Advancement on modification of chitosan biopolymer and its potential applications

Journal Pre-proof Advancement on modification of chitosan biopolymer and its potential applications

Nabel A. Negm, Hassan H.H. Hefni, Ali A. Abd-Elaal, Emad A. Badr, Maram T.H. Abou Kana PII:

S0141-8130(20)30419-0

DOI:

https://doi.org/10.1016/j.ijbiomac.2020.02.196

Reference:

BIOMAC 14813

To appear in:

International Journal of Biological Macromolecules

Received date:

14 January 2020

Revised date:

15 February 2020

Accepted date:

18 February 2020

Please cite this article as: N.A. Negm, H.H.H. Hefni, A.A. Abd-Elaal, et al., Advancement on modification of chitosan biopolymer and its potential applications, International Journal of Biological Macromolecules(2018), https://doi.org/10.1016/ j.ijbiomac.2020.02.196

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© 2018 Published by Elsevier.

Journal Pre-proof Advancement on modification of chitosan biopolymer and its potential applications Nabel A. Negm1,2#, Hassan H.H. Hefni1, Ali A. Abd-Elaal1, Emad A. Badr1, Maram T.H. Abou Kana3 1- Egyptian Petroleum Research Institute (EPRI), Nasr City, Cairo, 11727, EGYPT. 2- Egypt Nanotechnology Center (EGNC), Cairo University, El-Shiekh Zayed, 12588, EGYPT. 3- National Institute of Laser Enhanced Sciences, Cairo University, Giza, EGYPT. # Corresponding author: [email protected]

Abstract Chitosan is the second abundant biopolymer present on the earth after cellulose. Chitosan is extracted from the shells of shrimp and other crustaceans. Several methods were reported for its extraction, but the most commercial is the deacetylation of chitin. Chitosan as a biopolymer has numerous applications and uses. But, its mechanical, chemical and biological characteristics can be enhanced by modification of its chemical structures. Several

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modification methods and derivatives were reviewed in the literatures, and several were

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collected in this review. The reviewed modified chitosan derivatives herein were five types of derivatives. The first is substituted chitosan derivatives including thiolated, phosphorylated,

chitosan-glutaraldehyde,

chitosan-ethylene

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and N-phthaloylated derivatives. The second is crosslinked chitosan derivatives including diamine

tetraacetic

acid,

and

chitosan-

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epichlorohydrin derivatives. The third is carboxylic acid derivatives of chitosan obtained from

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Carboxyalkylation, acrylation, methacrylation, and benzoylation of chitosan. The fourth is ionic chitosan derivatives including highly cationic and sulfated derivatives. The last is

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bounded chitosan to specific molecules including cyclodextrin, thiosemicarbazone, dioxime, and crown ether precursors. The review also highlights the reported advantages and applications of the modified chitosan and the synthetic routes of the biopolymer modification.

1. Introduction

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uptake

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Keywords: Chitosan; modification; nonionic chitosan; ionic chitosan; drug delivery; metal

Chitosan is a copolymer formed of repeated units of 2-amino-2-deoxy-d-glucopyranose units, and residual 2-acetamido-2-deoxy-d-glucopyranose units (Figure 1). Chitosan is obtained from alkaline hydrolysis (deacetylation) of chitin, and it is also found naturally in some fungal cell walls. Chitosan has amenable functional groups such as primary amine (NH), primary as well as secondary hydroxyl group (OH) in its monomer (Figure 2), so it can be chemically modified without disturbing its degree of polymerization (Mourya and Inamdar, 2008). The chemical modification (Croisier and Jerome, 2013) of chitosan is a powerful technique to control the interaction of the polymer with other components, such as metal ions, organic compounds, e.g., drugs. Chemical modification of chitosan improves its bulk properties for the preparation of sustained drug release system. 1

Journal Pre-proof 2. Substituted chitosan derivatives 2.1. Thiolated chitosan The amino group in 2-position of glucosamine units of chitosan is the central position for the immobilization of thiol groups. The thiolated chitosan derivatives includes different compounds such as: chitosan-cysteine, chitosan-thiolactic acid, chitosan-thioglycolic acid, chitosan-homocystenine, chitosan-4-thiobutylamidine, chitosan-thioethylamidine, chitosanglutathione, chitosan-N-acetyl cysteine, and chitosan-6-mercaptonicotinic acid conjugates (Figure 3). Anticancer drugs have several drawbacks which were solved by employing thiolated chitosan

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which offers efficient mucoadhesivity, membrane permeation enhancing capability and improved inhibition for P-glycoprotein. Ciro et al., (2017) represented the synthesis and

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characterization of thiolated chitosan (Scheme 1) designed in transfer structures such as films,

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hydrogels, and nanoparticles were reported for anticancer drugs. The thiolated chitosan compounds were promising as drug carriers and efficient as nano-

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medicine for enhancing the ocular bioavailability. Shastri (2017) described several applications of thiolated chitosan as nano-carriers for ophthalmic drug delivery.

