Click chemistry reactions in polymer synthesis and ... · PDF fileClick chemistry reactions in polymer synthesis and modification U. Jaffry,A. Muñoz-Bonilla and P. Herrasti Departamento

Click chemistry reactions in polymer synthesis and modification

U. Jaffry, A. Muñoz-Bonilla and P. Herrasti

Departamento de Química Física Aplicada, Facultad de Ciencias, Universidad Autónoma de Madrid, C/Francisco Tomás y Valiente, 7, Cantoblanco, 28049 Madrid, Spain

This Chapter reviews the most important aspects of the application of click chemistry reactions in polymer science. The click chemistry approaches have revolutionized the polymer chemistry allowing the preparation of a wide range of functional polymers and complex macromolecules as well as facilitating the surface modification of diverse polymeric materials. Concisely, click chemistry encompasses a group of reactions that are fast, efficient, selective, tolerance to a variety of solvents and functionalities, and give high yields. While several reactions fulfil these criteria, Cu-catalyzed azide/alkyne cycloaddition (CuAAC), the metal free alternatives such as Diels–Alder cycloaddition and thiol-based reactions are the most employed in the polymer field that eventually are contributing to the next generations of polymeric materials. Herein, the fundamentals of click chemistry and the main strategies applied to the precise synthesis and modification of macromolecules are thoroughly examined with the aim to give an overview of the existing methodologies and enable the readers to select the most appropriate click reaction for a certain application. Besides, the most recent contributions and advances of click chemistry to current topics in polymer science will be briefly described.

Keywords: Click chemistry; CuAAC; thiol-based reactions; Diels–Alder cycloaddition; functional polymers; complex structures

1. Introduction

In 2001 Sharpless et al. [1] introduced the concept of highly efficient reactions for the rapid synthesis of new compounds and combinatorial libraries. Since then, click chemistry has been the key topic of a vast amount of fundamental and applied research in organic chemistry, biotechnology and biomedical chemistry along with polymer and material sciences, as demonstrated by a nearly exponential growth in related publications. Specifically, these publications have defined click chemistry as a group of reactions that “...must be modular, wide in scope, give very high yields, generate only inoffensive by-products that can be removed by non-chromatographic methods, and be stereospecific (but not necessarily enantioselective). The required characteristics of the process include simple reaction conditions (ideally, the process should be insensitive to oxygen and water), readily available starting materials and reagents, not use a solvent or use a solvent that is benign (such as water) or easily removed, and simple product isolation. Purification, if required, must be done by non-chromatographic methods, such as crystallization or distillation, and the product must be stable under physiological conditions”. A prime example of a click reaction that fulfils these criteria is the copper catalysed 1,3-dipolar cycloaddition between an azide and a terminal alkyne giving a 1,2,3-triazole moiety, also known as copper-catalyzed Huisgen cycloaddition (CuAAC) [2][3]. To date, this is by far the most popular click reaction; however it does present limitations, particularly the cytotoxicity of the copper used as the catalyst. Many other reactions have been identified as good candidates for click chemistry that possess non-toxic conditions whilst maintaining efficiency. Concretely in the polymer chemistry field, these efficient click reactions are postulated as a versatile tool that facilitate the easier synthesis and post-modification of known macromolecules but more importantly, also allow the design of unprecedented polymeric materials for high-tech applications. There is a wide variety of polymer materials that have been synthesized using click chemistry reactions, including end-functional polymers, polymers with pendant function groups, block copolymers, gels, complex architectures such as star or dendritic structures and even hybrid nanomaterials. In this regard, an increasing interest has developed in the combination of click chemistry reactions with living/controlled polymerization techniques such as atom transfer radical polymerization (ATRP) [4], reversible addition fragmentation chain transfer polymerization (RAFT) [5], nitroxide mediated radical polymerization (NMP) [6], ring opening polymerization (ROP) [7] and ring-opening metathesis polymerization (ROMP) [8], among others. Generally, the polymers obtained by these controlled techniques, in addition to being well-defined in terms of molecular weight, composition and topology; present functional moieties such as hydroxyl or bromide groups that can be easily transformed to clickable functionalities available for further post-modification reactions through click chemistry. Although the research activity in click chemistry applied to polymer science has been mainly focused on post functionalization, in recent years remarkable efforts have been devoted to the development of new polymerization techniques based on click chemistry. To this concern, important progresses have been made in the metal-mediated and metal-free click polymerization systems for the synthesis of linear and hyperbranched polytriazoles, involving CuAAC reactions [9]. But recently, research has been expanded to other types of click polymerizations, for instance, the Diels-Alder [10] and thiol-ene click polymerizations [11].

