Chemical Modification of Inulin, a Valuable Renewable Resource, and

Spring 2001

Published by the American Chemical Society

Volume 2, Number 1

© Copyright 2001 by the American Chemical Society

Reviews Chemical Modification of Inulin, a Valuable Renewable Resource, and Its Industrial Applications Christian V. Stevens,*,† Alessia Meriggi,† and Karl Booten‡ Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium, and Orafti, Aandorenstraat 1, B-3300 Tienen, Belgium Received November 27, 2000; Revised Manuscript Received January 29, 2001

Inulin, the polydisperse reserve polyfructose from plants such as Cichorium intybus (chicory), has been chemically modified in several ways to obtain industrially important biodegradable compounds. This review provides an insight on the different types of modification (neutral, anionic, and cationic modification as well as cross-linking and slow release applications) and describes its differences from starch and cellulose chemistry. It also highlights the applications of various compounds cited in the literature. Review Contents 1. Introduction 2.. Neutral Modification 2.1. Reduction of Inulin 2.2.Synthesis of O-(Cyanoethyl)inulin and Its Derivatives 2.2.1. Reduction of O-(Cyanoethyl)inulin 2.2.2. Synthesis of O-(3-Amino-3-oxopropyl)inulin 2.2.3. Synthesis of O-(Carboxyethyl)inulin 2.2.4.Synthesis of O-(3-Hydroxyimino-3-aminopropyl)inulin 2.3. Esterification of Inulin 2.4. Etherification of Inulin 2.5. Formation of Dialdehyde Inulin 2.6. Synthesis of Inulin Carbamate 2.7. Coupling of Inulin and Amino Acids 2.8. Synthesis of Methylated Inulin 2.9. Synthesis of Inulin Carbonate 2.10. Synthesis of Modified Cycloinulohexaose 3. Anionic Modification 3.1. Synthesis of O-(Carboxymethyl)inulin 3.2. Synthesis of Polycarboxylate Inulin by Oxidation 3.2.1. Oxidation with NaIO4/NaClO2 3.2.2. Oxidation Using Sodium Hypochlorite 3.2.3. Oxidation Using Pt Catalysis 3.2.4. Oxidation with TEMPO 3.3. Synthesis of Inulin Phosphates

1 3 3 3

4. 5. 6.

3 4 4 5 5 6 6 7 7 8 8 8 9 9 10 10 10 10 11 11

7.

3.4. Synthesis of Complexing Agents Derived from Oxidized Inulin Cationic Modification Cross-linking of Inulin Slow Release 6.1. Slow Release of Procainamide 6.2. Slow Release of Metronidazole 6.3. Inulin Derviatives with a Carrier Function Conclusion

11 11 13 13 14 14 14 15

1. Introduction The name inulin has been used for the first time in 18181 to indicate a new compound isolated from Inula helenium in 1804.2 Later, it has been shown that inulin is formed in several plants as a reserve polysaccharide and sometimes even in combination with starch. It took until 1950 to elucidate the structure of inulin. It is a polydisperse polysaccharide consisting mainly, if not exclusively, of β(2f1) fructosyl fructose units (Fm) with normally, but not necessarily, one glucopyranose unit at the reducing end (GFn).3,4 It is also known that the fructose molecules in the GFn form are all present in the furanose form. Only in the Fm forms, the ending and reducing fructose is in the pyranose form.5 Further studies on the structure of inulin showed that inulin is a slightly branched fructan: the amount of β(2f6)† ‡

Ghent University. Orafti.

10.1021/bm005642t CCC: $20.00 © 2001 American Chemical Society Published on Web 02/22/2001

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Stevens et al.

branches in chicory and dahlia inulin is 1-2% and 4-5%, respectively.6 The structure of the crystalline inulin has been investigated thoroughly, and different models have been developed. Electron diffraction patterns and X-ray powder diffraction studies revealed that the unit cell of the hydrated crystalline polymorph (one molecule of water per fructosyl unit) is orthorhombic and the semihydrated polymorph (half a molecule of water per fructosyl unit) is pseudohexagonal7 or orthorhombic8 and consists of two antiparallel 6-fold helices. Others suggested a model corresponding to 5-fold helices.9 In solution, models of a DP-5 (DP ) degree of polymerization) oligomer showed that a single helical conformation is preferred but that this conformation is not possible for longer oligomers due to severe steric interactions.10

Figure 1. Dionex chromatograms for Sigma’s dahlia and chicory inulin.

without formation of monosaccharides.16 As a result, no increase of glycemy or insulin is detected in the blood. In the large intestine, inulin is fermented by the intestinal microflora17 and studies in vitro have shown that inulin stimulates growth of the bifidobacteria.18

The DP of inulin varies from 2 to 70 and mainly depends on the type of plant from which it is isolated, on the weather conditions during the growth, and on the physiological age of the plant.11 The most important sources of inulin are Cichorium intybus (chicory), Dahlia pinuata CaV. (dahlia), and Helianthus tuberosus (Jerusalem artichoke) which have an average DP of 10-14, 20, and 6, respectively.12 Analysis of the composition of inulin is mostly performed by highpressure anionic exchange chromatography (HPAEC) coupled to a pulsed amperometric detector (PAD). Typical chromatograms of different plants are given in Figure 1. This analytical method permits the separation of all inulin oligomers and the discrimination between GFn and Fm derivatives. Unfortunately, the sensitivity of this method decreases with increasing molecular weight, preventing direct quantitative analysis.13 Inulin can also be synthesized enzymatically after transfer of the fructosyltransferase gene of Streptococcus mutans into Escherichia coli.14 The native inulin, present in many common foodstuffs,15 is largely employed because of its properties as dietary fiber. When used as food ingredient, inulin is only hydrolyzed in small amounts in the stomach and in the small intestine