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Yong et al., (2013) enhanced the removal efficiency of Cu2+ and Cd2+ from wastewater by modification of chitosan-beads throughout introduction of thiol groups to their skeleton to

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obtain thiolated chitosan-beads, ETB (Figure 4). The removal enhancement was accredited to the theory of Hard-Soft Acid-Base.

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Au(III) ion-imprinted thiol-modified chitosan was created by Monier and Abdel-Latif (2017) using epichlorohydrin as the cross-linker. The polymer presented greater uptake capacity of

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370 mg/g than the non-imprinted polymer which has the uptake capacity of 195 mg/g. Chang et al. (2010) synthesized molecular imprinted chitosan using dibenzothiophene as the template and studied the influence of crosslinking and its adsorption for gasoline. The removal of mercury from aqueous solutions using thiol modified chitosan in the cysteine as -SH was investigated by Merrifield et al. (2004), where the maximum uptake capacity was 8 mmol/g in neutral medium. Zhu et al., (2012) introduced thiol group on chitosan skeleton using xanthate. The competitive uptake of lead (II), copper (II), and zinc (II) were in the order of 79.9 mg/g, 34.5 mg/g, and 20.8 mg/g, respectively. Al-Ghamdi et al., (2018) were prepared novel type of sulfone-modified chitosan (SMC) derivatives in reasonable yield by the reaction of chitosan polymer and p-bromo-βketosulfone derivative (Figure 5) under mild acidic condition. The obtained sulfone-modified chitosan biopolymer was used as efficient adsorbent for Hg(II) metal ions from wastewater. 2

Journal Pre-proof 2.2. Phosphorylated chitosan Phosphorylated chitosan and phosphorylated chitosan derivatives acquired their importance due to their characteristics such as: high water solubility, and metal chelating tendency. These types of biopolymers had important applications during regeneration of tissues, drug delivery intermediates, fuel cells and in food industries (Jayakumar et al., 2006). Phosphorylation of chitosan was performed using phosphorous pentaoxide in methane sulphonic acid as a solvent at low temperature, and produced water soluble products with high substitution extent. Methane sulphonic acid acts also during the reaction as a catalyst (Scheme 2) (Jayakumar et al., 2008). Also, phosphorylated chitosan synthesized by reaction of chitosan

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and orthophosphoric acid at 150 °C in the presence of urea as a catalyst and DMF as a solvent (Scheme 3) (Jayakumar et al., 2008). The phosphorylated chitosan was also synthesized

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during grafting copolymerization reaction of and mono-(2-methacryloyl oxyethyl) phosphoric

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acid. The product exhibited zwitterionic properties and enriched antimicrobial activities (Scheme 4) (Jayakumar et al., 2008).

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Ramos et al., (2003) were synthesized N-methylene phosphonic chitosan derivative using chitosan, phosphoric and formaldehyde. The combination of methylene phosphonic groups

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and chitosan enhances its solubility in aqueous medium under mild conditions (Scheme 5). In another report (Heras et al., 2001), the functionalization of chitosan by phosphorous acid

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and formaldehyde instantaneously in acidic medium gives water soluble N-mono- and N-diphosphonic methylene derivatives (Scheme 6).

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Cellulose nano-fibrils (CNF) were modified (Mautner et al., 2016) with phosphate groups by reacting CNF derived from cellulose sludge, a waste stream from paper industries, with

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phosphoric acid (Scheme 7). It was found that nano-papers were able to adsorb copper from aqueous solutions up to 200 mg/m2. In Valmikinathan et al., 2018 study, new photocrosslinkable chitosan derivatives were innovated (Scheme 8) in a methodology allows construction of degradable, in-situ gelling hydrogels with reasonable gelling times and governable physical characters. 2.3. N-phthaloylated chitosan Chitosan polymer is poorly soluble in organic solvents, while N-phthaloylation of chitosan is efficient for solubilization. N-phthaloyl chitosan derivatives have high reactivity than N,Ophthaloylated chitosan derivatives (Kurita et al., 2007). Completely deacetylated chitosan polymer reacted by phthalic anhydride yields N-phthaloyl chitosan derivative which has high solubility in polar-organic solvents (Scheme 9) (Dutta et al., 2004).

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Journal Pre-proof Huh (2001) was synthesized two chitosan derivatives: chitosan-grafted poly(ethylene terephthalate) (C-PET) and quaternized C-PET to obtain antibacterial textile agents to prevent the growth of Staphylococcus aureus. C-PET and quaternized C-PET exhibited high efficacy against the bacterial growth within 75%–86%. The removal of the hydrogen atoms of amino groups of chitosan and introduction of some hydrophobic nature will result the destruction of its inherent crystalline structure and improve the solubility in general organic solvents. This has been initially demonstrated by the partial N-phthaloylation reaction of water-soluble chitin with phthalic anhydride and by the complete

(Nishimura et al., 1991). 3. Crosslinked chitosan derivatives

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3.1. Chitosan-glutaraldehyde crosslinked polymers

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N,O-poly acylation of chitosan with an excess of long chain acid chlorides (Scheme 10)

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Biosorbents, particularly crosslinked chitosan, are widely utilized during heavy metal uptake. Cross-linker type and degree of crosslinking are largely influence the metal uptake behavior

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of chitosan derived biosorbents.