Polymer science: research advances, practical applications and educational aspects (A. Méndez-Vilas; A. Solano, Eds.) _______________________________________________________________________________________________

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Click chemistry, through its unique features has demonstrated that it is an important tool in polymer chemistry and material science, and has contributed to the expansion of this area in recent years. In this Chapter, important aspects of click chemistry will be applied to polymer science alongside summarizing the overall potential of click chemistry, its emerging applications and the future perspectives.

2. Definition and classification of click chemistry reactions

As previously defined, click chemistry involves a range of liking reactions that meet efficiency, versatility and selectivity. These reactions are characterized by several common aspects, including:

Readily available starting materials and reagents Quantitative yields Rapid reaction rates Selectivity Simple reactions conditions (insensitive to oxygen and water) Tolerance to a variety of functional groups Simple product isolation

To date, the studied reactions that fulfil these criteria can be classified into four main categories (Fig 1): (i) cycloaddition reactions (principally, Huisgen 1,3-dipolar cycloaddition and Diels-Alder reaction), (ii) nucleophilic ring-opening reactions of strained heterocyclic electrophiles (epoxides, aziridines, etc.), (iii) carbonyl chemistry of non-aldol type (ureas, oximes and hydrazones) and (iv) additions to carbon-carbon multiple bonds (especially thiol based click, radical and nucleophilic mediated reactions).

Fig. 1 Scheme of the most common click chemistry reactions employed in polymer synthesis and modification.

3. Cycloaddition reactions

Cycloaddition reactions are among the most powerful methodologies in organic chemistry which involve heteroatoms. Brieflly summarised, cycloaddition reactions involve the combination of two or more π systems to covalently form a stable cyclic molecule. During this process sigma bonds are formed without the loss of any fragments. As aforementioned, the most employed cycloadditions in polymer chemistry are the 1,3-dipolar cycloaddition, which produces a 5 membered ring system, and the Diels-Alder reaction which ensues as the stereospecific formation of 6-membered ring systems.

3.1 Copper catalysed 1,3-Dipolar cycloaddition

The basic process constitutes of a reaction between alkynes and azides producing a five membered ring requiring elevated temperatures and habitually gives mixtures of regioisomers (1,4-triazole and 1,5-triazole). This Huisgen