These bifidobacteria are important because they inhibit the growth of several pathogenic intestinal bacteria such as Clostridium perfringens, Escherichia coli, Shigella, Listeria, Vibrio cholerae, etc. Inulin is metabolized in the large intestine by the bacteria into short-chain fatty acids (SCFA), lactic acid, and gas. The produced SCFA are absorbed by the large intestine and are further metabolized in the liver. This pathway is less efficient compared to the absorption of carbohydrates in the small intestine; thus the caloric value of a fructosyl unit of oligofructose is between 1 and 1.5 kcal/g or 30-40% of a digested fructose molecule.19 These properties make inulin favorable as an ingredient for diabetic foods.20 In addition, the use of inulin reduces the level of triglycerides in the blood and increases the high density lipoprotein (HDL) to low density lipoprotein (LDL) ratio.21 Native inulin can also be used as a fat-replacer: when an aqueous solution of inulin is vigorously stirred for a few hours, a smooth cream, which is suited for the replacement of fats in dressings, ice cream, spreads, baked goods, and dairy products, is obtained.5 Other important effects of inulin have been recently underlined,22 especially in the medical field. It has been demonstrated that a basal diet for mice containing 15% of inulin, inhibits significantly the growth of mouse tumors,23,24 especially colon25 and mammary tumors.26 A detailed overview on the use of inulin in the food industry, however, is beyond of the scope of this review. Recently, many efforts have been devoted to the chemical modification of inulin in order to develop industrial products

Chemical Modification of Inulin

based on renewable resources and with specific characteristics. This review gives an overview of the different methods of modification (excluding hydrolysis reactions and modification of hydrolyzed products) and indicates the industrial application areas of the modified inulin. Because many applications are cited in the patent literature, it is not always possible to define the applications precisely. The review is divided in three parts covering the modification resulting in neutral, anionic, and cationic end products (although a strict separation of the derivatives is not made in order to avoid a fragmentary review with many overlapping parts). Within this review, the structure of inulin and modified inulin is given to illustrate the selectivity of the reactions or to specify the position of the substituents in the modified inulin. In other cases, the inulin will be represented by GFn-OH. 2. Neutral Modification The section dealing with the neutral modification of inulin is further divided into subchapters according to the introduced moiety on the inulin backbone or according to the type of reaction that was used for the modification. 2.1. Reduction of Inulin. Inulin and its derivatives have a drawback in modification reactions in alkaline medium because of intense coloration and undesired formation of side products. This is believed to originate from the presence of short-chain analogues of inulin containing reducing groups, for example, glucose, fructose, and fructosylfructose.27 Inulin was found to have a residual reducing power of 0.5-2.5% (after removal of mono- and disaccharides) from the native inulin. These disadvantages can be overcome by treating the inulin with a reducing agent, e.g., sodium borohydride, molecular hydrogen, and a catalyst, or by electrochemical reduction, before further modification. 2.2. Synthesis of O-(Cyanoethyl)inulin and Its Derivatives. The cyanoethylation of polysaccharides has been described on cellulose and starch.

Cyanoethylated starch28 possesses good emulsifying and dispersing properties and is used in the textile industry.29 However, the relatively high viscosity of the solutions and the low solubility of the modified products substantially reduce their application. The cyanoethylation of inulin is therefore performed in an analogous manner by Michaeltype addition using acrylonitrile. The lower molecular weight of inulin was believed to result in lower viscosity of the solutions and a better solubility.30 Because the efficiency of the reaction is diminished using water as a solvent, which reacts with acrylonitrile producing 3-hydroxypropanenitrile and bis(2-cyanoethyl) ether,31 the reaction conditions have been optimized. A study was performed to determine the minimum, but necessary, amount

Biomacromolecules, Vol. 2, No. 1, 2001 3

of water in the reaction, the influence of temperature, the sodium hydroxide concentration, and the molar ratio of acrylonitrile/inulin. The highest acrylonitrile efficiency (AE) was obtained with a molar ratio inulin/water/NaOH of 1/17/ 0.2 at 45 °C and after 30 min of reaction. The concentration of NaOH was also critical since the cyanoethylation reaction is reversible and de-cyanoethylation starts at a higher pH due to β-deprotonation of the cyano function. The cyanoethylinulin 2 with a low degree of substitution (DS) is soluble in water (DS < 1.5), on the contrary the product with a high DS is insoluble (DS > 1.5). The distribution of the substituents in O-(2-cyanoethyl)inulin (2) has been studied using the statistical method developed by Spurlin32,33 for derivatives of cellulose.34,35 It confirms that the most reactive position is the hydroxy group at the C-4 carbon. This result can be explained by the higher acidity of the secondary alcohol in comparison with the primary one on the C-6 carbon and by the sterical hindrance on the C-3 carbon which is oriented cis with respect to the hydroxyl group at the C-6.36 The cyanoethylated inulin 2 is used as starting material to produce the corresponding amine via reduction, the O-carboxyethylinulin via hydrolysis, and the amidoxime by reaction with hydroxylamine. 2.2.1. Reduction of O-(Cyanoethyl)inulin. The nitrile group in 2 can be reduced to the corresponding primary amine using sodium borohydride in the presence of cobalt chloride hexahydrate.37 Activation of the nitrile function by complexation with the cobalt metal center polarizes the C-N bond so that the electrophilic carbon can be easily attacked by the hydride. During the reaction, Co(II) is reduced by sodium borohydride to Co(0) and Co(II) catalyzes the degradation of borohydride into H2 and borate. Therefore, a large excess of sodium borohydride and cobalt chloride is required.

The reduction can also be performed by catalytic hydrogenation of 2 using transition metal catalysts such as Pt/C, Ru/C, and Raney nickel, but only traces of primary amines were formed. Better results were obtained using Raney cobalt as a catalyst leading to a 10% conversion of the O-cyanoethyl groups in O-aminopropyl groups.36 The yield decreases with increasing chain length and with the degree of substitution of the starting material. This inhibition can be explained by adsorption of the reaction products onto the catalyst surface: primary amines are known to adsorb strongly onto Raney nickel compared to nitriles38 and the adsorption of polymeric products is normally stronger compared to monomers because of the multiple binding sites of the former. A better yield can be obtained either by adding ammonia to the reaction mixture (in order to enhance the desorption of amines from the catalyst surface)31 or by adding acid (to form protonated amines which have less affinity toward the catalyst). Reduction can also be performed using a metal

4


Stevens et al. Scheme 1

Scheme 2

(sodium, lithium, calcium) in liquid ammonia and methanol.39,40 In the absence of methanol, 25% of the primary amino groups were formed and 75% dealkylation of the O-(cyanoethyl) groups occurred. This result can be explained by the basicity of the solvent41 which gives rise to the deprotonation of the β-CH2 group with respect to the cyano function. When methanol is added as a cosolvent and a proton source, the basicity decreases and the yield of the reaction increases from 25% to 70%.

in order to prevent decomposition of the glycosidic bonds and to prevent decyanoethylation of the starting material. When hydrogen peroxide was used, no hydrolysis into carboxylate groups was detected. The peroxide anion attacks the nitrile group,43 and the product is formed by decomposition of the intermediate percarboxylic imide.

