Bio‐Based Polyurethanes from Carbohydrate Monomers

The production of sustainable and environmentally friendly materials constitutes a growing field of attention. The incorporation of sugar-derived units into traditional step-growth polymers such as polyamides, polyesters, and polyurethanes is a healthy method to prepare novel biodegradable and biocompatible materials for application in the biomedical field and other sectors such as foodstuff packaging.


Introduction
The exhaustible nature of the oil reserves and the pollution that oil-based technological polymers cause on the environment because of their low degradability have intensified the interest in natural renewing resources for the chemical synthesis of polymers. Thus, sustained efforts have been extensively devoted to render new polymers based on natural renewing resources with higher degradability [1,2].
Among the diverse natural sources, carbohydrates constitute highly convenient raw materials because they are inexpensive, readily available, and provide great stereochemical diversity. They are produced in large amounts by plants and microorganisms every year, and in some cases they even come from agricultural wastes. So, in the last few decades many research groups have been investigating on the preparation of new polymers, analogous to the more significant technical polymers, but based on monomers synthesized from natural and available sugars [3]. However, although several polymers have been synthesized using sugar-derived monomers with free hydroxyl groups [4][5][6], most syntheses of high-molecular-weight linear polymers involve derivatives having the hydroxyl groups appropriately blocked [3,7].
Synthetic polymers obtained from sugar-based monomers are innocuous for human health. Their hydrophilic nature ensures a greater hydrolytic degradability [3], and reduces their environmental impact compared to classic polymers. Thus, the incorporation of sugar-derived units into traditional step-growth polymers constitutes an excellent approach to prepare novel biodegradable and biocompatible materials for application in the biomedical field and other sectors such as foodstuff packaging.
This chapter describes polyurethanes (PU) having the sugar units incorporated into the main chain. This topic has been partially reviewed before, but during the recent years numerous papers on the subject have been published. Thus, the following sections report on the syntheses, main properties, and applications of this type of sugar-based polymers that have been published mainly during the past decade. Patents have not been included so as to make the reference list more concise.

From diol-diisocyanate
Among the different procedures followed for the synthesis of [AABB]-type polyurethanes (PU), the most widely used is the classical isocyanate-based route, a polyaddition reaction of diols (or polyols) and diisocyanates (or polyisocyanates) ( Figure 1, Table 1). This is a simple synthetic method conducted under inert atmosphere and in the absence of moisture at room temperature or above (from 25 to 80 C), either in solution or in bulk, with excellent conversions within 3-24 h for an extensive group of starting monomers. When the preparation of sugar-based PU is attended, the isocyanate-based method has been the route of choice so far, the sugar moiety being generally incorporated into the diol monomer.
In sugar-based PU, the polyisocyanates and polyisothiocyanates most widely used are displayed in Figure 3, most of them being commercially available.
Other isocyanate-based routes are those in which a rearrangement of several acyl derivatives such as acyl azides (Curtius rearrangement), carboxamides (Hofmann rearrangement), a n dh y d r o x a m i ca c i d( L o s s e nr e a r r a n g e m ent) conducts to the isocyanate monomer in situ ( Figure 1). Thus, an article on the preparation of bio-renewable polyurethanes through Curtius rearrangement has been published. Initially, the synthesis of two new non-hindered diisocyanates based on isosorbide (1) and isomannide (20) without using petroleum-based reagents was attempted. The diisocyanates formation was carried out as follows: first, diols 1 or 20 were esterified with succinic anhydride in bulk at 120 C; second, the acidic derivatives were transformed into the corresponding diacid chlorides at low temperature, and lastly the diacid chlorides led to the diisocyanate derivatives 47 and 48 via a two-step Curtius rearrangement with overall conversions ranging from 52 to 60% [28]. Both diisocyanates were proved to be useful as starting materials in the preparation of two PU: a stereoregular PU (with D-manno configuration in all the monomers) and a non-stereoregular PU (with D-gluco configuration).  To conduct the synthesis of linear [AB]-type homopolyurethanes, both the nucleophilic and the electrophilic groups (e.g., hydroxyl and isocyanate groups [32,41,42]) need to be present in one sole monomer ( Table 2).
Thiem and coworkers were the first to attempt this approach with success in order to synthesize sugar-based PU. They published the preparation of 2-deoxy-1,4:3,6-dianhydro-2-isocyanato-Liditol (50)f r o mi s o s o r b i d e ( Figure 4), and the difunctional monomer proved to be suitable to polymerize in the presence of a catalyst [32].