The study of Wang and Zhuang (2017) presented the synthesis of cross-linked

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chitosan/sporopollenin microcapsules using various concentrations of glutaraldehyde as crosslinking agent. The uptake efficiency of copper (II) at different concentration, contact

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time, amount of adsorbent, temperature and pH was studied. The equilibrium conditions of biosorption of manganese (II) from aqueous solution by

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chitosan biopolymer crosslinked by glutaraldehyde (GCC) were studied (Suguna et al., 2010), and the determined Langmuir capacity of GCC at 25 oC was 278 mg/g.

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Nagireddi et al., (2017) reported the ability of crosslinked gluteraldehyde-chitosan (GCC) copolymer towards the uptake and recovery of lead (II) ions from electroplating solutions. GCC adsorbent (Scheme 11) was prepared by grafting of chitosan and glutaraldheyde in 1:17 ratio. Chitosan in forms of membranes and beads were chemically crosslinked using gluteraldehyde (Adarsh and Madhu, 2014) and the adsorption tendencies of the produced adsorbents were represented that cross-linked chitosan have higher adsorption tendency for several metal ions as follows: Cd > Cu > Ni > Ag > Pb > Zn. Fe/Mn oxides were loaded on chitosan biopolymer (Ocinski, 2019) to obtain a hybrid adsorbent for removal of arsenic ions from the aqueous solution. The obtained adsorbents were effective toward arsenic ions adsorption with high durability as fixed-bed systems.

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Journal Pre-proof Chitosan-citric acid modified flakes crosslinked by gluteraldehyde (Suc and Ly, 2012) showed enhanced capacity towards lead (II) ions uptake. Chitosan-citric acid modified flakes can be applied as effective modified biosorbent during lead ions uptake from contaminated water. Modified chitosan-citric acid flakes represented maximum lead (II) capacity at 101.7 mg/g. Sobahi et al., (2014) reported the modification of chitosan with aldehydes and organic acids. Furthermore, some chitosan-carbohydrates blends were synthesized to produce modified chitosan biopolymers with certain physical and chemical characteristics. Beppu et al., (2007) reported the crosslinking process of chitosan biopolymer with

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gluteraldehyde, and showed that macro-properties and micro-properties were improved such as: permeability, wetting, mechanical properties and chemical resistance. Crosslinked

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chitosan biopolymer membranes had higher hydrophobic characters than the un-crosslinked.

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Pokhrel et al. (2017) reported the preparation of poly(vinyl alcohol)-chitosan (PVA-CS) biofilm using solution casting protocol in the presence of gluteraldehyde as cross-linker. The

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degradation rate of PVA-CS biofilm was increased by increasing the chitosan content. 3.2. Ethylene diamine tetraacetic acid chitosan polymer

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Several chemical modification methods were tried to increase uptake capacity of cross-linked chitosan beads. Aminated chitosan beads formed through the chemical reaction using ethylene

capacity for mercury ions.

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diamine and carbodiimide (Jeon and Holl, 2003) (Scheme 12) showed the highest uptake

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The chitosan biopolymer derivatives are more potent than the unmodified biopolymer. Grafting of ethylene diamine tetraacetic acid (EDTA) on chitosan biopolymer (Scheme 13)

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(Schnurch et al., 1998) enhances the antibacterial potency due to the chelating the magnesium ions which stabilizes the outer cellular membrane of gram-negative bacteria. Chitosan-EDTA modified biopolymer utilized as carrier matrix in the process of controlled drugs release. The controlling function of the drugs release came from the ionic crosslinking of the biopolymer by dicationic species as 1,8-diaminooctane or lysine. Chitosan-ethylene diamine tetraacetic acid (EDTA) sodium salt biopolymer (NaCN-EDTA) was examined (Valenta et al., 1998) in numerous topical uses. The chemical, physical, mechanical and microbial properties of NaCN-EDTA compared several hydrophilic biopolymers including: hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (NaCMC), sodium carbopol-980 (NaC980) and sodium polycarbophil (NaPCP). NaCN-EDTA hydrogels is chemically stable, colorless at 0.5% polymer concentration and

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Journal Pre-proof highly compatible with multivalent metal ions. General approaches for synthesis of mucoadhesive chitosan biopolymer derivatives were reported (Ways et al., 2018). Chitosan-graphene oxide (CS-GO) and chitosan/ethylene diamine tetraacetic acid-graphene oxide (CS-EDTA-GO) nanocomposite thin films were prepared (Syuhada et al., 2014) throughout environmental friendly technique. Particle analysis of the products showed fine dispersion of GO and EDTA-GO (Scheme 14) in chitosan matrix. Some interactions were occurred between the filler (GO) and the chitosan segments leads to well distribution of stress property. CS-GO and CS-EDTA-GO showed maximum tensile stress at 0.5% of GO by 51% and 71% compared to chitosan, respectively.