The O-(3-amino-3-oxopropyl)inulin (8) is also synthesized by Michael-type addition of acrylamide to inulin. 8 with a DS of 1 was obtained when inulin (1 equiv of fructose units) was reacted with 2 equiv of acrylamide, so that the maximum acrylamide efficiency was 50%.36 8 can be used as a surfactant or as an emulsifying compound (especially after introduction of a long alkyl chain on the amide) or can be hydrolyzed to give O-(carboxyethyl)inulin (9) (anionic species).

The O-(aminopropyl)inulin (3) can then be converted to the corresponding stearoyl amide 4 (Scheme 1) as shown using stearoyl chloride. The product shows good surfactant and emulsifying properties. The reaction with sodium chloroacetate gives the corresponding N-carboxymethylaminopropylated inulin 5 (anionic species) which is used as a sequestering agent in detergent formulations, as a dispersing agent, and as crystallization inhibitor for calcium carbonate. Aminopropylinulin 3 can also be converted to the 1-oxo3,6,9,9-tetrakis(carboxymethyl)-3,6,9-triazanonanoyl-3-aminopropylinulin 7a and 1,11-dioxo-3,6,9-tris(carboxymethyl)3,6,9-triazaundecanedioyl-bis(3-aminopropyl) derivative 7b (anionic species) by reaction with DTPA (diethylenetriaminepentaacetic bisanhydride) 6 (Scheme 2). Those products are used as contrast agent for diagnostic purposes, e.g., magnetic resonance imaging after complexation with lanthanide metals such as Gd or Dy.42 (See also section 6.3.) 2.2.2. Synthesis of O-(3-Amino-3-oxopropyl)inulin. The nitrile group can be converted into the corresponding amide by hydration using a small amount of hydrogen peroxide under mild basic conditions.36 Mild conditions are required

2.2.3. Synthesis of O-(Carboxyethyl)inulin. The nitrile function can be converted into the carboxylate function via transformation into the amide and subsequent hydrolysis with sodium peroxide44 in alkaline medium. The reaction occurs via an intermediate peroxy compound which decomposes into the carboxylate. However, partial dealkylation and partial degradation of the chain length are observed due to the alkaline medium.36 The O-(carboxyethyl)inulin (9) (anionic species, see also section 3.1) obtained shows excellent crystallization inhibition properties for sparingly soluble salts such as calcium carbonate. The crystallization inhibition property is higher at lower DS, for example, DS ) 0.65, because of the glycosidic bond cleavage which occurs during the synthesis of products with a higher degree of substitu-


tion.36 9 can also be used as metal ion carrier, dispersing agent, and hair fixative when mixed with 8.


The esterification of inulin is performed by reaction with acid chlorides or with anhydrides of suitable carboxylic acids in which the introduced alkyl chain can range from 1 to 22 carbon atoms (13).

2.2.4. Synthesis of O-(3-Hydroxyimino-3-aminopropyl)inulin. The cyanoethylated inulin is also a precursor for the corresponding amidoxime by reaction with hydroxylamine in neutral medium. About 80% of the O-(cyanoethyl) groups are converted into the product without any dealkylation.36

This product shows very good properties as a chelating agent for transition metal ions, especially for Cu(II) ions.

Amidoximes can exist in two geometrical and tautomeric forms, but the syn-hydroxyimino form 11 is the most stable one because of the formation of an intramolecular hydrogen bond.45,46 The chelating properties have been studied by potentiometry, polarimetry, and particularly using 17O NMR techniques. At a low molar ratio of Cu(II): amidoxime, stable complexes with a 1:2 stoichiometry, are formed and the optical rotation measurement indicates a conformational change of the inulin backbone that folds to form intramolecular complexes. At a high molar ratio, no additional binding is observed which suggest that defolding of the 1:2 complex to form a 1:1 complex does not occur. 2.3. Esterification of Inulin. Low molecular weight carbohydrate esters have been studied extensively and have been exploited in several industrial applications, e.g., as nonionic surfactants.47 Sucrose acetate and mixed esters with a high degree of substitution are also being used as bleaching agent activators and as plasticizers or softeners. Polymeric saccharides with a high molecular weight, especially starch esters, are used as sizing agents in the textile industry, as a surface glue in paper industry, and as thickeners in the film and fiber industry. Because of the envisaged amelioration of the solubility, attention has been paid to the synthesis of inulin esters. The inulin esters 13 have important advantages compared to other saccharide esters in that they are more soluble and can, therefore, be processed more easily compared to cellulose derivatives. The hydrophilicity or the hydrophobicity can be varied by changing the DS of the end products, so that a large number of compounds with different degrees of solubility can be synthesized.

The esterification reaction is usually performed in pyridine, dimethylformamide, or dimethyl sulfoxide or in the absence of a solvent using a kneader or (preferably) an extruder in order to reduce the thermal burden. The speed of the reaction can be increased using an acidic or basic catalyst, e.g., 4-(dimethylamino)pyridine, sodium acetate, potassium carbonate, ion-exchange resins in the acid or basic form, etc. With this methodology, it is possible to obtain products with a DS between 0.3 and 1,48 except for acetylated inulin where it is also possible to have a complete derivatization with a DS of 3.49,50 Variation of the length of the alkyl chain or the degree of substitution yields products with a wide variety of characteristics. In particular, inulin esters with a short chain and a low average degree of substitution (DS < 1) are able to decrease the surface tension of aqueous solutions. They form micelles at low concentrations (low cmc ) critical micelle concentration), making them suitable as additives in detergent formulations. The same inulin esters with a high degree of substitution (DS > 1) have a low tendency to migrate in films and sheets. They are however particularly suitable for use as plasticizers.47 Inulin esters with a long alkyl chain can be used as surfactants in laundry and dishwashing detergents, in cosmetics, or in pharmaceuticals as an emulsifier. They are also used in the textile industry as an additive and in the paper or paint industry because of their high surface activity. A very recent patent describes the use of acetylated inulins, obtained by reaction with acetic anhydride in the presence of sodium acetate in water at 120 °C (DS ) 0.8-1.6), as outstanding bleach activators comparable to tetraacetylethylenediamine and having a better biodegradability.51 By reacting inulin with cyclic anhydrides, the esterification is accompanied by the introduction of a carboxyl group, producing anionic species at the same time. Reaction between inulin and succinic anhydride allowed the preparation of succinoylated inulin in quantitative yield and with a desired degree of substitution. 1H NMR analysis suggested that the C-3 hydroxyl function is more reactive toward succinoylation than the C-4 position.52,53 Inulin esters are also applied as a crystallization modifying agent. The separation efficiency during the fractionation of triglyceride oils can be increased by adding a small amount of the so-called “crystallization modifying agent”. These

