NI4

-108.3

-151.4

-52.3

-88.4

-16.0

-34.8

CS/NI5

-163.7

-157.7

-89.2

-70.0

-78.7

-91.2

CS/NI6

-67.1

-164.2

-83.0

-160.4

-63.5

-69.4

CS/NI7

-161.7

-152.2

-83.0

-65.9

-52.4

-70.3

CS/NI8

-183.9

-182.7

-103.3

-63.9

-66.0

-53.5

CS/NI9

-109.1

-167.1

-97.9

-133.3

-73.7

-76.9

CS/NI10

-161.8

-158.4

-87.3

-70.0

-79.4

-91.2

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ur

na

lP

re

-p

of

NI

ro

Species

30

Journal Pre-proof in kJ mol-1 for

Table 2. Topological parameters in a.u. and the hydrogen bond energy ( CS/NI1-10 at M06-2X in solution phase. Atoms

ρ(r)

H7 - O101 H9 - O101 H13 - O102 H36 - O102 H32 - O102

0.0173 0.0115 0.0100 0.007929 0.008316

0.0576 0.0405 0.0329 0.026813 0.031008

H7 - O104 H9 - O104 H13 - O108 H36 - O108 H32 - O108

0.019288 0.007609 0.010434 0.007153 0.012643

0.05848 0.025706 0.037957 0.02465 0.040045

O42 - H106 H8 - O108 H16 - O108 H17 - O108

0.040605 0.007881 0.011216 0.021399

0.122208 0.029251 0.039121 0.076987

H33 - O104 H51 - O104 N60 - H97 H53 - O101 H80 - O102

0.010922 0.010697 0.013789 0.014147 0.011012

0.03639 0.038713 0.037184 0.04983 0.043575

O42 - H106 H29 - O108 H16 - O108

0.029688 0.014572 0.00921

0.09039 0.049273 0.03718

H38 - O108 H29 - O108 N18 - H106

0.002611 0.021745 0.044453

H38 - O108 O41 - H106 O65 - H106

0.031203 0.010256 0.021515

0.100459 0.039178 0.061779

H29 - O104 H11 - O104 N18 - H97 O20 - H97 H9 - O101

0.010384 0.020233 0.014909 0.010979 0.009729

0.036893 0.058976 0.04127 0.041576 0.034997

H11 - O108 O41 - H99 O41 - H106 H34 - C96

0.014576 0.005999 0.025797 0.011912

0.051517 0.024221 0.080737 0.042825

O42 - H106 H29 - O108 H11 - O108

0.029655 0.015896 0.014121

0.089869 0.054186 0.052781

−

(r)

0.9937 1.1090 1.0758 1.1261 1.1253

-19.12 -10.90 -9.36 -7.02 -8.13

-0.0005 0.0008 0.0011 0.0008 0.0001

0.9683 1.1528 1.1449 1.1643 1.0109

-20.47 -6.46 -9.65 -6.08 -12.85

-0.0006 0.0010 0.0009 -0.0001

0.9821 1.1911 1.1096 0.9947

-41.55 -6.94 -10.52 -23.65

0.0003 0.0009 0.0000 0.0005 0.0012

1.0400 1.1218 1.0026 1.0418 1.1455

-11.05 -10.21 -12.13 -15.08 -11.07

-0.0008 0.0002 0.0012

0.9687 1.0131 1.1833

-31.61 -15.74 -8.92

0.0008 -0.0001 -0.0036

1.3866 0.9952 0.8844

-2.69 -23.87 -41.17

-0.0004 0.0009 -0.0009

0.9841 1.1191 0.9495

-34.02 -10.37 -22.53

0.0005 -0.0009 0.0001 0.0012 0.0009

1.0626 0.9479 1.0052 1.1472 1.1299

-10.75 -21.58 -13.39 -10.53 -9.11

0.0007 0.0011 -0.0006 0.0015

1.0628 1.2927 0.9702 1.1941

-15.00 -5.01 -28.15 -10.11

-0.0009 0.0001 0.0008

0.9639 1.0106 1.0734

-31.76 -17.40 -15.09

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0.014569 0.072124 0.096525

-0.0001 0.0009 0.0005 0.0007 0.0008

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CS/NI1 0.0145 -0.0146 0.0092 -0.0083 0.0077 -0.0071 0.006029 -0.0054 0.006976 -0.0062 CS/NI2 0.015114 -0.01561 0.005675 -0.00492 0.008424 -0.00736 0.005401 -0.00464 0.009904 -0.0098 CS/NI3 0.031118 -0.03169 0.006301 -0.00529 0.008901 -0.00802 0.017941 -0.01804 CS/NI4 0.00876 -0.00842 0.008731 -0.00778 0.009272 -0.00925 0.011976 -0.0115 0.009666 -0.00844 CS/NI5 0.023352 -0.02411 0.012161 -0.012 0.008049 -0.0068 CS/NI6 0.002848 -0.00205 0.018117 -0.0182 0.02776 -0.03139 CS/NI7 0.025526 -0.02594 0.008852 -0.00791 0.016312 -0.01718 CS/NI8 0.008709 -0.0082 0.015601 -0.01646 0.010263 -0.01021 0.009213 -0.00803 0.007848 -0.00695 CS/NI9 0.012159 -0.01144 0.004937 -0.00382 0.020823 -0.02146 0.009208 -0.00771 CS/NI10 0.023342 -0.02422 0.013406 -0.01327 0.012351 -0.01151