Eco-friendly methods (isocyanate or/and stannous free) to prepare PU
Although polymerization reactions of diisocyanates with diols are the main method to synthesize linear PUs, in the last few years and due to the toxicity of stannous catalysts and common aromatic diisocyanates such as 4,4'-methylenediphenyl diisocyanate (MDI) and toluene diisocyanate (TDI), a large number of works have been reported in literature on the synthesis of isocyanate-free PU, also called non-isocyanate PU (NIPU) ( Figure 1, Table 3). Two interesting reviews have been recently published in which alternative pathways for PU syntheses are studied in detail [43,44]. Aspects of Polyurethanes

Dicarbamate and diols
One of the methods to use is the transurethanization polymerization between a dicarbamate and a diol in which the side product is an alcohol, usually of low-molecular weight. For example, linear polyurethanes with free hydroxyl groups have been successfully prepared by Galbis et al. [6] from xylitol (55) and the aliphatic carbamates dimethyl hexamethylenedicarbamate (HDC, 56) or di-tert-butyl-4,4'-diphenyl methyl dicarbamate (MDC, 59), to render NIPU with enhanced hydrophilic character.

Bis(chloroformate) and diamines
To avoid the use of diisocyanates, a variety of new materials can also be obtained by polycondensation of diamines with freshly prepared bis(chloroformate)s. For example, two reactive bis (chloroformates) were formed from methyl ether diols of L-arabinitol and xylitol (73, 74, Figure 5). They were polymerized with commercial diamines (cystamine and cystine dimethyl ester) by interfacial polycondensation using sodium lauryl sulfate as surfactant [48]. The new  Table 2. Selected examples of the use of a sole carbohydrate-based monomer for the preparation of PU.   Table 3. Summarized literature about linear sugar-based PU prepared by eco-friendly alternative pathways.

Aspects of Polyurethanes
NIPU, bearing the labile disulfide bond in their structure, were degradable under reductive environments.
It was demonstrated that the presence of methoxycarbonyl side groups in the PU makes those materials more degradable, not only under hydrolytic conditions but also under reductive environments, probably due to their lower crystallinity and a better water/glutathione penetration in their structure. Moreover, differential scanning calorimetry (DSC) studies showed that the incorporation of the abovementioned pendant methoxycarbonyl groups into the homopolymers resulted in a more rigid material.
This synthetic method provides a useful tool toward the synthesis of chemical diverse NIPU because of the large set of commercial diamines available and the excellent on-hand chemical procedures for the synthesis of amines.

Dicyclocarbonates and diamines
Among the numerous pathways leading to NIPU, the polyaddition of cyclic carbonates with amines seems to be the most interesting route, and it is being widely investigated by numerous research groups (Figure 1). This method has been tested in sugar derivatives by Prömpers et al.
Similarly, Besse et al. reported the preparation of linear and branched isosorbide-based polyhydroxyurethanes, with low T g values (from À8t o5 9 C) [47]. The isosorbide-based dicyclocarbonate monomer 70 (Figure 7) was prepared from a diepoxide according to the method previously described by Brocas et al. [49].
However, this route displays two major drawbacks: the low reactivity between cyclic carbonates and amines, and a limited degree of advancement of reaction during the room-temperature polymerization that leads to low-molecular-weight PHU. Consequently, highly polydisperse, low-molecular-weight materials were isolated.