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process can be rapidly accelerated via the addition of a metallic species into the reaction medium. Although metals such as Ru, Ni, Pt, Pd are also used, CuI metal is by far the most popular in this type of reaction, hence the most recognised reaction type being the copper-catalysed azide–alkyne cycloaddition (CuAAC) [12][13]. In addition to the accelerating the reaction process, allowing the reaction to proceed at low temperatures and results in quantitative yields, the incorporation of CuI metal provides higher regioselectivity, i.e. copper salts conduct preferentially to 1,4-disubstituted 1,2,3-triazoles (Fig 1(i)). Remarkably, the CuAAC reaction can be carried out in the presence of numerous functional groups and in a variety of solvents. This CuAAC click chemistry reaction has been extensively investigated as a ligation tool for synthesizing and modifying many different polymeric structures. As mentioned above, although a variety of catalysts can be used, the CuI catalyst is the most employed. There are different manners used to introduce the CuI metal: by the reduction of CuII salts, using Cu0/CuII systems or directly in form of CuI salts. The latter method requires a nitrogen base such as pyridine. Remarkably, as these catalytic systems are likewise employed in ATRP, the combination of both techniques has been extensively explored [14][15]. Common strategies for incorporating clickable groups into polymer chains for further attachment of other molecules yield terminal functionality and imply the use of functional initiators or transfer agents and the subsequent modification of the end groups after the polymerization. Among the variety of possibilities, the nucleophilic substitution of the terminal bromide of ATRP-obtained polymers by azide groups seems to be the most investigated approach [16]. This fast reaction is practically quantitative and has been employed to attach numerous functional groups [4] and even to prepare block copolymers [17] by posterior CuAAC click reactions. Alternatively, the incorporation of clickable moieties as pendant groups throughout a polymer chain is generally accomplished by polymerizing a functional monomer. Two main approaches have been proposed in this case, the polymerization of monomer bearing either pendant alkyne groups [18] or azide groups[19]. This strategy permits the synthesis of more complex structures such as comb-like and brush copolymers. Additionally, this CuAAC click reaction has the potential to become an interesting polymerization technique by itself when multifunctional alkine and azide are employed [9]. Linear and hyperbranched polytriazoles are readily obtained through this method. As shown, the CuAAC click reaction is becoming a common and versatile tool for the production of a variety of polymer structures which possess captivating properties and applications. Many of the polymers synthesized with clickable units are often applied in the area of surface patterning and modification [20]. Modification of polymeric surfaces has been done through the attachment of polymer chains via click chemistry reactions but also through a diverse range of materials and nanomaterials such as: carbon nanotubes, fullerenes, gold nanoparticles, etc. For instance, the CuAAC process is considered a very attractive strategy to covalently functionalize graphene with polymer chains for improving the dispersability of individual nanosheets [21]. Grafting-from and grafting-to approaches can be successfully used; however the grafting-to approach allows better control and higher grafting density resulting in good solubility and processability of the graphene nanosheets (Figure 2).

Fig. 2 Grafting to approach via CuAAC click chemistry used to functionalize graphene nanosheets with RAFT-obtained polymers, ref [21]. Bioconjugation is another important process in which CuAAC has found a niche of applications. In this process, synthetic polymers are attached to biological targets, such as proteins, peptides and DNA, with the aim of prolonging the circulation time and increasing solubility. Fluorescent probes can also be included for imaging and detection purposes. The CuAAC reaction proceeds under mild conditions, thus it can be used for in situ or in vitro applications. Furthermore, the triazole moieties can successfully replace the amide group of the peptide, maintaining its helical structure and its activity [22]. One of the first examples of bioconjugates based on polymers synthesised via CuAAC click chemistry was prepared by a reaction involving terminal azide functionalized polystyrenes and a alkyne

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functionalized fluorescent peptide, H-GlyGlyArg-(7-amino-4-methylcoumarin) [23]. The conjugation of the protein bovine serum albumin was also performed via this reaction. However, the use of the CuAAC-click reaction for in vivo applications is limited due to the cytotoxicity of the copper and reducing agents, which require additional purification steps and restrict some of its uses. Recent advances have been developed in an effort to combat this problem, mainly focused on two alternatives, reducing certain undesired reactions [24] and performing the reaction in the absence of the Cu catalyst [25].

3.2 Diels-Alder reaction

The Diels-Alder (DA) reaction involves the formation of a stable six membered ring via a [4 + 2] cycloaddition reaction between an electron-rich diene (typically furan and derivatives) and an electron-poor dienophile (typically maleimide and derivatives) (Figure 1(i)) [26]. This reaction requires very low energy when in the presence of catalysts (typically a Lewis acid), but can also proceed in the absence of catalysts at relatively low temperatures. This particular cycloaddition allows the formation of not only carbon-carbon bonds, but also bonds between heteroatoms. Thus it is a very versatile click reaction employed for the synthesis and functionalization of numerous molecules and macromolecules. However, what can be said is the most attractive aspect of the Diels-Alder reaction is its thermal reversibility, which is done through the retro-DA reaction thus enabling its use in a variety of applications. Hence, the decoupling reaction as well as the adduct formation can occur at a range of different temperatures depending on the diene/dienophile combination. This click reaction has been perfectly adapted for polymer synthesis and has often been considered for the preparation of complex architectures such as dendrimers, stars and graft polymers due to its simplicity, versatility and efficiency [10] [27][28]. Likewise, the combination of the Diels-Alder reaction with living/controlled polymerization methods is the preferential route for synthesizing such a variety of functional polymers and architectures. For instance an efficient method based on cationic ring-opening polymerization was employed for the preparation of cyclopentadienyl end-capped poly(2-ethyl-2-oxazoline). The subsequent Diels-Alder reaction with N-substituted maleimides was quantitatively proceeded at room temperature [29]. This publication demonstrates that block copolymers can be easily obtained following this approach. Another direct strategy for preparing block copolymers is based on the hetero Diels-Alder (HDA) reaction between the terminal thiocarnonylthio moieties of RAFT-obtained polymers and dienes groups (Figure 3) [30].

