1.22 Polymer Fundamentals: Polymer Synthesis☆

1.22 Polymer Fundamentals: Polymer Synthesis☆ V Hasirci, Middle East Technical University, Ankara, Turkey P Yilgor Huri, Ankara University, Ankara, Turkey T Endogan Tanir, G Eke, and N Hasirci, Middle East Technical University, Ankara, Turkey r 2017 Elsevier Ltd. All rights reserved.

1.22.1 1.22.1.1 1.22.1.2 1.22.2 1.22.2.1 1.22.2.2 1.22.2.2.1 1.22.2.3 1.22.2.3.1 1.22.2.4 1.22.2.4.1 1.22.2.4.1.1 1.22.2.4.1.2 1.22.2.4.1.3 1.22.2.4.1.4 1.22.2.4.1.5 1.22.2.4.2 1.22.2.4.2.1 1.22.2.4.2.2 1.22.2.4.2.3 1.22.2.4.2.4 1.22.2.4.2.5 1.22.2.5 1.22.3 1.22.3.1 1.22.3.1.1 1.22.3.1.2 1.22.3.1.3 1.22.3.1.4 1.22.3.1.5 1.22.3.1.6 1.22.3.2 1.22.3.2.1 1.22.3.2.2 1.22.3.3 1.22.3.4 1.22.3.5 1.22.3.6 1.22.3.6.1 1.22.3.6.2 1.22.3.6.3 1.22.3.6.4 1.22.4 1.22.4.1 1.22.4.1.1 1.22.4.1.2 1.22.4.1.3

Introduction to Polymer Science Classification of Polymers Polymerization Systems Polycondensation Characteristics of Condensation Polymerization Kinetics of Linear Polycondensation Molecular weight control in linear polycondensation Nonlinear Polycondensation and its Kinetics Prediction of the gel point Mechanisms of Polycondensation Carbonyl addition–elimination mechanism Direct reaction Interchange Acid chloride or anhydride Interfacial condensation Ring versus chain formation Other mechanisms Carbonyl addition–substitution reactions Nucleophilic substitution reactions Double bond addition reactions Free radical coupling Aromatic electrophilic substitution reactions Typical Condensation Polymers and Their Biomedical Applications Addition Polymerization Free Radical Polymerization Initiation Propagation Termination Kinetics of radical polymerization Degree of polymerization Thermodynamics of polymerization Ionic Polymerization Cationic polymerization Anionic polymerization Coordination Polymerization Typical Addition Polymers and Their Biomedical Applications Comparison of Addition and Condensation Polymerization Other Polymerization Techniques Atom transfer radical polymerization Nitroxide mediated polymerization Reversible addition
fragmentation chain transfer polymerization Click polymerization Polymer Reactions Copolymerization Types of copolymerization Effect of copolymerization on properties Kinetics of copolymerization

480 482 483 485 485 485 487 487 487 488 488 488 488 488 488 488 488 488 488 488 489 489 489 489 490 490 490 491 492 493 493 493 493 494 494 494 495 495 495 496 496 496 498 498 498 499 500

☆ Change History: June 2016. V. Hasirci, P.Y. Huri, T.E. Tanir, G. Eke and N. Hasirci made updates throughout the text. Sections on Click Polymerization and the Conclusions were added. Reference list has been updated with more up to date references.

This is an update of V. Hasirci, P. Yilgor, T. Endogan, G. Eke and N. Hasirci, 1.121 – Polymer Fundamentals: Polymer Synthesis. In Comprehensive Biomaterials, edited by Paul Ducheyne, Elsevier, Oxford, 2011, pp. 349–371.

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Comprehensive Biomaterials II, Volume 1

doi:10.1016/B978-0-12-803581-8.10208-5

Polymer Fundamentals: Polymer Synthesis 1.22.4.1.3.1 1.22.4.1.3.2 1.22.4.2 1.22.4.2.1 1.22.4.2.2 1.22.4.2.2.1 1.22.4.2.2.2 1.22.4.2.3 1.22.5 References

Kinetics of addition copolymerization Kinetics of condensation copolymerization Crosslinking Reactions Effect of crosslinking on properties Crosslinking of biological polymers Crosslinking of proteins Crosslinking of polysaccharides Crosslinking agents Conclusion