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Zhao et al., (2017) reported the fabrication of chitosan-ethylene diamine tetraacetic acid-pcyclodextrin (CS-EDTA-CD) trifunctional biosorbent (Scheme 15) using a facile and green

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one-pot reaction. The obtained biosorbent was examined in remediation of some toxic metal

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ions and organic pollutants from contaminated wastewater. The adsorption capacities of bisphenol-S, ciprofloxacin, procaine, and imipramine were: 0.177, 0.142, 0.203, and 0.149

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mmol/g, respectively.

3.3. Chitosan-epichlorohydrin crosslinked polymers

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Chen and coworkers (2008) synthesized the crosslinked chitosan by the homogeneous reaction of chitosan in aqueous acetic acid solution with the epichlorohydrin (Scheme 16) and

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investigated the adsorptions of Cu (II), Zn (II), and Pb (II) ions. Adsorption of these metal

adsorption.

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ions in aqueous solution followed monolayer coverage of adsorbents through physical

Tirtom et al. (2012) prepared epichlorohydrin crosslinked chitosan-clay composite beads as

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biosorbent for the removal of Ni (II) and Cd (II) ions from aqueous solution. Cross-linked chemically modified chitosan namely epichlorohydrin cross-linked xanthate chitosan (ECXCs) (Figure 6) was prepared by crosslinking of xanthate-chitosan with epichlorohydrin and the prepared modified polymer was applied in uptake of copper (II) metal ions from aqueous medium (Kannamba et al., 2010). 4. Carboxylic acid chitosan derivatives 4.1. Chitosan carboxyalkylate derivatives Carboxyalkyl (mainly carboxymethyl) chitosan is one of the most significant water soluble, amphoteric chitosan derivative, which had a great potential in medical applications as it is excellent water soluble, nontoxic, biocompatible and biodegradable (Zargar et al., 2015; Jiang et al., 2015). Carboxymethyl chitosan has attracted great interests in various fields such as

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Journal Pre-proof antimicrobial activity, biosensor, wound healing, food industry and bio-imaging. Sun et al. (2006) reported the preparation of quaternized carboxymethyl chitosan (Scheme 17). The solid-phase interaction of native mono- or dicarboxylic acids such as phthalic, succinic, and maleic ones with chitosan in a screw extruder and in absence of solvents and condensing agents was carried out (Demina et al., 2011) (Scheme 18). Acylation of chitosan was performed by reaction of chitosan with acetic, propionic, butanoic, valeric, and hexanoic acids anhydrides and yielded grafted amides with the modification degree of 20–50% to achieve biodegradable compounds with high compatibility with blood (Lee et al., 1995) (Scheme 19).

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The modification of chitosan with linear poly(anhydrides) of dicarboxylic acids was carried out in toluene medium, and yielded 60.3% and 51.1% of poly(adipine) and poly(sebacine)

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anhydrides, respectively. The derivatives were promising carriers for DNA and genes

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(Mutasher et al., 2016) (Figure 7).

Succinic, maleic, and phthalic anhydrides were used in a solid phase modification of chitosan

(Scheme 20).

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4.2. Chitosan methacrylate derivatives

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biopolymer to obtain the carboxyalkyl chitosan bio-derivatives (Rogovina et al., 1998)

Water soluble chitin-methacrylate (CM) was synthesized by Khor et al., (2011) via reaction of

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methacrylic acid and chitin in 5% lithium chloride/dimethyl acetamide and N,N’dicyclocarbodiimide and dimethyl aminopyridine (Scheme 21). The obtained hydrogel was

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prepared from chitin-methacrylate by photochemical crosslinking reaction in the presence of Irgacure-2959 photo initiator. CM-hydrogels were assessed in in-vitro cytotoxicity.

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Chitosan (CN)-methacrylate (M) product was prepared (Cankaya, 2019) by esterification of CN biopolymer and M in 1:0.25 ratio, respectively. Grafting reaction was performed on the prepared CN/M polymer using different monomers (Scheme 22) such as: 1-vinylimidazole, methacrylamide and 2-acrylamido-2-methyl-1-propanesulfonic acid throughout free radical polymerization. The graft copolymers exhibited higher resistance to bacteria than the chitosan-methacrylate biopolymer. For the first time, Savin et al., (2019) were prepared polymeric nano-carriers for drugs delivery based on chitosan grafted-poly(ethylene glycol) methacrylate copolymer. The high soluble chitosan grafted-poly(ethylene glycol) methacrylate in aqueous medium was obtained from Michael addition reaction to synthesize nontoxic micro/nanoparticles (MNPs) (Scheme 23). The chemical modification of chitosan was enhanced its solubility in aqueous media.