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Stevens et al.

products contain at least 50% of the hydroxyl groups esterified with C8-C24 unbranched fatty acids and the remaining ones are esterified with C1-C7 acid chlorides, preferably with acetyl chloride. A very good result has been obtained for the fractionation of palm oil by addition of 0.01-1 wt % of the inulin derivatives on the total amount of oil.54 2.4. Etherification of Inulin. The etherification of inulin with epoxides such as ethylene oxide 14a and propylene oxide 14b in aqueous medium in the presence of a basic catalyst, mostly sodium hydroxide 2-10% (w/w) or a basic ion-exchange resin, has been described in a recent patent.55 This reaction leads to the etherified products 15 (n ) 1) together with some derivatives after a consecutive reaction with the epoxide (n ) 2). The use of a basic ion-exchange resin gives the advantage that the product does not need to be neutralized (aqueous hydrochloric acid), thus avoiding considerable amounts of salt in the end product.

The reaction was performed with a 20-50% solution (w/ w) of inulin at temperatures of 40-100 °C. The desired degree of substitution could be obtained by varying the amount of epoxide added to the reaction mixture and is ranging from 0.1 to 2, but preferably from 0.5 to 1 for most of the applications. It was noted that the reactivity as well as the solubility in water decreased with an increasing chain length of the epoxide. This solubility problem could be solved by addition of small amounts of 2-propanol. The purification of the modified inulin could be done by cation exchange chromatography (in the case a hydroxide base was used), followed by drying of the product. The modified inulin derivatives show a better solubility in cold water and also show an inverse solubility pattern which means that they precipitate at 45-60 °C and solubilize again during cooling of the mixture. The products show a viscosity of 15-25 mPa for 3% (w/w) solutions and also a moderate to good reduction of the surface tension (29-65 mN/m).

Also the reaction with epichlorohydrin 16 has been performed and the 3-chloro-2-hydroxypropyl 17 derivative was obtained in a very good yield.56

In the old literature the etherification of inulin was also described using allyl bromide 18 and sodium hydroxide as basic catalyst.57

The etherified products are industrially quite interesting and are claimed to be useful in cosmetics and in pharmaceuticals as carriers for water-insoluble substances or as stabilizing agents for aqueous solutions of poorly soluble molecules. Other potential applications are as emulsifiers or as additives in the textile and paper industry and as softeners for thermoplastic polymers. 2.5. Formation of Dialdehyde Inulin. Neighboring hydroxyl groups of polysaccharides can be easily oxidized to aldehyde functions using periodate as oxidizing agent (Scheme 3).58 The use of periodate is suitable because only the gem-diol is oxidized to two aldehyde functions. The reaction progress can be determined by titration of excess periodate in the solution using standard iodometry.56 The generated aldehyde functions (20) can form hemiacetals either within the oxidized unit of fructose by an intramolecular reaction or with a hydroxy group from a neighboring fructose unit by an intermolecular reaction (21).56 Probably an equilibrium exists between the hemiacetal and the free aldehyde or their solvated form. This mechanism is confirmed by kinetic studies and also by the formation of the corresponding diphenyl-formazan.59 The kinetic data give an indication of the occurrence of an inter-residual hemiacetal formation56 during the periodate oxidation.60 The hemiacetal formation reduces the accessibility of the aldehyde function considerably towards further nucleophilic reactions with, e.g., amines, and thus also its application.

Scheme 3


Chemical Modification of Inulin Scheme 4

Scheme 5

The modification of inulin with an alkyl isocyanate in a polar organic solvent has also been described recently. The resulting inulin carbamates 22 possess tensioactive properties and can be used in detergent formulations and as an emulsifier in cosmetics or pharmaceutical applications.62

2.6. Synthesis of Inulin Carbamate. A new chromatographic application of inulin derivatives has been described for the separation of mixtures of enantiomers by liquid chromatography using modified inulin as a stationary phase.61 Inulin was modified using isocyanates, normally methyl isocyanate, to obtain inulin carbamates. The reaction is

performed in the presence of a basic catalyst such as a tertiary amine or a Lewis acid (e.g., a tin compound). The resulting powder can be used directly or can be supported on a stationary phase in order to prevent its swelling or shrinking and to improve the number of theoretical plates. The carriers normally used include porous organic or inorganic carriers such as polystyrene, polyacrylate or silica, alumina, silicates, etc. The inulin carbamate can be packed in a column, applied in a capillary column as a coating, or spun into fibers so that a bundle of fibers can be used as a column.

2.7. Coupling of Inulin and Amino Acids. Coupling of inulin and amino acids has been performed utilizing Nprotected amino acids in the presence of (dimethylamino)pyridine (DMAP) as catalyst and dicyclohexyl carbodiimide (DCC) as condensing agent (Scheme 4).63 The reaction was performed under mild conditions and the products Cbz-Gly-inulin 23a and Cbz-Lys-inulin 23b were obtained in good yield (67% and 72%, respectively) and were fully characterized. The correct DS values were determined by amino acid analysis after acid hydrolysis. The maximum DS obtained was 1, even after addition of 2 equiv of amino acid, due to the steric hindrance of the hydroxyl groups and due to the high viscosity of the reaction mixture. In comparison with inulin, the products show a slightly increased viscosity and a lower melting point (186.9 for inulin and 135.2 and 122.3 for the modified products 23a and 23b, respectively). The second reaction step involves the deprotection of the amino group by hydrogenation using palladium on activated carbon (10 wt %) as catalyst and 1,4cyclohexadiene as a hydrogen donor. The products obtained (24) are used as starting material for liquid-phase peptide synthesis and chelating agent for metal ions. They can also be used for attaching various drugs or some biologically