Fig. 3 Preparation of block copolymers via hetero Diels-Alder click reaction [30].

Moreover, coupling reactions between anthracene and maleimide functional groups have been extensively explored for the preparation of various structures such as graft polymers by side chain functionalization [31]. The Diels-Alder click reaction has also been used as a polymerization technique involving multifunctional monomers, e.g. di- or tri-furan derivatives and bismaleimide. By this method a variety of linear and non-linear structures such as hyperbranched, star, dendrimers and crosslinked polymeric architectures have been synthesized principally by furan/maleimide systems. The main applications of these polymeric structures obtained via Diels-Alder reactions encompass the thermoreversibility of the reaction, especially in the preparation of polymer networks for interesting uses such as encapsulants [32], self-healing materials [33][34], recyclable networks and coatings [35]. Figure 4 shows a schematic representation of the self –healing process involving polymers based on the Diels-alder reaction.

Fig. 4 Self-healing process of thermoset polymers based on Diels-Alder click reaction. Reprinted with the permission from ref [33]. Copyright (2011) ACS.

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When microcracks appear in thermoplastic polymers, they can be healed easily by simply heating the material that favors the diffusion of the polymer chain. However, in thermoset polymers heating does not melt or diffuse the crosslinked chains. In such polymers, the reversibility of the Diels-Alder reaction upon heating enables the healing of the material. Concisely, the polymer material is heated above the temperature required for the retro Diels-Alder reaction, provoking the decoupling of the polymer chain. This leads to an increase in the mobility of the chains and in turn helps the healing of the crack. Upon cooling, the Diels-Alder adduct is formed again and the material is able to recover its properties. Another emerging application of Diels-Alder reactions involves the conjugation of biomolecules. Particularly interesting are the so-called inverse electron demand Diels-Alder reactions (iEDDA) between 1,2,4,5-tetrazines and olefins [36]. The increase in interest towards this particular reaction stems from its orthogonality, high speed rates and biocompatibility.

4. Nucleophilic ring-opening reactions

Click chemistry reactions also incorporate the ring-opening of electrophilic heterocycles, these species possess a considerable amount of ring-strain that can be released. [1][37]. There is a broad variety of substrates suitable for this reaction including epoxides, aziridines, cyclic sulfates and episulfonium ions, among others. Of those, epoxides and aziridines are the most common heterocycles substrates used for click reactions due to their regioselectivity, stereospecificity and high yield. Typically, these reactions are performed either in alcohol or alcohol/water mixtures or in the absence of solvents and the resultant products can be easily isolated. These reactions are yet to be extensively used in polymer chemistry. A common strategy employed is the polymerization of the commercially available glycidyl methacrylate, followed by the subsequent ring-opening reaction of the epoxide pendant groups with nucleophilic groups such as amines [38]. The ring opening reaction of epoxide has also been investigated in combination with other click reactions, i.e. CuAAC reaction (Fig 5) [39]. The opening of the oxirane ring was conducted by the azide anion sodium azide, which lead to the attachment of the clickable group to the side chain.

Fig. 5 Ring opening of the epoxide ring in the presence of sodium azide and the posterior CuAAc reaction.

However, the epoxide moieties are highly reactive under ambient humid conditions, which often leads to undesired polymerization and crosslinking reactions. Alternatively, a recent publication describes a novel approach for post-modification of clickable polymers bearing aziridine moieties [40]. In this study, a methacrylate monomer with an aziridine as pendant group was designed and copolymerized by radical polymerization. A posterior modification via a nucleophilic ring opening reaction was carried out between the aziridine moieties and alcohol derivatives in the presence of a Lewis acid activator.