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Journal Pre-proof In the study of Kyzas et al., (2008), three chitosan microsphere derivatives were synthesized and evaluated in removal of basic dye (Basic blue 3G). The biosorbents were prepared by cross-linking of chitosan biopolymer and ionic gelation with tripoly phosphate followed by cross-linking using glutaraldheyde, to obtain the maximum swelling for the powdered form. In another study, Kyzas et al., (2008) modified chitosan derivatives via grafting of chitosan biopolymer by poly(acrylic acid) and poly(acrylamide) using free radical polymerization. 4.3. Chitosan Benzoylate derivatives Chitosan biopolymer was chemically functionalized by 3-nitro-4-amino benzoic acid moiety and the fabricated modified biopolymer was applied in collection and concentrating traces of

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molybdenum. The modification process of the chitosan biopolymer was preceded via attachment of carboxyl group of 3-nitro-4-amino benzoic acid to -NH2 groups through amide

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linkage (Scheme 24). The adsorption tendencies of molybdenum, vanadium, gallium, arsenic,

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selenium, silver, bismuth, thorium, tungsten, tin, tellurium, and copper metal ions on the modified biopolymer were tested. The highest selectivity and adsorption tendency was

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observed for molybdenum in acidic medium of pH 3-4 with uptake capacity of 380 mg.g-1 resin (Sabarudin et al., 2007).

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A new industrial scale approach was used for synthesis of o-benzoyl chitosan derivatives of benzoic acid and p-methoxybenzoic acid by using tetrafluoroacetic acid anhydride/phosphoric

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acid mediated acylation (Scheme 25). Benzoyl chitosan biopolymers play significant role during drug delivery and cosmetics, wound healing preparation, and chromatographic

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separation technologies. The modified chitosan biopolymers were soluble in organic solvents such as dimethyl formamide, dimethyl sulfoxide, acetone, and not in tetrahydrofurn and ethyl

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alcohol. Scanning electron microscopic pictures of native and modified biopolymers showed significant structural changes, which was interpreted due to hydrogen bonds breakdown and the interaction between the introduced phenyl groups (Lee et al., 2012). 5. Ionic chitosan derivatives 5.1. Cationic chitosan derivatives The cationic nature of the chitosan is essential during several applications such as absorption enhancement, bio-adhesion, and transfection efficiency as well as to biological activities such as antitumor, antimicrobial, anti-inflammatory, and anti-hypercholesterolemia effect. Therefore, highly cationic derivatives of chitosan have been prepared. They can be prepared by reaction of chitosan and dialkyl aminoalkyl chloride in alkaline condition (Je and Kim, 2006). Chitosan dialkyl aminoalkyl modified by N-aminoethyl, N-dimethyl aminoethyl, N-

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Journal Pre-proof diethyl aminoethyl, N-dimethyl aminoisopropyl displayed substantial b-site APP-cleaving enzyme inhibition (BACE1) property and cytotoxic activity (Je and Kim, 2005). A novel water soluble trimethyl quaternary derivative contains quaternary and amino functional groups on the glycoside units, of chitosan, was prepared through protectiondeprotection protocol (Seidi et al., 2016). Trimethyl chitosan derivative was prepared by multi-step reaction pathway (Scheme 26). N-(2-hydroxy) propyl-3-trimethylammonium chitosan chloride (HTCC) was prepared (Mivehi et al., 2008) in water soluble form by reaction of chitosan with glycidyl trimethyl ammonium chloride under neutral condition.

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In the study of Tan et al., (2016), some chitosan ammonium salts such as: chitosanbromoacetate, chitosan-(mono, di, tri)chloroacetate, and chitosan-trifluoroacetate were

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effectively prepared by one-step reaction. The prepared chitosan salts were water soluble and

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exhibited high antifungal activities.

A simple and green method of functionalizing chitosan was effectively performed by

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dissolving chitosan in a new solvent formed of alkali and urea (Song et al., 2018). Afterward, quaternized chitosan was prepared by reaction of the dissolved chitosan and 3-chloro-2-

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hydroxypropyl trimethyl ammonium chloride as quaternizing agent at different reaction times and temperatures.

phosphonium

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Tan et al., (2017) were innovated two cationic chitosan derivatives modified by quaternary salts throughout

trimethylation, chloroacetylation,

and reacted with

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tricyclohexyl and triphenyl phosphine (Scheme 27). Antifungal activities of the derivatives showed significantly improved antifungal efficiency compared to chitosan.

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N,N,N-trimethyl chitosan biopolymer and highly substituted N-alkyl-N,N-dimethyl chitosan were synthesized (Scheme 28)(Benediktsdottir et al., 2011) in efficient selectivity using ditert-butyldimethylsilyl-3,6-O-chitosan (di-TBDMS chitosan). Chitosan and glycidyl trimethyl ammonium chloride were used (Bu et al., 2012) to synthesize water soluble N-(2-hydroxy)propyl-3-trimethyl ammonium chitosan chloride (HTCC) (Scheme 29). The cationic chitosan derivative was used in modification of cotton fabrics to improve their aqueous pigment based inkjet printing and to act as antibacterial agent. HTCCtreated textile was performed superior crocking and laundering fastness than the untreated cotton textiles and antibacterial potential against Staphylococcus aureus Escherichia coli. N-trimethyl chitosan-poly(vinyl alcohol) (TMC-PVA) copolymers were synthesized (Scheme 30) in water (Martins et al., 2013) by variation PVA-succinate-TMC ratio. The effect of