Abbreviations ACVA 4,40 -azobis(4-cyanovaleric acid) AIBN Azobisisobutyronitrile ASP Aspartic acid ATRP Atom transfer radical polymerization CL Crosslinker CRP Controlled radical polymerization EDC 1-Ethyl-3-diaminopropyl carbodiimide GAG Glycosaminoglycan

Symbols α Branching coefficient αc Critical value of α for gelation ΔG Gibbs free energy ΔH Enthalpy ΔS Entropy f Initiator efficiency f functionality I Initiator Iabs Intensity of the light absorbed k Rate constant kd Dissociation rate constant ki Rate constant of initiation kp Rate constant of propagation ktc Rate constant for termination by combination ktd Rate constant for termination by disproportionation kt Rate constant for termination k0 Rate constant of condensation polymerization kact Rate constant of activation kdeact Rate constant of deactivation

Glossary Addition polymerization A polymerization type based on use of double bonded monomers where no small molecules are eliminated during polymerization as in condensation. Anionic polymerization Type of addition polymerization which is initiated and carried out by an anion. Cationic polymerization Type of addition polymerization which is initiated and carried out by a cation. Condensation polymerization Polymerization in which bi- or poly-functional monomers bind to produce

479

500 500 502 502 502 502 504 504 505 505

Glu Glutamic acid HDI 1,6-Hexamethylene diisocyanate HDPE High density polyethylene HI Heterogeneity index NHS N-hydroxysuccinimide NMP Nitroxide mediated polymerization P Protein RAFT Reversible addition − fragmentation chain transfer polymerization

Keq Equilibrium constant M• Monomer radical Mn Number average molecular weight Mw Weight average molecular weight N Total number of molecules N0 Initial number of molecules Ni Number of moles of molecules with a molecular weight of Mi p Extent of reaction r Stoichiometric imbalance R• Radical R Reaction rate Ri Rate of initiation Rp Rate of propagation Rt Rate of termination X̄ n Number average degree of polymerization Tg Glass transition temperature Tm Melting point Φ Quantum yield ν Kinetic chain length

macromolecules where generally a small molecule is eliminated. Coordination polymers Stereospecific polymers linked to metal centers where macromolecules are ligands and obtained by specific catalysts. Copolymer Polymers formed by polymerization of more than one type of monomers. Degree of polymerization Average number of repeating units in a mixture of polymeric chains. Gel point The stage at which crosslinks between macrochains begin to cause polymer insolubility.

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Glass transition temperature (Tg) Temperature below which a polymer is hard as glass, and above which polymer gains local or segmental mobility. Initiation Starting reaction of polymerization with the help of an initiator, electromagnetic radiation or energy absorption. Propagation Progression of chain extension by addition of monomers to the end of a growing chain in a polymerization reaction.

1.22.1

Repeating unit It is the basic molecular unit that represents the polymer backbone and is repeated along the chain. Tacticity Regular arrangement of the pendant groups in space; ie, isotactic, syndiotactic, atactic. Termination Loss of the activity of the growing chain either by combination, disproportionation or transfer reactions.