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Table 3. Relative energies (kJ mol-1) for all configurations in the mechanisms.

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species E species E species E R 0.0 R1 0.0 R2 0.0 TSI 107.7 TSIII 70.2 TSV 45.0 I -19.3 I1 -15.8 I2 5.8 TSII 155.4 TSIV 105.5 TSVI 77.7 P 0.8 P1 -4.3 P2 -10.9

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Table 4. The elemental analysis of the investigated species. Experimental % Species CSB

C32N6H48O19

C

H

N

Metal ion

C

H

N

Metal ion

42.05

5.26

7.80

-

46.83

5.90

10.24

-

6.52

40.24

5.07

8.80

6.65

6.42

40.44

5.09

8.84

6.18

[Cu(CSB)Cl2] [CuCl2(C32N6H48O19)] 39.01

4.87

5.36

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[NiCl2(C32N6H48O19)]

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[Ni(CSB)Cl2]

Calculated %

Proposed formula

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Journal Pre-proof Table 5. Selected experimental and calculated IR vibrational frequencies (cm-1) of the CSB ligand and its complexes. Experimental frequencies

Calculated frequencies [Ni(CSB)Cl2]

CSB [Cu(CS B)Cl2]

Vibrational assignment Intensity Frequency

Intensity

788 (m)

99

501

93

508

126

δout of plane (N-H) of the pyrrole ring

-

-

559

23

560

31

υ(M-N, M-O)

707

177

728

181

719

98

δwag(-NH2 group)

842

113

Breathing of the aliphatic rings

846

105

840

79, 125

131, 29

146

1060, 1037 1087

1065, 1035 1083

1188 (m)

1181

120

1187

161

1249 (m)

1274

30

1281

45

1333

262

1336

340

1339

63

1341

1542

97

1554

1599

224

1600

1609

77

1677

61

1785

321

28522965 31323108

1327 (s)

1326 (s)

1334 (s)

1581 (s)

1588 (s)

1582 (s)

1636 (vs)

1658 (vs)

1633 (vs)

2921 (m)

3360 3425 (vs, br)

3447 (vs, br)

3477

υ(C-O-C) of the ring

1189

91

1282

112

Breathing of the aromatic rings+ υ(C-C) aliphatic υasym(C-C-N) of the pyrrole ring

1337

210

υsym(O-N-O) of the –NO2 nitro group

60

1343

197

72

1554

72

υ(C-N) carbon-nitrogen bond of the –NO2 nitro group υasym(O-N-O) of the –NO2 nitro group

152

1601

282

δsci of the –NH2 groups

1629

219

1612

183

υ(C=N, C=C) of the aromatic rings

1712

133

1632

120

υ(C=N) azomethine group

1818

350

1752

281

υ(C=O) carbonyl group

28043011 31633116

61

28002966 31393090

165

υ(C-H) aliphatic

22

υ(C-H) aromatic of the benzene ring

31

3380

42

3362

24

υsym(N-H) of the –NH2 groups

19

3470

26

3474

19

υasym(N-H) of the –NH2 groups υ(N-H) of the –NH group of the pyrrole ring υ(O-H)

111 22

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3441 (vs, br)

υ(C-O) of the CH2-OH groups

122

225

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1181 (m) 1255 (m)

66, 209

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1178 (m) 1243 (m)

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1070 (s, br)

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69

1070 (vs, br)

2878 (m)

501

1060, 1036 1087

1103 (s, br)

2933 (m)

(km.mol-1)

na

767 (m)

523 (w)

Frequency (km.mol-1)

ur

754 (m)

512 (w)

Intensity

Frequency (km.mol-1)

467 (w)

[Cu(CSB)Cl2]

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CSB

[Ni(CS B)Cl2]

39

3515

73

3543

135

3514

111

36983567

12-285

37673633

51-197

36933552

30-190

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Surface functionalization of chitosan with 5-nitroisatin were examined Hydrogen bonds play a major role in noncovalent functionalization Stability and solubility increase as a result of functionalization Solvent plays an important role in the mechanism of covalent functionalization A new chitosan Schiff base was synthesized and characterized

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