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Journal Pre-proof PVA/TMC biopolymer at different polymerization ratios on the cytotoxicity and CC50 values was tested. Quaternized N-alkyl chitosan biopolymers with diverse alkyl substituents were synthesized (Vallapa et al., 2011) and evaluated as antibacterial agents against S. aureus and E. coli. The modified chitosan biopolymers showed enhanced efficacy during antibacterial activity. 5.2. Sulfated chitosan derivatives Sulfation of chitosan is preceded using different sulfating reagents, including: concentrated H2SO4 (Nagasawa et al., 1971), oleum (Vikhoreva et al., 2005), SO3, SO3/pyridine (Gamzazade et al., 1997), SO3/trimethyl amine (Je et al., 2005), SO3/SO2, and chlorosulfonic

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acid-sulfuric acid (Huang et al., 2003). Chemical modification of sulfated chitosan is fascinating due to its improvement of the structural similarity of chitosan salt to heparin

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(Paulo et al., 1999). The anticoagulant activity of sulfated chitosan is produced by the

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interaction of –SO42- groups and positively charged peptide segments. N-acetyl groups are shown to improve the anticoagulant activity. Sulfated chitosan showed anticoagulant as well

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as inhibition heama-agglutination activities due to the structural similarity to heparin (Cao et al., 2014). Other biological activities of chitosan sulfates including: antisclerotic, antioxidant,

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antibacterial, anti-HIV, antiviral, and enzyme inhibition were established (Xing et al., 2005). 6. Bounded chitosan to specific molecules

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6.1. Cyclodextrin (CD) linked chitosan

Chitosan bearing cyclodextrin derivatives were developed in order to combine the exceptional

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potential features of chitosan and cyclodextrin to form non-covalent attachment complexes with a number of species that alters the physicochemical properties for improved applications

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as medical delivery, and cosmetics (Prabaharan and Mano, 2006; Tanida et al., 1998). Cyclodextrin-linked chitosan derivatives (Scheme 31) have gained interests in numerous applications as: drug delivery, cosmetics and in analytical chemistry (Martel et al., 2001). There are different mechanisms for linking cyclodextrin and chitosan (Scheme 32). Several reports (Tanida et al., 1998) were reported the preparation of α-CD-linked chitosan using 2-O-formylmethyl-α-CD in reduction reaction with p-nitrophenol (Figure 8). Auzely-Velty and Rinaudo (2002) described analogous preparation of chitosan-cyclodextrin derivatives via reductive amination reaction by 4-tert-butyl benzoic acid (Figure 9), or by adamantyl groups. Cyclodextrin-chitosan derivative monoaldehyde was prepared and evaluated for mucoadhesion (Venter et al., 2006).

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Journal Pre-proof Chen and Wang, (2001) prepared cyclodextrin-chitosan biopolymer using tosylated βcyclodextrin (Scheme 33) and evaluated the product in the release of radioactive iodine (I131). The cyclodextrin-chitosan derivative was also synthesized by reacting monochlorotriazinyl cyclodextrin with chitosan biopolymer (Figure 10), in the presence of a spacer of triazinyl (Martel et al., 2001). The product was acted as adsorbent for textile dyes from wastewater. El-Tahlawy et al. (2006) used a novel technique for preparation of β-cyclodextrin-chitosan by the reaction of β-cyclodextrin citrate and chitosan biopolymer using formic acid solution as a reaction medium (Scheme 34), and the product was evaluated as antimicrobial agents. In

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another report, the reaction between β-cyclodextrin-itaconate and chitosan (Scheme 35) yielded a modified biopolymer utilized as ion exchange resin (Gaffar et al., 2006).

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β-cyclodextrin-chitosan modified by 1,6-hexamethylene diisocyanate was prepared (Chen et

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al., 2007) and evaluated as cholesterol adsorbent. The spacer can be 2-hydroxypropyl moiety introduced by grafting β-CD on chitosan using epoxy-activated chitosan (Scheme 36) (Zhang

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et al., 2004), reducing sugar derivative, and maleic spacer (Scheme 37) (Aime et al., 2006). An insoluble cross-linked chitosan bearing β-CD was prepared using N-succinyl chitosan and

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aminated-β-CD via amide bond formation in the presence of the water soluble 1-ethyl-3-(3dimethylaminopropyl) carbodiimide (Scheme 38) (Aoki et al., 2003).

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6.2. Thiosemicarbazone linked chitosan

Thiosemicarbazone-o-carboxymethyl chitosan derivatives were prepared (Mohamed et al.,

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2014) via by condensing thiosemicarbazide-o-carboxymethyl chitosan by: p-chloro benzaldehyde, o-hydroxy benzaldehyde, and p-methoxy benzaldehyde (Scheme 39). The