Introduction to Polymer Science

A polymer is a macromolecule that is formed by the combination of many small entities which repeat themselves throughout the large molecule. The small molecules that are the starting materials of the polymers are called monomers, and the unit which repeats to form the macromolecule is called the repeating unit. In general, polymer chains have several thousand repeating units. The length of a polymer chain is determined by the number of repeating units per chain and is called the degree of polymerization. Most of the monomers are composed of carbon, hydrogen, oxygen and nitrogen. Few other elements such as fluorine, chlorine, sulfur, etc. may also exist. Synthesis of polymers is carried out in vessels or large reactors, sometimes with application of heat and pressure, and the small monomeric units connect to each other through the chemical reactions. The chemical process used for the synthesis of polymers is called the polymerization process. Polymers which have the ability to melt and flow are used in manufacturing and are generally identified with the common name of plastics. In general, plastic products are not pure and contain other added ingredients such as antioxidants and lubricants to give the desired properties to the object produced. Most of the macrochains obtained in polymerization reactions are linear polymers and are formed by the reactions of monomers containing either carbon–carbon double bonds or have at least two active functional groups. Many monomers have different active groups on the same molecule such as one end of the monomer contains a carboxylic acid group and the other end contains an alcohol group, and the reaction of the acid with the alcohol via condensation binds the monomers and forms polyesters. Polymerization reactions also take place when one monomer contains two acid groups and the other contains two alcohol or two amine groups. If there are some monomers which have more than two functionalities (eg, 3- or 4-functionality), their presence in the chain causes the formation of extra chains linked to the main backbone. In this case, branched polymers are obtained. If the extent of branching is very high and all the macrochains are connected to each other, then they form a highly crosslinked, three-dimensional structure called a network. These networks have infinite molecular weights. In a polymer structure, all chains are entangled around each other forming the bulk structure. At low temperatures they are solid, but in a good solvent, the chains start to separate from each other. For linear and branched polymers, this separation leads to complete solubility. The crosslinked network polymers, however, cannot dissolve in a solvent; they swell and form gels. If the solvent is very strong, swelling may reach to extreme case causing rupture of chemical bonds and degradation of the gel structure. The process of creating macromolecules from monomers is called polymerization. If only one type of monomer is used in polymerization, there will be only one type of repeating unit in the chain. Such a macromolecule is called a homopolymer. If the polymer is formed from two different monomers (have two different repeating units), it is called a copolymer. If a chain is formed from only ethylene, the polymer is a homopolymer and named as polyethylene. On the other hand, copolymer of ethylene and vinyl acetate has two monomers or two different repeating units, and is named as poly(ethylene-co-vinyl acetate). If three different monomers are used to produce a polymer, the product is a terpolymer. Biological polymers such as enzymes are formed from many different amino acids, and therefore, their structures contain a variety of repeating units. Since a large number of combinations of these molecules are available, it becomes possible to design and synthesize polymers with the desired properties ranging from hard to soft, stiff to elastomer. This versatility makes them essential materials to be used in various applications ranging from macro sized products to nano scale devices for use in biomedical applications.1,2 Polymers such as cellulose, silk and chitin can be obtained from natural sources. On the other hand, polymers such as polyethylene, polystyrene and polyurethane can be synthesized in the laboratories and plants. The macrochains like DNA, RNA and enzymes have biological importance and are crucial for life. In general, the backbone of a polymer is formed mainly of carbon atoms. These are called the organic polymers. There are also a few inorganic polymers; the atoms in their backbones are different than carbon. An example is silicone, the backbone of which is constituted of silicon and oxygen. One very important property which strongly influences the mechanical strength of the polymer is its molecular weight. Smallest hydrocarbon molecules with increasing number of carbons are methane, ethane, propane, butane, pentane, etc. Those containing up to five carbons are in the gaseous state under standard conditions. As the number of carbons, and therefore, the molecular weight increases they become liquids, wax type solids, and eventually solids. The ones that contain more than 100 repeating units within the chain are called polymers. Most polymers which are useful as plastics, rubbers, fibers, etc. have at least 500 repeating units and have molecular weights between 104 and 106 g mol
1. Most of the properties of the polymers are dependent on the chain length. As the molecular weight increases, the softening point, melting point, or mechanical strength of the polymers also

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increases. Molecular weights of polymers are average values because there is always a distribution in chain lengths that forms during polymerization process. Although there are various averaging approaches, the most commonly used ones are the number average molecular weight (Mn) and the weight average molecular weight (Mw). The equations for these parameters are given below: P Mi Ni ð1Þ Mn ¼ P Ni P 2 M Ni Mw ¼ P i Mi Ni