5. Carbonyl chemistry of non-aldol type

Non-aldol type carbonyl reactions can also fulfil to the requirements of the definition of click chemistry reactions [1], these reactions include the formation of groups such as ureas, thioureas, aromatic heterocycles, oxime ethers, hydrazones, and amides. In contrast, the aldol type carbonyl reactions do not meet the click chemistry characteristics due to their low thermodynamic driving force. When considering click reactions involving non-aldols, the most efficient reactions are those in which aldehydes and ketones react with alkoxyamines or hydrazides to give oximes and hydrazones, respectively, by imine-forming condensations (Fig. 1). One of the main features of these resulting hydrazones and oximes is the reversibility of the linkages that are labile to hydrolysis. These products have found significant utility in numerous fields including biomaterials, biomedicine and drug delivery. Whilst oxime bonds have received much less attention, most likely due to their greater stability compared to hydrazine, their stability can be beneficial for other applications.


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These types of reactions have been successfully applied to synthesise polymers using controlled polymerization techniques, thus producing the well-defined structures normally required in biotechnological applications. For example, a poly(norbornene) bearing ketone-like functionalities along its side-chain has been synthesized using ring-opening metathesis polymerization (ROMP). Following this, side-chain functionalization was carried out by reacting it with a hydrazide derivative leading to a hydrozone linkage [41]. Likewise, ketone moieties can be also introduced as a terminal group of synthesized polymers, created for example via RAFT polymerization. A possible synthesis strategy consists of using a ketal-containing trithiocarbonyl compound as a chain transfer agent in a RAFT polymerization, thereby ketone-end functionality is readily obtained [42]. Hydrazone conjugation of the ketone-terminated polymer with hydrazide derivatives was further performed using biotin hydrazide, fluorescein, biotin, and Gd- DOTA derivatives, yielding the expected fluorescent, protein-binding, and relaxivity properties, respectively, to the polymeric material. As mentioned, polymers containing ketone/aldehyde functionalities can be also conjugated with alkoxyamines to form oxime linkages. For instance, the post-polymerization conjugation of RAFT-obtained polymers containing ketones as side-chain groups with different alkoxyamines has been reported [43]. This publication also demonstrates the preparation of reversible crosslinked structures by reactions with difunctional alkoxiamines. Alternatively, polymers functionalized with alkoyamines can be reacted with ketones and aldehyde derivatives through this oxime linkage formation. An aminooxy end-functional polymer rapidly synthesized by ATRP and various other synthetic steps was conjugated with levulinyl-modified proteins containing ketone functionalities without additional reagents. This synthesis leads to the production of well-defined bioconjugates. As aforementioned, the use of these click reactions in bioconjugation is of great importance, they hold a particularly promising future in drug delivery due to the lability of the unions. Hydrazone and oxime are pH sensitive, being stable at a physiological pH and disassociating at an acidic pH. In general, the pH in tumor tissues, inflammatory tissues and the endosomal is slightly acid, thereby research in pH sensitive delivery vehicles are attracting a substantial interest to trigger the drug at the targeted disease sites. Therefore, these reactions that imply the formation of hydrazine and oxime linkages have been extensively used for the preparation of pH-sensitive polymer-drug conjugates [44]. The conjugates of Doxorubicin, an anticancer drug, with polymers via a hydrazone linker have received vast amounts of attention [45][46]. Figure 6 shows an example of this polymer-Doxorubicin conjugate.

Fig. 6 Schematic illustration of the polyethylene pH-sensitive poly(glycol monomethylether)-b-poly(methacryl amide tert-butyl carbazate-DOX) (MPEG-b-DOX) pH-induced drug release mechanism, adapted from ref [46]. Copyright (2014) RSC. The reversibility of the oxime linkages have been exploited in other important biotechnological applications, i.e. in stem-cell differentiation and tissue engineering [47][48]. In those particular works, the redox responsive chemistry of the oxime based conjugation was examined; concluding that it can be selectively cleaved under particular reductive conditions. By this strategy, it is possible to rewire cell surfaces and modulate the cell-cell interactions to promote 3D tissue structures.