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prepared derivative showed improved antimicrobial action. Tailoring of chitosan through involvement of amino and hydroxyl groups by thiosemicarbazone derivatives (Scheme 40) gave derivatives with improved solubility and anticancer efficacy (Adhikari et al., 2018). Chitosan-oligosaccharide-thiosemicarbazide compound was synthesized in one-pot (Jinping et al., 2019) by reaction of chitosan-thiosemicarbazide and 2-pyridine carboxaldehyde (Figure 11). Antifungal behaviors evaluation of the products against P. capsici, P. nicotianae, F. graminearum was showed inhibiting efficacy at 74.19% and 66.60%, respectively. 6.3. Dioxime linked chitosan A new vic-dioxime-chitosan derivative was prepared (Demetgul and Serin, 2008) by heterogeneous reaction of chitosan and monochloro-glyoxime at room temperature (Scheme 41). 11

Journal Pre-proof New crosslinked derivative of chitosan was prepared (Timur, 2019) by the condensation reaction of chitosan and dichloro-glyoxime (Scheme 42). Metal ion uptake capacity of the obtained modified biopolymer was studied towards some selected transition metals ions of: Cu(II), Ni(II), Co(II), Fe(III) and Cd(II) in aqueous medium. According to the results of the analyses; water retention capacity and metal uptake capacity of new cross-linked chitosan derivative was higher than chitosan, and metal uptake sequence was Cu(II) > Fe(II) > Cd(II) > Co(II) > Ni(II) respectively. 6.4. Crown ether linked chitosan The literature showed new synthetic polymers carrying out both types of structures as well as

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general properties of both chitosan and crown ethers as well. Crown ethers have good complexing selectivity for metal ions due to their specific molecular structures. Crown ether

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bound chitosan were synthesized with Schiff’s base type reaction (Scheme 43) (Tang et al.,

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2002).

Wan et al. first prepared N-benzylidene chitosan (CNB) from chitosan and benzaldehyde.

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Chitosan-dibenzo-18-crown-6 crown ether (CNBD) and chitosan-dibenzo-18-crown-6 crown ether (CND) (Scheme 44) were prepared from 4,4-dibromodibenzo-18-crown-6 crown ether

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with CNB and CTN, respectively. Their adsorption and selectivity for Ag, Cu, Pb, and Ni ions showed that CNBD had better adsorption properties (Wan et al., 2002).

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Two kinds of novel chitosan-crown ether resins, Schiff base type chitosan-benzo-15-crown-5 (CTS-B15) and chitosan-benzo-18-crown-6 (CTS-B18) were synthesized through the reaction

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between-NH2 and -CHO (Scheme 45). Adsorption properties of CTS-B15 and CTS-B18 for Pd2+, Cu2+ and Hg2+ were studied and showed good adsorption characteristics and selectivity

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for Pd2+ when Cu2+ and Hg2+ were existed (Peng et al., 2003). Chemically stable porous aza-crown ether-crosslinked chitosan films were prepared (Toeri et al., 2017) by reacting different molar amounts of N,N-diallyl-7,16-diaza-1,4,10,13-tetraoxadibenzo-18-crown-6 (molar equivalents ranging from 0, 0.125, 0.167, 0.25 and 0.5) with chitosan (Figure 12). The crosslinking chemistry between allyl and amine groups of the reactants was further evidenced with solution NMR studies on model compound of glucosamine with the aza-crown. X-ray diffraction analysis of the chitosan/aza-crown films using wide angle X-ray scattering, revealed that the crystalline arrangement of chitosan was partially destroyed with increasing grafting of aza-crown ether proportion on chitosan polymer chain. 7. Conclusions

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Journal Pre-proof As a result of the presence of various reactive functional groups on chitosan biopolymer, it can be functionalized by numerous function groups. The functionalization of chitosan biopolymer can be addition, coupling, cross-linking or bounded to small molecules. The modification of chitosan biopolymer can be undergoes through substitution reaction according to thiolation, phosphorylation, N-phthaloylation. Crosslinking of chitosan can be performed using different crosslinking agents such as: glutaraldehyde, ethylene diamine tetraacetic acid and epichlorohydrin. Carboxylation of chitosan can be performed by attachment of different carboxylic acids by chitosan such as: free carboxylic acids, alkylcarboxylate, methacrylic acid, and benzoic acid. Ionic chitosan can be formed in different forms such as cationic and

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sulfated forms. Chitosan can be bounded to specific molecules such as cyclodextrin, thiosemicarbazones, dioxime, and crown ethers. The functionalized chitosan biopolymers

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have upgrade characteristics in drug delivery, gene delivery, antimicrobial activity against

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different germs, and enhanced metal uptake efficiency with high selectivity than the unfunctionalized chitosan.

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Acknowledgement

This work was supported and funded by Science & Technology Development Fund (STDF),

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Project No. 26370/2019. 8. References

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Figure 1: Chemical structure of chitosan.

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Figure 2: Functional groups in chitosan unit.

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Figure 3: Thiolated chitosan derivatives.

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Figure 4: Modified chitosan-beads by thiol groups.

Figure 5: p-Bromo-β-ketosulfone chitosan derivative.

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Figure 6: Chemical structure of epichlorohydrin cross-linked xanthate chitosan.

Figure 7: Chemical structure of chitosan modified by modified by linear poly anhydrides.

Figure 8: α-CD-linked chitosan using 2-o-formylmethyl-α-CD.

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Figure 9: Chitosan-cyclodextrin derivative obtained by reductive amination reaction.