ð2Þ

where Ni is the number of moles of molecules with a molecular weight of Mi. The simplest polymer is polyethylene and has the repeating unit of (–CH2–CH2–). The repeating units of polyethylene have high regularity and the chains may come close to each other and initiate a large number of intermolecular interactions. If one of the hydrogen atoms of polyethylene repeating unit is changed with a different atom or moiety such as a halogen atom or R group, the arrangement of the chain may have different possibilities. The arrangement of atoms or groups fixed by chemical bonding in a molecule is called the configuration. Some examples are cis- and trans-isomers, and also D and L forms of molecules. Chains may have different orientations arising from the rotation of the chain about single bonds. These rearrangements continuously changing are called conformations. A chain can have many different conformations. In vinyl polymers, isomerism is also defined with head-to-tail configuration. If there is a substitute attached to one of the carbon atoms of the double bond, this side is named as the head, and the other becomes the tail. During polymerization, the carbon atoms containing a substitute come together in a head-to-tail, head-to-head or tail-to-tail configuration. Carbon atoms make four bonds in a tetrahedral geometry. If the –C–C– main backbone which forms a zig-zag structure is assumed to be on a plane, the other two bonds are on the different sides of the plane. If there is a side group attached to the main backbone, depending on the orientation of these side groups, tacticity is created. If the polymer is isotactic, it means that all the side groups on each successive chiral center are on the same side of the backbone plane and have the same stereochemical configuration. For syndiotactic polymers, the side groups take place alternatingly on opposite sides of the backbone plane, and each successive chiral center has the alternating stereochemical configuration. If there is no regular arrangement of the subgroups, then it is an atactic polymer and the substituents are placed randomly along the chain. Different placements of substituent R groups in vinyl polymers are shown in Fig. 1. Since tacticity creates a highly ordered organization of repeating units along the chains, those polymers are more rigid with higher crystallinity and strength compared to atactic ones. Although this is the case, in the industry for most of the processes, atactic polymers are preferred because of the ease of their processing. In a polymer structure, long chains are entangled with each other forming a solid mass. This type of polymer has no ordered intermolecular arrangements and is called amorphous polymer. The vinyl polymers which contain bulky substitutes such as poly (methyl methacrylate) or polystyrene are amorphous polymers. On the other hand, in some polymers, intermolecular attractions are very strong and many chains form closely packed structures as a result of these forces. In these cases, they form crystalline

Fig. 1 Tacticity of vinyl polymers. (A) Isotactic, (B) syndiotactic, (C) atactic.

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polymers. Some polymers are partially crystalline; certain regions of different chains or within the same chain have strong attractions and are closely packed. These highly ordered domains are distributed in the amorphous matrix. In such a case, the material is a semi-crystalline polymer. If a polymer is highly crystalline, it is stronger, has higher mechanical and thermal properties than their amorphous counterparts.

1.22.1.1

Classification of Polymers

During the early years of polymer science, two categories of classifications were used. One, based on polymer structure and the backbone, classified the polymers as Condensation and Addition polymers. The other classification used polymerization kinetics and mechanism as the criteria, and classified the polymers as products of step and chain polymerizations.3 These classifications and the terms are generally used interchangeably, because most condensation polymers are produced by step polymerizations and most addition polymers are produced by chain polymerizations. There are also other types of classifications since polymers can be synthesized from a variety of monomers which come together in numerous combinations and in very different forms. Some of the classifications of polymers are given below. Polymer classification according to 1. The origin a. Natural polymers: Proteins, starch, cellulose, natural rubber, etc. are of natural origin. b. Synthetic polymers: These are manmade polymers synthesized in the laboratories. 2. The structural forms of the chains a. Linear polymers: These polymers are composed of long chains and their monomers have two active groups. This can be either two functional groups if the polymer is a condensation polymer, or a single double bond if it is an addition polymer. b. Branched polymers: They are similar to linear polymers, but have long chains with shorter side chains (branches) caused by the presence of small amounts of tri- or more functional monomers for condensation or two or more double bonds for addition polymers. c. Network polymers: These are cross-linked three-dimensional polymers. They consist of long chains which are all connected via multifunctional units and form a network. 3. The polymerization process a. Condensation polymers: These polymers are formed when two di- or polyfunctional molecules react and condense forming macromolecules with the possible elimination of a small molecule (such as water in the case of polyester). All natural polymers are condensation polymers. b. Addition polymers: These polymers are produced by chain reactions of double bonded monomers. The active group of the chain can be a radical or an ion which are the carriers of the process. Free radicals are usually formed by the decomposition and attack of a relatively unstable compound called initiator on the monomers. 4. The composition of the main backbone of the polymers a. Homopolymers: These polymers contain only carbon–carbon bonds in their backbone. b. Heteropolymers: These polymers contain atoms other than carbon in their main chain. The most common non-carbon atoms found in these polymers are oxygen and nitrogen. 5. The structure a. Organic polymers: The backbone of these polymers mainly consists of carbon atoms. b. Inorganic polymers: The main chain of these polymers is not composed of carbon but mainly of inorganic atoms such as silicon in silicone rubbers. c. Coordination (chelate) polymers: In this type of polymers, a chelate ring is formed from an ion or metal and different organic ligands which make donor-acceptor bonds in between. 6. The molecular weight a. Oligomers: These are the polymers with molecular weights in the range 500–5000 g mol
1. b. High polymers: These are the polymers used in the industry in the production of materials and have a molecular weight in the range 10–1000 kDa. 7. The thermal behavior a. Thermoplastics: These polymers contain linear or slightly branched chains, and they soften and flow when the temperature is increased. If they are loaded in a mold in this soft form and cooled, they solidify forming a product in the shape of the mold. Since there is no new chemical bond formation during the heating and cooling process, they can be reshaped with further application of heat and pressure. b. Thermoset polymers: During the processing of these polymers, cross-linking reactions take place upon increase of temperature and they set in the shape of the mold they are in. They cannot be melted and reshaped with the application of heat; they decompose at high temperatures. 8. The arrangement of the repeating units a. Homopolymers: They are formed from single type of monomers and have repeating units with definite chemical structure. b. Copolymers: They are made of two or more types of monomers. The arrangements of the different repeating units in the chain can be different, and therefore, copolymers can be further divided into groups as given below.

