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Synthetic polymers affected the modern life so badly that its hard to imagine the world without them. From last few decades, polymers are not only used in the automotive industry, semiconductor industry but are also widely used in the more advanced fields like nanotechnology, pharmaceutical industry in drug delivery and biomaterials (Hamerton 2002). Polymers or macromolecules are very large molecules with high molecular weight. Scientists are mainly focussing on the synthesis of polymers with desired structure and properties. Macromolecules are basically obtained by polymerisation of small molecules known as monomers which exhibits some specific properties. Due to these specific properties of monomers and by the help of initiator, solvent and catalyst, polymers of desired chain length, end groups, topology and side chain groups can be obtained. Well organised and controlled polymerisation techniques are needed for the controlled growth of the macromolecules (Morawetz 2002).
In 1956, Michael Szwarc discovered the living anionic polymerisation which has a great effect on the polymer science (Szwarc 1956, Szwarc et al. 1956). The work done by Michael Szwarc has leads to important development in the field of synthetic polymer science. Well-defined and organic polymers with good control on molar mass (Mn), polydispersity index (PDI) can be produced by using living radical polymerisation techniques. The basis of Szwarc's work was the elimination of termination and transfer reactions from the chain growth polymerisation (Syrett et al. 2010, Szwarc 1956). Synthetic chemists started focussing on the radical polymerisation because of the increasing demand of the ionic polymerisation, which leads in the development of controlled radical polymerisation (CRP) techniques in late 1990's. In other research fields also CRP attracted great attention.
CRP techniques works on the basis of equilibrium between the dormant and active species. To obtain well-defined macromolecules for a specific monomer or initiator, there is large variety of catalysts have been used. Therefore, there is a need of optimization reactions. Most of the chemical industries have established their own high-throughput experimentation laboratories. But there are very few laboratories which has the ability for the rapid screening and optimization of reactions by the help of automated parallel synthesizers. By using the parallel synthesis robots libraries of the compounds can be prepared under the similar experimental environment. In last decades, accurate and fast analysis of macromolecules is possible by the help of newly developed analytical tools.
CRP techniques help in the formation of polymers with specific and required functional groups at a specific position on the polymer chain with the help of initiators, monomers and catalysts. Block copolymers are also synthesised by using pre-synthesised macromolecules from post polymerisation modification reactions and their reaction with other small organic molecules like drugs and other macromolecules. Block copolymers also known as star-shaped copolymers has wide applications in nanotechnology and electronics.
The work done by Sharpless on the chirally catalysed oxidation reactions earned him to win Nobel Prize in 2001 (Syrett et al. 2010). In his work he also explained the concept of "click" chemistry. Click chemistry is the highly effective chemical reactions in between two easily approachable groups like azides and alkynes. Following the concept of click chemistry various reactions are carried out and are widely accepted in the field of biochemistry, medicinal chemistry and polymer science. The growing interest of "click" reactions among the scientists helps them to in the synthesis of macromolecules with future applications.
Controlled radical polymerisation techniques
To synthesise the well-defined polymers living radical polymerisation techniques always remain the first choice since 1956. In an anionic polymerisation reactions of styrene carried out by Szwarc showed that there is continuous increase in the polymer chain until all the monomer consumed in the reaction; with the addition of more monomer the polymer chain again started growing (Szwarc 1956). IUPAC stated that ionic polymerisation is a type of chain polymerisation reaction where ions or ion pairs acts as kinetic-chain carriers (). However, these techniques possess some limitations such as contrary between the monomers and reactive centres, need of highly pure chemicals and the limitation in the monomer selection due to specificity towards certain chemical groups.
These challenges in polymerisation reactions forced scientists to develop the new polymerisation techniques. Radical polymerisation is one of the alternative polymerisation techniques. Radical polymerisation techniques disfavour the polymerisation of vinyl monomers and found to be more progressive towards various functional groups. Free radical polymerisation is known as the most common route to obtain polymers with wide distribution in molar mass. But, in industries polymers having high polydispersity indices are advantageous for example, plasticizing effects is observed during processing of low molar mass polymers with small polymer chains and having high molar mass distributions. But, polymers with these properties are not suitable for future applications and also make the development of structure property relationships difficult for the polymer chemists.