Synthesis of cross-linked sugar-based PU and segmented PU
For the preparation of cross-linked sugar-based PU, a monomer with functionality above two is required. Just one work was found in which the cross-linker was a triisocyanate derived from L-lysine derivative [35]. In general, the cross-linking is accomplished by the use of a mono-or a disaccharide with all its hydroxyl groups unprotected. Thus, glucose and sucrose are widely used in the formulations of carbohydrates-based networks [38-40, 50, 51] although    other monosaccharide and disaccharide derivatives such as xylaric acid [37], maltose [36], and glucosides [51] have also been chosen ( Table 4). For example, Ates et al. [34,36] prepared some non-aromatic cross-linked polyurethanes with potential use as surgical tissue adhesives. PEG diol 81 and 4,4'-methylenebis(cyclohexyl isocyanate) (MCHI, 82) were polymerized with a certain amount of a sugar (maltose, sucrose, or xylose) as cross-linker. The reaction was carried out in THF or DMF-THF mixtures, at high temperatures in the absence of catalyst or adding triethylamine (TEA). The material cross-linked with xylose 55 [34] displayed high adhesiveness and biocompatibility properties, making it suitable for being used in the medical field. Depending on the final use of the cross-linked material, the reaction can be conducted in bulk [33,38,40,50].  [51] (in combination with other diols) can lead to segmented PU as well as carbohydrates-based cross-linked materials with differentiated regions. The synthesis can be carried out "one pot," in which the polyols are incorporated into the polymer feed together with the sugar-based monomers and the other components. For example,the synthesis of highly functionalized low-molecular-weight polyether-polyols initiated by PGL and mixtures of PGL and sucrose has been described [33]. In the "one pot" preparation of rigid polyurethane foams in bulk and using MDI as diisocyanate, the polyether and/or polyols constituted the soft segment.
Even though materials obtained "one pot" displayed good physical and mechanical properties, excellent dimensional stability as well as low friability, an improvement of microphase separation can be accomplished when the polymerization is performed in two stages and the flexible polyol is incorporated in the first step [23,26,27]. The last step promotes the formation of urethane or urea linkages, in the so-called hard region with a high density of hydrogen bonds that provides stiffness to that section and elastomeric properties to the final product.
Koning et al. have investigated water-borne polyurethanes based on isosorbide (1) and other renewable building blocks, such as amino acids and fatty acids [26,27,53]. The synthesis of waterdispersible polyurethanes prepolymers was carried out from 1, ethyl ester L-lysine diisocyanate (46), dimethylpropionic acid, and a dimer fatty acid-based diisocyanate [53]. The regioselectivities of the endo-and exo-OH functional groups of 1 and the primary ε-NCO and secondary α-NCO of 46 were found to have only minor consequences for the formation of NCO-terminated PU prepolymers. PU dispersions prepared from these four-component prepolymers showed good storage stability. Fully renewable poly(ester urethane urea)s (PEU) were also synthesized from bio-based starting materials: the renewable polyester diol poly(1,2-dimethylethylene adipate), isoidide diisocyanate (11), and  Thermoplastic and cross-linked bio-based PU with tailored properties and high renewable carbon content were synthesized from isosorbide (1), 1,3-propanodiol, and 1,1,1-tris-(hydroxymethyl) propane as the cross-linker reagent, in bulk by varying the molar ratio of the components and without using any chemical catalysts [55].

Other conformationally restricted linear PU
The bicyclic structures of the dianhydrohexitols (1, 20, 21) provide conformational restriction and stiffness to the polymer chain, with a significant increase in the T g . Galbis et al. [7] reported new conformationally restricted linear polyurethanes based on bicyclic carbohydrate-based monomers having D-gluco, galacto,a ndD-manno configurations (33, 43, 44)a nd their secondary hydroxyl groups protected as cyclic acetals ( Figure 9). The T g values of these conformationally restricted polymers were similar to those observed for the polyurethanes [PU(Is-HDI) and PU(Is-MDI)] based on the isosorbide (1) [52] and higher than their acyclic analogs. They also proved that the diacetalization of the sugar unit of the polyurethane chain improved the thermal stability, which was comparable to those based on isosorbide.
The two orthoesters 86 and 87 having a rigid adamantane-like structure (Figure 10), obtained from naturally occurring myo-inositol (85), were used as new triol-and diol-type monomers to give the corresponding networked and linear polyurethanes by polyaddition reaction with diisocyanates [56].