Scheme 6

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Stevens et al.

active compounds such as the arginine-glycine-aspartic acid (RGD) peptide. 2.8. Synthesis of Methylated Inulin. In a few old papers, the complete methylation of inulin is reported.64-66 The reaction involves first a treatment of inulin with a potassium hydroxide solution at 70 °C for 2 days. After the mixture is cooled at 30 °C, dimethyl sulfate is added to the solution and methylated inulin 25b is obtained in a very good yield and with a DS of maximum 2.5 (Scheme 5). To synthesize a fully methylated inulin, the reaction was also performed using methyl iodide and silver oxide. The trimethyl inulin 25a has been characterized by elemental analysis, by studying the [R]D values of different products, and by hydrolysis to yield 3,4,6,-trimethylfructofuranose.44,67 2.9. Synthesis of Inulin Carbonate. Inulin carbonates have been studied because of their potential for the insolubilization of biologically active molecules.68 The trans-2,3carbonate group can be utilized for the formation of active, water-insoluble covalent derivatives of enzymes, immunoglobulins, ... (e.g., cellulose-2,3-carbonate for human immunoglobulin IgE). Although unprotected polysaccharides usually produce a mixture of cyclic and acyclic carbonates, inulin carbonate was prepared by reaction of inulin with ethyl chloroformate 26 in dimethyl sulfoxide in the presence of triethylamine as catalyst. The reaction leads to two products

(Scheme 6) with an IR absorption at 1750 and 1820 cm-1, respectively. The first one was attributed to the presence of the O-ethoxycarbonyl group (27) and the second one partially to the trans-2,3-cyclic carbonate group on the terminal D-glucose residue (29) and to the trans-4,6-carbonate on the fructofuranose residues of the inulin chain (28), which both contain strained carbonate rings. From this study, it appeared that the higher the carbonate substitution of inulin, the more soluble the end product became in the reaction medium (DMSO). 2.10. Synthesis of Modified Cycloinulohexaose. Cycloinulohexaose 30 is synthesized by reaction of inulin with cycloinulo oligosaccharide fructanotransferase.69 Chemical modifications of the chiral 18-crown-6 structure have been investigated for their application in the construction of artificial enzymes or receptors. A first derivatization involved the sulfonylation of the primary hydroxyl function using 2-naphthalenesulfonyl chloride (Scheme 7). The reaction gave rise to the formation of all three possible regioisomers 30, 31, and 32 in a very low yield. With a change to biphenyl-4,4′-disulfonyl chloride, a selective derivatization could be performed since the structure of the starting material only permitted the reaction on the primary hydroxyl group in relative positions A and

Scheme 7



Inulin was carboxymethylated by heating an aqueous solution with monochloroacetic acid (MCA, 39) in the presence of an excess of sodium hydroxide. Using an aqueous medium, competition between carboxymethylation and hydrolysis of MCA into glycolic acid 40 was detected.76

C (34). Treatment of 34 with thiophenol/Cs2CO3 led to the corresponding sulfide 36. Since the transannular sulfonates can be substituted by a nucleophile, it was possible to synthesize chiral crown ethers having a functional group at the specific positions 6A and 6C.70 Cycloinulohexaose 30 was also permethylated, peracetylated, and perbenzoylated. The complexation behavior of the permethylated compound with various metallic guest cations has been determined. A series of association constants (Ks) with metallic cations in acetone (Li+ < Na+ < Cs+ < K+ < Ba2+) show that the selectivity pattern is similar to that of 18-crown-6, but its binding abilities (KS) are a factor 100 lower. It was shown that the metallic ion is not captured by the central hole of the 18-crown-6 moiety but that it is in the pocket constructed both by the upper rim 3-OMe oxygens of the furanose ring and by the crown ether oxygens.71 3. Anionic Modification Because negatively charged molecules behave very differently from neutral molecules, their synthesis and applications are described in a separate chapter. The chapter is further divided into subchapters according to the introduced moiety or according to the type of oxidation generating the anionic species. 3.1. Synthesis of O-(Carboxymethyl)inulin. The carboxymethylation reaction has been performed using mono-, oligo-, and polysaccharides. Particularly, carboxymethyl cellulose72,73 (CMC), dicarboxymethyl cellulose,74 and carboxymethyl sucrose75 (CMSU) are used as metal ion carrier and in detergent formulations (as anti-redeposition agent and as cobuilder), to prevent calcium carbonate crystallization during the washing of laundry. However, CMC has a relatively high viscosity which allows only limited use in detergent compositions, whereas CMSU does not possess any crystallization inhibition properties. To expand the range of applications of carboxymethylated products, carboxymethylation of inulin 38 was studied.

Many efforts have been performed in order to improve the MCA efficiency (calculated as (DS obtained/ratio MCAinulin)). The influences of the reaction temperature, the amount of water, and the ratio between MCA and inulin have been studied. The MCA efficiency was higher at a lower molecular ratio of MCA-inulin and with a decrease in the amount of water used during the reaction. Maintaining the molar ratio MCA-inulin between 0.5-1 and 4-1, products with a degree of substitution of 0.21-1.05 were obtained. The best reaction conditions for products with a low DS were found by applying a molar ratio inulin/MCA/NaOH of 1/2/ 4; the MCA efficiency in this case was maximum 0.42. The DS of the products could be determined using 13C NMR techniques, HPLC analysis, and by titration of the carboxylic acid groups after treatment with an acidic cation-exchange resin.36 It has been demonstrated that during the carboxymethylation of cellulose the C-2 position in the glucose unit is more reactive than the C-3 and the C-6 position.77,78 In contrast to cellulose, the carboxymethylation of inulin is not a selective reaction and neither temperature nor concentration of the reaction mixture influences the substitution. The molecular weight distribution of the products has been determined by gel permeation chromatography (GPC). O-(Carboxymethyl)inulin (CMI, 38) is a good inhibitor of the crystallization of calcium carbonate even at very low concentrations (5-200 ppm), has a good biodegradability, and is now industrially manufactured for that application. It was observed that products with a higher DS prolong the induction period for crystallization because of the ability of the anionic carboxylate groups to absorb on the crystal surfaces. The complexation between 38 and CaII has also been studied using multinuclear magnetic resonance spectroscopy and potentiometry. LnII ions (DyII, GdII, and LaII) were used as model ions for CaII, because they give rise to significant NMR effects after coordination, such as chemical shift changes and relaxation rate enhancements in 1H, 13C, and 17O spectra. After analysis of the NMR data, it was possible to prove the existence of a tri-tetradentate equilibrium in which two carboxylate oxygen atoms (an ethereal oxygen atom and a hydroxyl group) are involved at the same time.79 9, whose synthesis has been described previously, shows also the inhibition of crystallization of calcium carbonate and performs even better than 38.80 CMI can be used as well for further modifications using a diamine and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride consecutively in order to prepare alkalistable polysaccharides. These were utilized for coupling to immunogen carriers or to sheep red blood cells for use in hemaglutination.81