6. Additions to carbon-carbon multiple bonds

This category is fundamentally based on thiol click reactions. These reactions are known to present several advantages over other click reactions. In addition to being a metal-free reaction which is of importance in bio-related applications, there are an extensive number of substances capable of efficiently reacting with thiol due to its high reactivity. Furthermore, this high reactivity allows the reaction to proceed more rapidly in comparison to other reactions. However, the orthogonality of this type of reaction is comprised as a consequence of this reactivity, along with the lack of stability which makes its handling difficult in certain conditions. Nevertheless, these disadvantages do not limit the applicability of the thiol-based reactions that are fully implemented in polymer chemistry as one of the most powerful tools in the synthesis and modification of polymeric materials [49][50][51].


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Thiols are prone to react with multiple C-C bonds either via radical or catalysed processes under mild conditions. The most important reactions applied in polymer chemistry (Figure 1) include the readily occurring reaction between thiols and electron rich -enes and alkynes (both radical reactions) and electron poor -enes (Michael addition).

6.1 Radical addition

There are two radical mediated thiol click reactions, thiol-ene and thiol-yne, that proceed following the requirements of simplicity, efficiency and possessing a robust nature. In terms of the thiol-yne reaction, two equivalents of thiol form a double addition product in comparison to the single addition product formed in the thiol-ene process (Figure 1). However, mechanistically, both reactions proceed in a similar manner. Although any double and triple bonds present are susceptible to a thiol radical addition, the reactivity of these thiols is dependent on the electronic nature of the bond as it is highly reactive with strained or electron rich bonds. Concerning the initiation part of the process, radical generation can be done thermally or photochemically (Figure 7).

Fig. 7 The radical-mediated thiol–ene reaction mechanism.

In principle, the formation of radicals by light irradiation (typically UV or sunlight) at ambient temperature offers numerous advantages over the thermal initiation for the polymer synthesis and modification [52]. The reaction can be controlled spatially and temporally with greater efficiency, shorter reaction times as well as a tolerance to many functional groups. The thiol or alkene and alkyne groups can be easily incorporated into polymer chains as either end or as pendant groups allowing the synthesis and modification of a large variety of macromolecular structures. The combination of this click chemistry reaction with RAFT polymerization is an interesting concept due to the inherent sulfur groups containing the RAFT-obtained polymers. Thiol-terminated chains are obtained in a straightforward manner via the reduction of the thiocarbonlythio-end groups. For example, this strategy has been used to modify the surface of polydivinylbenzene (DVB) microparticles [53]. Poly(N-isopropylacrylamide) was first prepared by the RAFT process followed by an end-group cleavage carried out via a reduction reaction, resulting in thiol terminated polymers. These thiol functionalized polymer chains were then reacted with the residual vinyl groups on the surface of the nanoparticles via a thermally initiated thiol-ene reaction (Figure 8).

Fig. 8 Scheme of the grafting approach for the functionalization of DVB microparticles via thiol-ene click reaction with RAFT-obtained polymers.

Similarly, polymers with side olefins such as polybutadiene and poly(allyl methacrylates) have been post-functionalized with a variety of thiol compounds via a highly efficient thiol-ene reaction in the presence of a photocatalyst and blue LED light [54]. When considering the thiol-yne reactions, the fact that one alkyne bond reacts

Δ / hν

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with two thiols opens the possibility to synthesize dendritric and hyperbranched macromolecular structures in a very simplistic manner [55].

6.2 Michael addition

This reaction comprises of the addition of thiols, or thiolate anions, to electron deficient C=C bonds, following the mechanism displayed in Figure 9. Due to the weakness of the sulfur-hydrogen bond, a wide range of precursors can initiate this reaction demonstrating its versatility. Concretely, bases and nucleophiles are capable of successfully catalyzing the thiol-Michael addition process. In recent years, this click reaction has acquired a great relevance in polymer synthesis and modification, with relevant investigations done into the optimization of this process under mild reaction conditions to yield an efficient and modular click reaction with quantitative conversions [56]. One of the main advantages of the thiol-Michael addition reaction is the almost complete absence of side products, in contrast to the radical mediated reaction that leads to, for instance, radical-radical termination products.

Fig. 9 The Michael addition reaction mechanism.