Aspects of Polyurethanes
The linear polyurethanes obtained from 87 showed high values of T g , ranging from 105 to 177 C, due to the rigidity of the adamantane-like structure units introduced into the main chains. T g 's of the networked polyurethanes obtained from 86 were higher than those of the linear polyurethanes, and ranged from 155 to 248 C.

PU with enhanced hydrophilicity
PU with free hydroxyl groups (PHU) have been synthesized from acetalized sugar-based monomers, mainly isopropylidene and benzylidene groups, which are very easily cleaved under acidic conditions. Thus, deacetalization of those polyurethanes containing di-Oisopropylidene-D-mannitol units (44) yielded multihydroxy polymers in good yields without apparent degradation of the polymer chain ( Figure 9) [7]. The latter polymers showed enhanced hydrophilicity and hydrolytic degradability as well as lower T g values and thermal stability than their acetalized counterparts.
Polyaddition reaction of L-gulonic acid-based diols (16,17) to diisocyanates, followed by the hydrolysis of the isopropylidene groups, yielded PU containing lactone rings and free hydroxyl groups in the main polymer chains (Figure 12) [11]. The free hydroxyl groups also enhanced the hydrolysis of lactone rings and, hence, of carbamate groups in the polyurethanes. The multihydroxy polyurethane prepared from L-gulonolactone 16 and HDI was degradable at pH 8.0 under mild temperatures.  (4), and subsequent deprotection in acidic media [23]. Likewise, copolyurethanes from 37 and poly(oxytetramethylene) glycol were also prepared to estimate the effects of the D-mannitol unit on their degradability.
The O-benzyl derivatives 29, 31, and 32 with L-arabino,L -threo,a ndxylo configurations, respectively, were used to prepare PU, and the effect of pendant bulky benzyl groups in the polymer chain was investigated [16,17]. The removal of benzyl groups was attempted by hydrogenolysis, and the best results were obtained for the PU derived from L-threitol and HDI, which became debenzylated up to 70%. It was found that O-benzylated PU were highly resistant to hydrolytic degradation, whereas PU with free hydroxyl groups degraded to a great extent under physiological conditions.
To achieve a facile preparation of sugar-based multihydroxy PU, the use of unprotected saccharides was also investigated. Thiem et al. reported the synthesis of novel PU and polyureas based