Figure 10: Chemical structure of monochlorotriazinyl cyclodextrin-chitosan biopolymer.

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Figure 11: Condensation product of chitosan-thiosemicarbazide and 2-pyridine carboxaldehyde.

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Figure 12: Chemical structure of aza-crown ether crosslinked chitosan.

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Scheme 1: Synthesis of different thiolated chitosan derivatives.

Scheme 2: Phosphorylation of chitosan using phosphorus pentaoxide.

Scheme 3: Phosphorylation of chitosan using orthophosphoric acid. 26

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Scheme 4: Phosphorylation of chitosan using mono-(2-methacryloyl oxyethyl) phosphoric acid.

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Scheme 5: Phosphorylation of chitosan using phosphoric and formaldehyde.

Scheme 6: Functionalization of chitosan by phosphorous acid and formaldehyde.

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Scheme 7: Reaction of cellulose nano-fibrils with phosphoric acid.

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Scheme 8: Formation of photocrosslinkable chitosan derivatives.

Scheme 9: N-phthaloyl chitosan derivative.

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Scheme 10: N-phthaloylation reaction of water-soluble chitin with phthalic anhydride.

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Scheme 11: Grafting of chitosan by glutaraldheyde.

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Scheme 12: Formation of aminated chitosan.

Scheme 13: Grafting of ethylene diamine tetraacetic acid (EDTA) on chitosan biopolymer. 30

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Scheme 14: Formation of chitosan/ethylene diamine tetraacetic acid-graphene oxide nanocomposite.

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Scheme 15: Fabrication of chitosan-ethylene diamine tetraacetic acid-p-cyclodextrin.

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Scheme 16: Chitosan-epichlorohydrin modified biopolymer.

Scheme 17: Preparation of carboxymethyl chitosan in its quaternized form.

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Scheme 18: Interaction of mono- and dicarboxylic acids with chitosan in screw extruder.

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Scheme 19: Interaction of mono-carboxylic acids with chitosan.

Scheme 20: Modification of chitosan by succinic, maleic, and phthalic anhydrides.

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Scheme 21: Formation of Water soluble chitin-methacrylate.

Scheme 22: Esterification of chitosan and methacrylic acid.

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Scheme 23: Formation of chitosan grafted-poly(ethylene glycol) methacrylate copolymer.

Scheme 24: Chemically functionalization of chitosan by 3-nitro-4-amino benzoic acid.

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Scheme 25: Modification of chitosan by benzoic acid and p-methoxybenzoic acid.

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Scheme 26: Formation of trimethyl quaternary chitosan using protection-deprotection protocol.

Scheme 27: Formation of cationic chitosan derivatives modified by quaternary phosphonium salts. 36

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Scheme 28: Formation of highly substituted N-alkyl-N,N-dimethyl chitosan.

Scheme 29: Synthesis of N-(2-hydroxy)propyl-3-trimethyl chitosan ammonium chloride.

Scheme 30: Formation of N-trimethyl chitosan- poly(vinyl alcohol) (TMC-PVA) copolymers.

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Scheme 31: Modification of chitosan by cyclodextrin derivatives.

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Scheme 32: Mechanisms of linking cyclodextrin and chitosan.

Scheme 33: Preparation of cyclodextrin-chitosan using tosylated β-cyclodextrin.

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Scheme 34: Reaction of β-cyclodextrin citrate and chitosan biopolymer.

Scheme 35: Reaction of β-cyclodextrin-itaconate and chitosan. 39

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Scheme 36: Grafting of β-CD on chitosan in the presence of 2-hydroxypropyl spacer.

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Scheme 37: Grafting of β-CD on chitosan in the presence of sugar and maleic spacer.

Scheme 38: Preparation of chitosan-β-cyclodextrin via amide bond formation.

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Scheme 39: Condensation of thiosemicarbazide-o-carboxymethyl chitosan and aldehydes.

Scheme 40: Preparation of chitosan thiosemicarbazide modified biopolymer.

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Scheme 41: Synthesis of monochloro-glyoxime chitosan modified polymer.

Scheme 42: condensation of chitosan and dichloro-glyoxime.

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Scheme 43: Formation of crown ether-chitosan derivative via Schiff’s base type reaction.

Scheme 44: Preparation of chitosan-dibenzo-18-crown-6 crown ether (CNBD) and chitosan-dibenzo-18-crown-6 crown ether (CND).

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Scheme 45: Preparation of chitosan-benzo-15-crown-5 (CTS-B15) and chitosan-benzo18-crown-6 (CTS-B18) derivatives.

CRediT author statement

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Nabel A. Negm: Conceptualization, Methodology, Writing - Review & Editing, Project

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administration.

Hassan H. Hefni, Maram T.H. Abou Kana: Conceptualization, Methodology, Writing.

lP

re

Ali A. Abd-Elaal, Emad A. Badr: Validation and Investigation

Highlights

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Chitosan biopolymer can be functionalized by numerous function groups. Functionalization can be addition, coupling, and crosslinking.

Jo

ur

Modification of chitosan upgrades its potential applications.

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