As previously stated, the thiol-Michael addition reaction can be nucleophile- or base-catalysed, and numerous efforts have been made to develop efficient catalysts. However, the most widely used catalysts still remain as the readily available standard reagents, such as sodium methoxide and trimethylamine as bases and phosphines as nucleophiles. As well as the radical mediated reaction, the Michael addition reaction has also been extensively used to post-functionalize polymers obtained by RAFT polymerization due to their inherent sulfur groups as a result of the chain transfer agent, in this case the click reaction presents an additional advantage. The terminal dithiocarbonate RAFT agents can be reduced to thiol functional groups through a reaction catalysed by amines or phosphines allowing the functionalization of the polymer in one single pot involving both processes; reduction of the RAFT agent and the thiol-Michael addition reaction [57]. In addition to the post-functionalization of polymers with a variety of different molecules or even nanomaterials, this reaction has been utilized to form block copolymers, star polymers and many other structures. For instance, 3-arm star polymers were synthesized under nucleophile-catalyzed conditions by reacting a RAFT-prepared poly(N,N-diethylacrylamide) with a triacrylate via a thiol-Michael click reaction [58]. Thiol based click reactions, radical and Michael additions, are all powerful tools used for the modification or synthesis of polymers utilized for a diverse range of applications. Particularly interesting are the uses of these polymers in biological and biomedical applications. The stability and biocompatibility of the resulting thioether linkage in extreme, physiological environments are attractive concepts for biological applications. In addition, thiols are present in many biological systems such as proteins, DNA, antibodies, etc., which enable their bioconjugation with diverse polymers bearing vinyl groups [59]. Figure 10 shows an example of a macromolecular conjugate obtained in a one-pot synthetic protocol via phosphine-mediated thiol–ene click chemistry [60] During this synthesis, polyethylene glycol chains bearing vinyl groups were reacted with the hormone salmon calcitonin through a disulphide bridge that can be reduced to sulfhydryl units. This conjugation, known as PEGylation, prevents the agent from the host's immune system and prolongs its circulation time in the organism.

Fig. 10 Schematic representation of the bioconjugation process performed via thiol-ene click chemistry. Reprinted with the permission from ref [60]. Copyright (2009) RSC. Another niche of application of the thiol based click reactions is the preparation of crosslinked polymeric networks with improved mechanical properties employing multifunctional thiols and alkenes or alkynes[51].


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7. Perspectives

There has been rapid development in the field of click chemistry in recent years; this has provided a versatile toolbox of available reactions that can be combined with other synthetic and polymerization approaches to prepare a diverse range of polymeric materials with a variety of properties and applications. Without any doubt, the application of click strategies in the area of polymer chemistry will continue to facilitate the synthesis of macromolecules in a more efficient and simple manner alongside the design of unprecedented macromolecular structures. However, each of the reactions described previously present limitations, and reasonable efforts should be made to meet all the criteria of click chemistry, including using non-toxic reagents and carrying out aqueous or solvent-free reactions. In relation to this, recent research has been focused on the implementation of the 1,3-dipolar cycloaddition in the absence of a copper catalyst for bio-related applications. The strain-promoted azide-alkyne cycloaddition (SPAAC) reaction is postulated as an appropriate alternative, this reaction implies the coupling of azides with strained cycloalkynes, such as dibenzocycloctynes [25]. Although this reaction is relatively fast and proceeds to high conversion, it demonstrates lower efficiency in comparison to the traditional CuAAC reaction. An ideal reaction would proceed with electron-deficient reagents, an absence of catalysts and at a low temperature [61]. Another promising click chemistry reaction is the so-called inverse electron demand Diels–Alder (iEDDA) addition, due to its high selectivity, extraordinary reaction speed and lack of catalysts or initiators [36]. Future challenges include the development of click polymerization techniques for the preparation of well-defined and monodisperse sequence controlled polymers to be used as building blocks for advanced applications such as the synthesis of mimic natural biopolymers. The synthesis of these sequence controlled polymers, in which multiple repeating units are ordered in a predetermined manner, has been pursued for many years [62]. However, an efficient route that enables total control over both the sequence and structures is still a key challenge to overcome.

Acknowledgements The support by MINECO (Project MAT2012-37109-C02) is gratefully acknowledged.

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