10



3.2. Synthesis of Polycarboxylate Inulin by Oxidation. Selective oxidation of oligo- and polysaccharides yields polycarboxylates with many potential applications. Glycolic oxidation of polysaccharides such as starch, cellulose, etc. gives rise to ring-opened polycarboxylates which show very good calcium binding.82,83 Therefore, they can substitute nonbiodegradable synthetic polymers such as polyacrylate, presently used as cobuilder84 in detergent formulations.84-86 However, there is still some doubt about the biodegradability of the starch and cellulose derivatives, because of their high molecular weight.68 The oxidation of inulin has been performed in order to obtain products with similar complexation properties but with a higher biodegradability. In particular, partially oxidized inulin behaves quite differently from partially oxidized starch with respect to the binding of calcium ions. The sequestering capacity of oxidized starch is low at a low degree of oxidation. It only improves when the degree of oxidation is more than 40% because two neighboring oxidized glucose units are required to provide a strong calcium binding. In the case of inulin, a linear relation exists between the degree of oxidation and the calcium sequestering capacity because each oxidized fructose unit results in coordination.87 Several methods have been investigated for the oxidation of inulin.88 3.2.1. Oxidation with NaIO4/NaClO2. Oxidation of inulin can be performed in a two-step reaction using sodium periodate in the first step to form dialdehyde inulin (see section 2.5) and sodium chlorite or sodium chlorite together with hydrogen peroxide in the second one (Scheme 8).87 Due to the formation of stable hemiacetal compounds in the first reaction step, the end products initially showed a poor calcium binding capacity.87 3.2.2. Oxidation Using Sodium Hypochlorite. Inulin can also be oxidized in a one-step reaction using sodium hypochlorite in the presence of sodium bromide in order to improve the reaction rate.

The catalytic effect of bromide is explained by the formation of the more active oxidant (hypobromite) upon oxidation with hypochlorite.89

NaClO + NaBr f NaBrO + NaCl The best results were obtained by adding the oxidant in one portion to the reaction mixture and carrying out the oxidation at a pH higher than 10. These conditions were important in order to prevent disproportionation of the reagents taking place at pH 7 for hypochlorite and at pH 9 for hypobromite. Because of the hydrolysis of inulin, the reaction could not be performed at a pH lower than 7. 3NaClO f NaClO3 + 2NaCl

pH < 7

3NaBrO f NaBrO3 + 2NaBr

pH < 9

The products (41) are isolated in very good yield (80-95%). By variation of the amount of sodium hypochlorite, it is possible to obtain products with a different degree of oxidation, which can easily be determined by titration of the acidic form with sodium hydroxide. The calcium carbonate binding capacity was found to be excellent (2.0-2.5 mmol of Ca/g), comparable to that of commercial builders and better than the products prepared from starch.90 The sequestering activity of the oxidized inulin shows indeed a linear relationship with the degree of oxidation of inulin. 3.2.3. Oxidation Using Pt Catalysis. Oxidation of carbohydrates using Pt catalysis has been studied extensively,91,92 especially the oxidation of sucrose.93,94 Similarly, the oxidation of inulin has been investigated and the reaction is performed preferentially using O2 as oxidant and Pt as catalyst in the presence of sodium hydroxide.36

The reaction is monitored by the consumption of sodium hydroxide and the degree of oxidation is determined after hydrolysis by quantitative 13C NMR or by HPLC. It was observed that the chain length of the starting material can influence the reaction rate and the degree of oxidation. The decrease of the reaction rate is confirmed by the values of the initial turnover frequencies for the oxidation which are 234, 114, and 42 min-1 for methyl R-D-fructofuranoside, sucrose, and inulin, respectively. Particularly, the amount of byproducts increases with an increasing molecular weight of the saccharide and with an increasing degree of oxidation.



The low conversions obtained with inulin can be explained by a combination of site-covering of the catalyst with starting material or with byproducts and by the low affinity of the platinum surface for carboxylates already formed. The maximum degree of oxidation is limited to 20%. Another consequence of the strong adsorption of the starting material on the catalyst surface is the lower selectivity of the oxidation for the primary hydroxy function compared to monomeric substrates. The selectivity for the C-6 position in inulin is 65% at 25% conversion in comparison with 83% at 100% conversion for methyl R-D-fructofuranoside. Also degradation of inulin was detected during the reaction using GPC. 3.2.4. Oxidation with TEMPO. Recently, a new method for selective primary alcohol oxidation of polysaccharides has been developed.95,96 Inulin was oxidized using 2,2,6,6tetramethyl-1-piperidinyloxy (TEMPO) as a catalyst which can be oxidized itself by a hypobromite/bromide system in combination with a hypochlorite/chloride system. The actual oxidizing agent is the nitrosonium ion. The selectivity of the oxidation of primary hydroxy groups compared to secondary hydroxy groups is good which makes TEMPO very suitable to use in carbohydrate chemistry. However, oxidation of the primary hydroxy groups is followed by further oxidation at C4 and C6, which can lead to degradation of the molecule. Therefore, the reaction needs to be quenched after 1 mmol of sodium hydroxide per millimole of anhydrofructose is added in order to keep the selectivity >90% (87% yield). 3.3. Synthesis of Inulin Phosphates. Inulin phosphates have been synthesized by reaction with sodium trimetaphosphate (43) (Scheme 9). The reaction gives rise to the formation of the mono- and diphosphates 44 and 45, respectively.97 Spectrophotometric methods may be used to determine total phosphate content, but it is not possible to distinguish between the two forms. The phosphate derivatives show an increased viscosity compared to native inulin, and this remains relatively constant even up to temperatures of 60 °C when they start to dissolve. Both native inulin and its phosphate derivatives form “thermoreversible gels” which are stable at room temperature and melt at temperatures above 60 °C. Phosphate derivatives are also obtained by reaction of inulin with phosphorus oxychloride. The reaction is performed in