In free radical polymerisation kinetics initiation reaction rates are extremely slower than the termination rates. Due to these reasons high molar mass chains formed during the initial stage but later with decrease in monomers concentration leads to the formation of low molar mass polymers are obtained, which also leads in the broad distributions in the molar mass of proteins. There are various recorded attempts which were carried out to gain improved control over free radical polymerisation (Moad and Rizzardo 1995). "Inferter" is the one of the technique used to control the free radical polymerisation. In these technique compounds perform their action as initiator, terminating and transferring agent (Ajayaghosh and Francis 1998, 1999, Otsu and Matsumoto 1998). In another technique bulky organic compounds like triarylmethyl derivatives were used (Borsig et al. 1967, Qin et al. 1999, Sebenik 1998). These techniques have various disadvantages like monomer reacts directly with the counter radicals, slow exchange and initiation and also thermal decomposition. Therefore a desired control on free radical polymerisation was not obtained from these techniques.
In mid 1990's new controlled radical polymerisation techniques were developed. These new techniques were developed by mainly focussing on the equilibrium between dormant and active species. Three main techniques Atom Transfer radical Polymerisation (ATRP) (Wang and Matyjaszewski 1995), Reversible Addition Fragmentation chain Transfer Polymerisation (RAFT) (Chiefari et al. 1998, Moad et al. 2008) and Nitroxide Mediated Radical Polymerisation (NMP) (Hawker et al. 2001, Moad and Rizzardo 1995) provide best control on the polymer growth. These three techniques gained most of the attention due to simplicity in the procedure and their ability to introduce stable chain end groups which can be reactivated by various post polymerisation changes.
Atom transfer radical polymerisation
In 1995, Swamoto and Matyjaszewski was the first who reported ATRP technique (Wang and Matyjaszewski 1995). Among CRP techniques ATRP is the most widely used method. ATRP technique allows scientists to form polymers in piece-by-piece method and controlled manner just by putting together monomers. Polymers with specific functionalities and good polydispersity index (PDI) can be obtained using ATRP. ATRP allows the formation of complex polymer structures by using a specific catalyst that has capability to add one or more monomers to a growing polymer chain at a given time. By varying the temperature and other reaction conditions ATRP process can be shutdown and re-started. This provides a uniform and precise control on the architecture and composition of the polymer.
Nine international companies in Japan, USA and Europe basically producing polymers based on the ATRP technique developed by Matyjaszewski and his co-workers. ATRP is widely used in the preparation of pigments dispersants for cosmetics, adhesives, printing ink, chromatographic packing and sealants. ATRP technique has various other applications such as: preparation of coating material for cardiovascular stents, scaffoldings for bone regeneration, degradable plastics, and automobile industry and in drug delivery (Matyjaszewski et al. 2002).
The mechanism on which ATRP works is the reversible redox chemical reaction between transition metal complexes and alkyl halides. Metal complex leads to the reversible activation of the carbon-halogen terminals which helps the ATRP to proceed. Scheme 1.1. shows the redox reaction between the halogen atom at the polymer terminal and metal centre.
ATRP works similar to inner sphere electron transfer process, which contains homolytic halogen transfer between a lower oxidation state transition metal complex (Mtn/Ligand) and dormant species (R-X) also known as initiator(Matyjaszewski 1998, Matyjaszewski et al. 2007, Matyjaszewski and Woodworth 1998). The transfer leads to the formation of radicals (R*) and higher oxidation state metal complex (Mtn+1/Ligand). Halogen on the higher oxidation state metal complexes reacts with the free radicals to form R-X again or formation of oligomeric structures by the addition of monomer(Singleton et al. 2003). After sometime free radicals combine with the halogen form Mtn/Ligand leads to the formation of dormant species, which usually depends on the deactivation rates. The metal complex activates the dormant species carbon-halogen bond and as a result to that a similar carbon-halogen bond formed at polymer terminal by various set of reactions. In a given time low concentration of free radicals but, there fast and reversible transformation into dormant species before addition to monomers are the key factors for ATRP.
Most ATRP requires four essential components which are needed to be added or to be formed in situ are:
Monomers which can radically polymerise.
An initiator with one transferrable group or atom preferably halogen atom.
A transition metal compound for one electron redox reaction.
A ligand to form a complex with transition metal compound.
Activation and deactivation constants define the rate for an ATRP reaction. Conversion of monomer (P), initiator concentration ([RX]), targeted degree of polymerisation (DPn), deactivator concentration X-CuIIY/Ln (denoted by [CuII]), and the ratio of propagation rate constant (kdeact) defines the PDI (Mw/Mn) for a polymer. It is more challenging to determine the kdeact directly but, if the values of kATRP and kact are known it can be calculated by using equation. The kATRP helps in determining the values for kp and the radical concentration ([Pm.]) and these values defines the values for rate of polymerisation. To determine all these values kATRP becomes more crucial. Catalyst CuIY/Ln e.g. [CuI] is used in less concentrations in the modern ATRP techniques(Qiu et al. 2000).