Aspects of Polyurethanes
on modified glycosylamines and glucosamines by catalytic polymerizations [31]. It was found that the anomeric hydroxyl groups were more reactive than the amino groups.
The selective reaction of primary hydroxyl groups of xylitol (55) with dimethyl hexamethylene dicarbamate (HDC, 56)orditert-butyl-4,4'-diphenyl methyl dicarbamate (MDC, 59) led to two new linear polyurethanes [PU(X-HDC) and PU(X-MDC)] ( Figure 13) [6]. Likewise, by the reaction of xylitol with the analogous diisocyanates HDI or MDI, similar polyurethanes [PU(X-HDI) and PU(X-MDI)] were obtained. However, the reaction conditions needed to be adjusted, and so low temperatures were required. Even so, a certain degree of cross-linking was encountered because of the higher reactivity of the diisocyanate comonomers. PU(X-MDC) and PU(X-MDC) were semicrystalline materials showing well-defined melting transitions with high melting enthalpies.
Two novel sugar-based polyol monomers from methyl α-D-glucopyranoside and sucrose and epoxidized methyl oleate were synthesized ( Figure 14) [51]. Linear and cross-linked PU were obtained by polyaddition with isophorone diisocyanate (80) as comonomer, at 60 C using DBTDL as catalyst. The amphiphilic nature of the sugar-based monomers had a marked impact on the final product isolated. Thus, linear or cross-linked PU were obtained depending on the solvent used, that is, DMF or THF. It was found that the polyol monomers were fully soluble in DMF, and therefore cross-linked PU were obtained. By contrast, the formation of linear PU with one pendant sugar moiety per monomer unit was attained in THF. The hydroxyl functions from the sugar moiety were quasi nonreactive under those conditions due to the self-assembly of the sugar-based polyols into nanoparticle structures.
Although polyurethanes are widely investigated, their sulfur analogs, polythiourethanes (PTU), are a relatively poorly investigated group of polymeric materials [57]. The synthesis and characterization of a new linear functional polythiourethane based on D,L-1,4-dithiothreitol [PTU(DTT-HDI)] has been accomplished ( Figure 15), and its properties as excipient in drug release formulations investigated [58]. This PU with free hydroxyl groups in its structure showed a major ability  to form matrix systems and promoted a significant decrease in the release rate of the model drug theophylline; as a result, it proved to be an excellent controlled release matrix forming excipient.
An homopolyurethane with free secondary hydroxyl groups based on 3,4-O-isopropylidene-D-mannitol and 2,2'-dithiodiethyldiisocyanate has been used as sustained matrix forming excipient for site-specific drug release in the gastrointestinal tract [59].
The reaction of diglycerol dicarbonate, synthesized from diglycerol and dimethyl carbonate, and various diamines led to amorphous poly(hydroxy urethane)s, in bulk at mild temperatures, without any catalyst. The abundance of hydroxyl groups along the polymer backbones allows curing purposes and/or further functionalization [60]. Very rigid polyurethane foams with high cross-linking density were obtained from sorbitol-based polyols. The cross-linking density of the formed PU network was directly modified by the polyol mixture ratio, and microstructure and properties also changed in consonance. The incorporation of different amounts of a diol with longer chain length between hydroxyl groups allowed fixing the rigidity of the foams [61].  The O-protected L-threitol, L-arabinitol, and xylitol diols (24-26, 29, 31, 32) were used [14] to prepare a series of linear [AABB]-type PU ( Figure 16) by polyaddition reaction to HDI (3) and MDI (23). The O-methyl-protected polyurethanes derived from 38 and 39 were amorphous and their T g was highly dependent on the aliphatic or aromatic nature of the diisocyanate used. The hydrodegradability of these PU was conditioned by the number of methoxy side groups present in the repeating unit.
In order to enhance degradability, a series of homo-and copolyurethanes containing the hydrophilic monomer [triethylene glycol (TEG)] and 1,4-di-S-benzyl-D,L-dithiothreitol (DTTSBn) (34) with HDI (3) [19] was synthesized ( Figure 17). Enzymatic degradation studies were carried out with a variety of proteolytic and esterase enzymes. They were thermally stable up to 250 C, and PU(TEG-HDI) homopolymer was degraded under physiological conditions. In addition, a study of the properties of this PU as matrix-forming excipient for controlled drug delivery was carried out [20].

Reductive degradation
Galbis et al. reported the introduction of disulfide linkage into the polymer backbone of novel reduction-sensitive biodegradable sugar-based polyurethanes. Although hydrolytical degradation of PU has been extensively reported, a faster degradation method under milder degradation conditions was achieved mediated by glutathione (GSH) [21]. Thus, polyaddition reactions of mixtures of 2,2'-dithiodiethanol (DiT) and 2,3,4-tri-O-methyl-L-arabinitol (25), 2,3,4-tri-O-benzyl-L-arabinitol (29) or L-arabinitol (35)toHDI(3) were carried out ( Figure 18). PU(DiT-HDI) homopolymer exhibited high crystallinity but the introduction of the L-arabinitol-based diols led to a reduction in the crystallinity of the copolymers. All the copolyurethanes were biodegraded under physiological conditions being crystallinity an important factor in the degradation rate. Thus, the amorphous copolymers with low DiT repeating unit contents were more easily cleaved, despite the lower disulfide ratio. Their DiT repeating units do not pack into semicrystalline segments and