pyridine during 12 h, and the products are analyzed by the determination of the total phosphorus content. This method reveals that the reaction of inulin with 1 equiv of POCl3 leads to inulin monophosphate 44 only.98 3.4. Synthesis of Complexing Agents Derived from Oxidized Inulin. Several heavy metals such as zinc, cadmium, etc., are found in sludge and manure, which are used as building soil or fertilizer, respectively. These materials should be treated as waste or the heavy metals need to be removed. The most important process to remove heavy metals is the complexation using an aqueous solution of ethylene diaminotetraacetic acid (EDTA) as sequestering agent. The disadvantage of using EDTA is its poor biodegradability and the fact that a large amount of EDTA is required due to the preferential complexation and flocculation of the Ca complex. Therefore, inulin derivatives have been synthesized in order to evaluate the replacement of EDTA for the complexation of heavy metals.99 The oxidation of inulin with sodium periodate gives rise to the formation of the dialdehyde 20 (vide supra). In the second step, the dialdehyde 20 is reduced to the corresponding diol 46 using sodium borohydride or reduced catalytically using Pt/C and hydrogen (Scheme 10). The resultant polyol 46 can be derivatized in order to obtain different products with good complexing properties. The polyol 46 either can be reacted with carbon disulfide in the presence of NaOH yielding xanthate 47 or can be reacted with SO3-pyridine in order to obtain the inulin sulfate 48. The regiospecificity of the reaction was not determined. The dialdehyde 20 can also be reductively aminated using diaminoethane (49) and sodium cyanoborohydride. Compound 50 was then reacted with monochloroacetic acid sodium salt leading to formation of carboxymethylamino inulin derivative 51. The DS of these inulin derivatives ranges from 0.2 to1.5. The products 47, 48, and 51 are suitable complexing agents and can be used to precipitate heavy metals as an alternative to EDTA. 4. Cationic Modification Because of the interesting properties of the positively charged polysaccharides, cationic modification of inulin has also been investigated. Cationic inulin normally contains a nitrogen group which can be a quaternary ammonium group or a primary, secondary, or tertiary amine (positively charged

12



Scheme 11

in acidic medium). In a recent patent several modifications of inulin have been described,100 applying several reagents such as N,N,N-tris(2-chloroethyl)amine, N,N,N-tris(3-chloro2-hydroxypropyl)amine, trialkylammoniumethyl-2-chloroethyl ether, substituted aziridines, 2-dialkylamino-3-halopropionamide, 2-dialkylamino-3-halopropionic acid, and 4-chloro-1-methylpiperidine. Also hydroxyalkylated, carboxymethylated, and oxidized fructans can serve as the basis for the cationic modification leading to multifunctionalized inulins. The introduction of cationic groups on inulin derivatives containing carboxyl groups leads to amphoteric

compounds such as 54 (Scheme 11) which have interesting properties. The reactions are normally performed in aqueous medium, in the presence of a base and at a temperature ranging from 30 to 150 °C. An advantageous process for these reactions involves the use of an extrusion reactor with intensive kneading and a small amount of solvent. After the reaction, the mixture is neutralized following the addition of an acidic solution. The product is purified from salts using normal techniques such as electrodialysis, nanofiltration, or precipitation with an



Scheme 13

alcohol. The degree of substitution of the products ranges from 0.1 to 1.5 and the reaction efficiency (calculated as (DS obtained/molar ratio inulin-reagent)) is 80-90%. Reduced inulin (see above) is particularly suitable for conversion into cationic derviatives with the reagents mentioned above. Alternatively, dialdehyde-inulin can be reductively aminated to produce aminopolyols 50 which can be quaternized to produce the cationic derivatives 56 (Scheme 12). Cationic derivatives of inulin show a better solubility, a lower viscosity, and a better biodegradability than the known cationic polysaccharides. Derivatives with a high degree of substitution (DS g 1) can be used as desinfectants or as an ingredient for hair conditioners and molding gels: they can neutralize the excess negative charge on the hair lamellae and have a moisturizing ability. Another application is as shale inhibitors in oil extraction because of the ability to shield the negative charge in the clay layers over which the drilling mud is fed. They can be also used as flocculants and corrosion inhibitors (in the treatement of sludge, effluent, and process water), as demulsifier (in the metal-processing and petrochemical industries), as textile additives (like softeners, antishrink agents, and agents promoting color), as adhesives, and as an auxiliary for the building, plastics, and ceramics industries. A particular application of aminated inulin, produced by reaction of inulin with 2-bromoethylamine hydrobromide in DMSO, was also evaluated in the study of the detection of diffuse glomerular lesions in rats. The aminated inulin, however, did not differentiate between controls and rats with glomerular disease any better than DTPA, probably because the number of amino groups conjugated was insufficient to produce the charge effect.101

to develop superabsorbers and drug delivery systems. Therefore, inulin has been treated with epichlorohydrin. Investigation of the physical and chemical properties of these cross-linked samples revealed their ability to swell in waterproducing gels and to form complexes with higher thermostability in comparison with inulin.102 Another method to synthesize cross-linked inulin consists of the reaction with glycidyl methacrylate 57 (GMA)103 in order to introduce double bonds, which could be cross-linked in a radical way (Scheme 13). However, transesterification of inulin and glycidyl methacrylate takes place instead of epoxide ring opening. This result can be explained by (dimethylamino)pyridine (DMAP) catalysis resulting in the formation of the methacryloylpyridinium salt, which is easily attacked by a hydroxyl group of inulin. Methacrylation of inulin takes place on the carbon C-6 resulting in products with a DS ranging from 0.015 to 0.1. The reaction efficiency, calculated as the ratio between (DS obtained/DS theoretical), is quite high (0.7-0.8) and seems to decrease with the increase of the molar ratio of GMA to inulin. The free radical polymerization of methacrylated inulin using ammonium persulfate (APS) or N,N,N′,N′-tetramethylenediamine (TMEDA) as an initiating system, gives rise to inulin hydrogels by conversion of the double bonds into covalent cross-links. Rheological experiments were performed in order to follow the gelation process. Determination of the elastic modulus of hydrogels revealed that their rigidity and their biodegradability is related to the degree of substitution and to the concentration used to produce hydrogels.104 The dynamic and equilibrium swelling properties of the inulin hydrogels have also been studied in order to evaluate their ability as colon-specific drug delivery systems.105,106