Ligands also play an important role in the ATRP procedure. Matyjaszewski et al. showed a comparison chart for the nitrogen based ligands (Tang and Matyjaszewski 2006). Figure 1.2. shows the EtBriB with activation rate constants (kact) for various ligands. Activation rate constant values are measured directly and converted in a logarithmic scale to compare the activities of copper complexes with various ligands. kact are sometimes underestimated for active complexes because of the extrapolation. Electrochemical studies states that Cu(II) catalyst will become more active when it is better stabilised by the ligand. In a general scheme the most stable complexes are formed by tetradentate ligands. Cyclam-B found to be most active ligands because Cu(II) catalyst is stabilised further by ethylene linkage. During the formation of Cu complex, cyclic ligands shows normal activity and shown in the middle of the scale. Left hand side of the scale shows most of the linear tetradentate ligands, except BPED. Moderately active complexes are formed by tridentate ligands e.g. BPMPA and PMDETA. Left hand side of the scale showing all the bidentate ligands which forms the slightest active complexes.
Structure of the copper complexes also defines the activity and follows the following order: bidentate ligands < tetradentate (linear) < tridentate < tetradentate (cyclic) < tetradentate (branched) < tetradentate (cyclic-bridged). Nitrogen atom nature is also important and follows the order: imine < aliphatic amine â‰¤ pyridine. In case of linkage for nitrogen atoms ethylene is better than propylene. Ligand structure plays a wide role in the activity of copper complexes and large difference in activity will be observed for a very small change in structure.
Carbohydrates are known as natural saccharides which are widely used as biomass, raw material and in foods. At industrial scale also saccharides are modified chemically to develop materials such as surfactants, fibres and moisturizers (Miura 2007). Carbohydrates have wide biological applications like signal transmission, cellular recognition, etc. Cytotoxic radiotherapy can be life-threatening because of the non-specific action especially in the cancer treatment. To overcome this situation carbohydrate can be used as ligands to improve the distribution of drugs in the biological systems.
It has been studied that carbohydrates ligands binds to lectins on the cell surface that can act as a receptor with a strong affinity towards various drugs (Lee and Lee 2000). But, there are various parallel interactions that take place to get a strong interaction between the receptors on the cell surface and the drug targeting ligands (Lee and Lee 2000). A weak interaction is observed between the one carbohydrate molecule and one protein molecule. Therefore, to get a strong interaction carbohydrate molecules are placed along a polymer backbone which is known as glycocluster effect (Ting et al. 2010).
Synthetic polymers carrying carbohydrate functional groups are known as glycopolymers. Glycopolymers include linear glycopolymers, spherical glycopolymers and glycodendrimers in the form of nanoparticles and vesicles (Pieters 2009). These advanced materials have broad applications in the biological field such as: multivalent interactions with the lectins on the cell surface and the ability to bind mannose receptors. Miura studied the glycopolymers of poly (vinyl saccharide). She observed amplification in the interaction of protein-saccharide due to glycopolymers. She also suggested the use of glycopolymers to develop various biomaterials such as: in tissue engineering and pathogen inhibitor(Miura 2007). In another experiment Stenzel et al. carried out the synthesis of glycopolymers and studied there multivalent recognitions with plant, animal, bacteria and toxin lectins (Ting et al. 2010).
Polymer science and Click chemistry
In 2001, Sharpless and his co-workers introduced the concept of click chemistry defines a two step procedure which can be used to label and detect a molecule of interest using biologically or bio-orthogonal moieties (Breinbauer and Kohn 2003, Kolb et al. 2001, Rostovtsev et al. 2002, Wang et al. 2003). The two step click chemistry involves the formation of a copper-catalyzed triazole from an azide and the alkyne. The azide and alkyne moieties are biologically stable, inert, unique and very small. Interchange of both the moieties is possible like one moiety can tag the molecule and second moiety can be used for subsequent detection. Click chemistry has wide applications especially when the use of antibodies or direct labelling methods is not efficient. Molecules like nucleotides, amino acids and sugars can be easily tagged by using click chemistry label because of the small size of these moieties. Mild permeabilization of click chemistry detection molecules helps them to easily penetrate through complex structures like supercoiled DNA.