Functional PU
The chemical modification of polymers is an important task for further applications. In this sense, click chemistry (CC) is the most popular approach to achieve chemical transformations; for instance, the thiol-ene coupling reaction of a thiol and an alkene/alkyne and the alkyne-azide cycloaddition reaction. This strategy provides a simple and versatile platform for the design of new materials whose functionality can be easily modified to anchor diverse biologically active molecules. From  Aspects of Polyurethanes 184 monomer 49, a series of new biodegradable comb-like copolyurethanes was achieved by the combination of step-growth polymerization and click chemistry [30]. Stiffness, hydrophilic/lipophilic character, and degradability could be adjusted by the appropriate selection of the comonomers and their feed ratios.
The preparation of novel reduction-sensitive biodegradable multiallyl-and multiamine-based copolyurethanes was also accomplished. The two functional allyl diol monomers 36 and 40 and the commercial 2,2'-dithiodiethanol (DiT) were made to react with HDI (3) and MDI (23) to give novel linear multiallyl-based copolyurethanes, useful as carriers of anionic drugs or gene materials [25]. Thus, reduction-sensitive multiamine copolymers were obtained [25] from sugar-based diol monomer Ar(NHBoc) 3 (41), with the amine groups conveniently protected to prevent undesirable side reactions ( Figure 22). Subsequent N-deprotection led to the target materials in high yields. The copolymers functionalized with amino groups (protected or free) exhibited lower thermal stability than those bearing allyloxy pendant groups. Functionalization of the sugar moieties greatly affected the T g of the polymer precursors. At the same time, the DiT diol content controlled the T m values of the random copolymers. The best degradation rates in reductive environments were obtained for the aliphatic amino-based copolymer, with an associated weight loss close to 90% after 10 days. This polymer was used in the preparation of colon-targeted drug delivery systems. An in vitro study of tablets containing the anticancer drug methotrexate demonstrated its impressive ability to control the drug's release, despite its low concentration in the tablet. Similarly, the preparation of PU with well-defined "tunable" macromolecular comb-like architectures was successfully accomplished [30] by means of a two-step procedure: preparation of multipropargyl copolyurethanes based on the tri-O-propargyl-L-arabinitol derivative 49 and DiT and their subsequent derivatization via alkyne-azide click reaction with chemically diverse azides-dodecyl azide, triethylene glycol azide, and polyethylene glycol azide. This methodology allowed the generation of PU with an extensive chemical diversity that has been unapproachable until now. It is remarkable that a wide variation in degradability under reductive environment could be attained simply by adjusting the chemical structure of the polymer to synthesize.

Conclusions
Monosaccharide-based polyurethanes (PU) have been usually prepared by step-growth polymerization from diisocyanates and sugar-based diols but, in the last years, and due to the toxicity of stannous catalysts and common aromatic diisocyanates, other eco-friendly methods have been developed and many works have been reported on the synthesis of isocyanate-free PU, also called non-isocyanate PU (NIPU). Although most syntheses of high-molecular-weight linear polyurethanes involve monosaccharide derivatives having the hydroxyl groups appropriately blocked, several PU with enhanced hydrophilicity and hydrolytic degradability have been synthesized using sugar-derived monomers with free hydroxyl groups or by deprotection of PU prepared from O-protected sugar-based monomers.
In order to enhance degradability, a series of homo-and copolyurethanes containing the hydrophilic monomer [triethylene glycol (TEG)] was synthesized. The introduction of disulfide linkage into the polymer backbone of novel reduction-sensitive biodegradable sugar-based polyurethanes has also been reported. Thus, a faster glutathione-mediated degradation method was accomplished under milder degradation conditions. The chemical modification of PU is important in order to search further applications. Click chemistry (CC) is the most widely used approach to achieve these chemical transformations; for instance, the thiol-ene/yne coupling reaction and the alkyne-azide cycloaddition reaction. In this sense, di-and tri-O-allyl-and tri-O-propargyl-L-arabinitol derivatives have been used as versatile materials for the preparation of tailor-made polyurethanes with varied degrees of functionalization.
We can conclude that it is viable to prepare monosaccharide-based polyurethanes analogous to the more qualified conventional polymers, but having a larger functionality and an enhanced hydrophilicity and degradability. However, in most cases, the high costs that represent the preparation of the monomers restrict the application of these polymers to the biomedical and other specialized fields.