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i. Alternating copolymers: The repeating groups of two different monomers follow each other in an alternating manner along the macrochains. ii. Random copolymers: There is no order in the positions of the repeating units of different monomers. iii. Block copolymers: In these polymers, one type of the monomer reacts and forms a long chain (a block) and then reacts with the other type of monomer forming a different block. These block copolymers can be diblock copolymers which are formed as AB type blocks, triblock copolymers which are formed as ABA type blocks, or graft copolymers in which the main chain is a block of one type and block of the other type is attached to the main chain as a side chain. 9. The linkages repeating in the chains: These polymers are classified according to the chemical linkages between the monomeric units which repeat along the chain. For example, polyethers have ether linkages, polyesters have ester linkages, polyurethanes have urethane linkages, etc.

1.22.1.2

Polymerization Systems

Polymerization reactions are carried out in vessels or reactors, generally with application of heat and with the addition of different substituents. Depending on the phases that exist and the forms of the medium, the polymerization processes are classified as homogeneous and heterogeneous systems, which consist of the different techniques given below: 1. Homogeneous polymerization systems: All chemicals are in one phase and homogeneously dissolved in the phase. These are either bulk or solution polymerization processes. a. Bulk polymerization: In these polymerizations, there are only monomers and initiators in the reaction medium. These processes are generally used in the production of condensation polymers in which the reactions are mildly exothermic, of low viscosity, and therefore, mixing, heat transfer and control of the process is easier compared to chain polymerization of vinyl polymers. b. Solution polymerization: Monomer and initiator are dissolved in a solvent and the reaction takes place in this solution. This approach can be used for addition or condensation polymerizations since the medium does not get too viscous which makes mixing, heat transfer and control of the process easy. On the other hand, it requires purification and removal of the solvent. 2. Heterogeneous polymerization systems: In these systems, there are more than one phase creating a heterogeneous media for the monomer, polymer and initiator. a. Gas phase polymerization: In these systems, the monomer is in gaseous state and the polymer formed is either in liquid or solid form. Ethylene polymerization is an example (Fig. 2). b. Precipitation polymerization: This is similar to bulk or solution polymerization, but the polymer formed precipitates as soon as it forms because the polymer is not soluble in its monomer and the solvent of the monomer is not a solvent for the polymer (Fig. 3). c. Solid phase polymerization: Some solid crystalline olefins or cyclic monomers polymerize by solid state polymerization. In these systems polymerization generally starts with exposure to electromagnetic radiation such as X-rays or gamma rays (Fig. 4). d. Suspension polymerization: In these systems, organic phase containing the monomer and the initiator is dispersed as droplets in the aqueous phase containing stabilizers (in order to increase the viscosity and keep the suspension stable; as cellulose or polyvinyl alcohol). Initiator is soluble in the monomer phase. In the droplet, the polymerization mechanism is very similar to bulk polymerization. Size of the droplets is in the range 0.01–0.50 cm and the polymer forms as solid particles of this size (Fig. 5). e. Emulsion polymerization: This system is similar to suspension polymerization system, except that the initiator is soluble in aqueous phase and there is an emulsifier in the medium. The polymerization starts in the aqueous phase and the emulsifier molecules surround the growing chains forming micelles. As the polymerization proceeds, monomer molecules from the organic phase diffuse into the micelles. Micelles therefore get bigger and the monomer droplets get smaller. The polymeric particles obtained at the end of reaction are very small (about 0.1 mm) (Fig. 6).