Click chemistry reactions has various characteristics:
Specificity: Label and detection tag reaction is always selective and specific.
Stability: Presence of covalent bond in the reaction product makes it irreversible.
Inert: No side reactions by the components of the reaction.
Efficiency: The reaction finish in less than one hour with the need of solvents and extreme temperature.
Variety of click chemistry reaction exists in organic chemistry with wide applications. From all the reactions which achieve "Click status", Huisgen 1, 3-dipolar cycloaddition (CuAAC) of the azides and alkynes known as the "Cream of the Crop" (Moses and Moorhouse 2007). There is some safety concerns related to reaction because of the azide moiety explosive nature. But, except this property azide moiety shows very classical properties like less susceptible to hydrolysis than other moieties and more stable towards dimerization. Catalysts such as transition metal ions greatly increase the reaction rate for the Huisgen 1, 3-dipolar cycloaddition of azides and alkynes. Presence of catalyst also provides stereospecifity to the reaction which makes this cycloaddition equivalent to click chemistry. Nitrogen based ligands and copper as catalyst helps to perform the reactions. Other transition metal ions (Pd, pt, Ru, Ni and Fe) and ligands (bipyridine based, terpyridine derivatives and PMDETA) are also examined to amplify the current field of copper-catalyzed cycloaddition reactions (Boren et al. 2008, Chassaing et al. 2008, Golas et al. 2006, Rodionov et al. 2005, Urbani et al. 2008).
Chemists are working to develop new "Click" reactions which can work without the presence of any metal catalyst. In 2008, Lutz presented an idea to perform azide-alkyne cycloaddition without any copper catalyst (Lutz 2008). Other, click chemistry reactions are also present which works in the absence of metal catalysts and follow the click chemistry requirements. Other click chemistry reactions are: radical addition, nucleophilic substitution, Diels-Alder and Retro-Diels Alder reactions. Potential toxicity due to metal catalysts plays a vital role when the synthesised products are to be used in biological applications (Wang et al. 2003). In case of copper-catalyzed amide-alkyne cycloaddition, a ppm amount of copper remains in the product even after the purification. Therefore, there is a significant need of alternative click reactions which don't need any metal catalyst.
Post-polymerisation modifications, curing reactions and certain polymerisation reactions are widely performed by free-radical addition of thiol to a double bond (David and Kornfield 2008, Dondoni 2008, Nilsson et al. 2008). Schlaad et al. synthesised poly [2-(3-butyl)-2-oxazoline] using living/controlled cationic isomerisation polymerisation and also performed the thio-click modification of the synthesised polymer. Model reactions were also carried out using various mercaptans e.g. dihydroxy functionalized thiols, fluorinated thiols and acetylated glucose thiols. To perform the "thio-click" reaction mild conditions (UV light to generate radicals) are used and also the reaction was carried out in the absence of transition metal (Gress et al. 2007). In an another report Schlaad et al. described the "thio-ene" modification of 1,2-polybutadiene polymer. In this experiment they used sunlight to produce radicals. This method is well suited for the production of biohybrid polymers containing sugars or amino acids on its backbone (ten Brummelhuis et al. 2008). In 2008, Hawker et al. presented a divergent approach for the synthesis of Poly (thioether) dendrimers using thiol-ene "click" chemistry. They performed the thiol-ene reactions without using any metal catalyst and solvent. A UV lamp with wavelength of 365 nm was used for 30 minutes for the irradiation of reaction mixture. A small amount of photoinitiator was also used to increase the rate of reaction by increasing the radical concentration(Killops et al. 2008).
Click chemistry technique has wide applications in the production of glycopolymers for biomedical applications. Perrier et al. reported a new strategy for the synthesis of hyper-branched and highly functionalised glycopolymers. They used the combination of living radical polymerisation and click chemistry. RAFT copolymerisation was used to synthesise the highly branched clickable backbone of the TMS-protected alkyne acrylate monomer with EGDMA. A group of "click" chemistry reactions mainly CuAAC and also, thiol-yne and thiol-ene addition were carried out to click glucose and galactose moieties on the highly branched polymer chain(Semsarilar et al. 2010). Haddleton and Mantovani established the one-pot synthesis of the glycopolymers by concurrent ATRP of an alkynyl monomer and copper catalysed azide-alkyne cycloaddition with azido functionalised sugars (Geng et al. 2008).