5. Cross-Linking of Inulin

6. Slow Release An interesting application of soluble macromolecules, especially blood-compatible polysaccharides, consists of their

In view of the gelatinizing characteristics of native inulin in water, the cross-linking of inulin has been studied in order

14



Scheme 15

Scheme 16

utilization in the medicinal field as drug carrier in order to optimize the rate of delivery of therapeutic agents.107 Dextrans are used as plasma expanders, displaying blood flow improvement and a thrombophylatic effect. Native inulin can be used as an inert extracellular marker for studying the processes of receptor-mediated, endocytotic uptake or diffusion-controlled uptake by cells. Once inulin is internalized, it is useful as an intracellular marker for quantification of cellular uptake, because it can neither diffuse easily out of a cell nor be readily degraded by intracellular enzymes. Consequently, inulin has been used as a reliable marker for studying the intracellular uptake of drug delivery systems. Inulin is also a nondiffusable marker for studying the processes of transport of drugs or drug carriers through diffusional barriers of layers of cells, such as the epythelial barrier in the skin, the stratum corneal, and the endothelial layers of the blood-brain barrier. Biodegradable hydrogels, previously discussed, are evaluated as colon-specific drug delivery systems because they are degraded by the colonic bacteria, normally bifidobacteria, so that the drug loaded in the hydrogels is released.

6.1. Slow Release of Procainamide. The pynocitic properties of inulin drug conjugates have been investigated, and procainamide 60 has been chosen as a model drug. In the body, free procainamide gains access to all body compartments by passive diffusion. Linkage to a polymer (Scheme 14), however, prevents diffusion and restricts the uptake of the drug into cells by a mechanism known as pinocytosis. As described above, the oxidation of inulin with sodium periodate gives rise to the formation of the corresponding dialdehyde 20. The procainamide or a N-(ω-aminoalkanoyl)procainamide is then introduced by formation of the corresponding Schiff base, followed by reduction with sodium cyanoborohydride. However, the yield of the imination reaction is low due to the formation of intra- and intermolecular bonds, which prevents further reaction. An alternative approach for preparing inulin-procainamide consists of the coupling of inulin with epichlorohydrin and formation of the 3-chloro-2-hydroxypropylinulin, which was reacted with procainamide.56 The pinocytic uptake of inulin-procainamide into yolk sac cells by fluid-phase pinocytosis was studied. The study revealed that the capture rate depended on several factors such as drug loading and the nature of the spacer used for the attachment of the drug to inulin.108 6.2. Slow Release of Metronidazole. Macromolecular derivatives of metronidazole, an antiprotozoal compound, have been synthesized in order to evaluate the slow release of this active ingredient after administration, because this could lead to an enhanced duration of activity, a reduced toxicity, and possibly to cell targeting. Metronidazole has been reacted with succinic anhydride in the presence of (dimethylamino)pyridine (DMAP) as catalyst, and the corresponding monosuccinate 63 was coupled with inulin (64) (Scheme 15). Better results were obtained using 1,1′carbonyldiimidazole (CDI) as coupling agent in the presence of triethylamine (TEA) and DMAP as coupling promotors. The degree of esterification of the products was determined to be 43.5% with a yield of 96%.109 6.3. Inulin Derviatives with a Carrier Function. The synthesis and the potential application of a diethylenetriaminepentaacetic acid (DTPA) derivative of inulin with liposomes as a model of a drug delivery system have been investigated. In the first reaction step, N-protected ethylenediamine is coupled with diethylenetriaminepentaacetic anhydride (DTPA anhydride) (Scheme 16).110



The obtained product 67 was then reacted with inulin dialdehyde followed by NaBH3CN reduction of the imine bond (Scheme 17). The four-step synthesis of the DTPA-conjugated inulin proceeded in a good overall yield of 72%. The radiolabeling of the liposome-entrapped 69 also proceeded in high radiochemical yield (>85%). This liposome-entrapped inulin derivative 69 can be loaded with radioactive heavy metal cations such as 111In3+ or 67Ga3+, and the stability of the formed complex makes 68 a versatile marker for many applications in studying transport and delivery of drugs. Because of the macromolecular size, the hydrophilic nature of inulin, and the fact that inulin is not metabolized to any significant extent, the tissue distribution allows the estimation of the intracellular delivery of drugs by the liposomal drug delivery system. Following the intravenous administration of the liposomal encapsulation of the indium-111-labeled inulin derivative, the entrapped compound had a biodistribution characteristic for liposomes and allowed an estimation of the extent of the intracellular uptake of the liposomes. The chelate conjugated inulin permits studies of drug delivery in primates or human subjects by noninvasive techniques such as γ-scintigraphic or NMR-imaging methods. Similar approaches were also used to prepare water-soluble gadolinium(III) DTPA inulin conjugates111 and GdIIIDO3A inulin complexes (prepared via O-aminopropylinulin)112 (DO3A ) 1,4,7,10-tetraazacyclodecane-1,4,7-triacetic acid) as magnetic resonance imaging (MRI) contrast agents. The GdIIIDTPA complexes were more efficient proton-relaxation agents than the corresponding low-molecular-weight metal chelates at 10 MHz but less efficient than the corresponding protein derivatives. The GDIIIDO3A inulin complexes, however, are promising potential MRI contrast agents, because they are very efficient relaxation-rate-enhancing compounds, especially the complexes with a high degree of substitution. 7. Conclusion Because of considerable interest in the chemistry and use of renewable resources, an overview is given on the chemical modification of inulin, classified in terms of the charge of the end products. The link with the use of these compounds as industrial reagents is made as much as possible although claims are always quite broad in the patent literature. The further development in the production technology of inulin and other renewable resources will certainly result in more

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