Fig. 2 Gas phase polymerization.

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Fig. 3 Precipitation polymerization.

Fig. 4 Solid phase polymerization.

Fig. 5 Suspension polymerization.

There are numerous types of synthetic polymers or copolymers which are produced in the laboratories and every year new ones are added to the list. In addition, there are some new biological polymers obtained by some novel molecular techniques added to the list. Some of these can be produced from renewable biomass sources such as vegetable oil, corn starch or microbial sources. Some examples for these polymers are starch based polymers (in the pharmaceutical sector they are used in the production of drug capsules), polylactic acid (PLA, produced from sugar cane or glucose, and used in the production of bone plates in the medical sector), poly(3-hydroxybutyrate) (PHB, is biodegradable and produced by certain bacteria, used in pharmacy and medical applications), polyamide-11 (PA11, derived from natural oil and not biodegradable), bio-derived polyethylene (can be produced

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485

Fig. 6 Emulsion polymerization.

by fermentation of agricultural feed stocks (eg, sugar cane or corn, and is chemically and physically identical to synthetic polyethylene), and bioplastics (produced by genetically modified (GM) organisms, such as GM crops).

1.22.2 1.22.2.1

Polycondensation Characteristics of Condensation Polymerization

Condensation polymerization is used for polymerization of monomers with functional groups and involves a series of chemical condensation reactions, progressing generally with the elimination of low molar weight side products, such as water, alcohol, etc. In condensation polymers, the elemental composition of the repeating unit is the same as that of the two monomers minus the eliminated small molecule.

1.22.2.2

Kinetics of Linear Polycondensation

The chemical structure of the product formed in a condensation reaction depends on the number of reactive functional groups per monomer. Bifunctional monomers form long, linear polymers. In cases where monofunctional monomers are used with bifunctional monomers, only low molecular weight products can be obtained. The monomers used in the process can have the same or different type of functional groups and in the former case two different difunctional monomer types are necessary for product formation. Polyesters are formed by typical condensation reaction of glycols and difunctional carboxylic acids with the elimination of water. The first step is the reaction of the alcohol and acid groups of monomers, and the process continues as given below: HO
R
OH þ HOOC
R 1
COOH-HO
R
OOC
R 1
COOH þ H2 O

ðiÞ

HO
R
OOC
R 1
COOH þ HO
R
OH-HO
R
OOC
R 1
COO
R
OH þ H2 O

ðiiÞ

HO
R
OOC
R 1
COO
R
OH þ HOOC
R 1
COOH-HO
R
OOC
R 1
COO
R
OOC
R 1
COOH

  HO2R2OOC2R 1 2COO2R2OOC2R 1 2COOH þ HO2R2OH-HO
R
OOC
R 1
COO m
H

ðiiiÞ ðivÞ

Chains having different molecular weights can also react with each other to form longer chains with higher molecular weights.4       HO
R
OOC
R 1
COO m
H þ HO
R
OOC
R 1
COO n
H-HO
R
OOC
R 1
COO x
H

ðvÞ

The polymerization reaction proceeds in this stepwise manner, and therefore the chain length and molecular weight gradually increasing with time. The monomer disappears at very early stage of the reaction and before the production of any polymer having sufficiently high molecular weight that is of practical use. The rate of a condensation polymerization is the sum of the rates of all reactions between various sized molecules, and to analyze the kinetics of such a situation with innumerable separate reactions is very difficult. However, in the calculations it is generally assumed that the rate of reaction of a group is independent of the size of

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the molecule to which it is attached. Therefore, the rates of reactions between different sized species are assumed to be the same and independent of the molecular weight. These simplifications accept equal reactivity for all functional groups, and make the kinetics of condensation polymerization identical to reaction of any two small molecule with similar functional groups. There are both theoretical and experimental justifications of these simplifying assumptions.3 The kinetics of condensation polymerization can be explained by taking the formation of a polyester from a diol and a diacid as a model system. This reaction is normally catalyzed by acids; however, in the absence of a strong acid, the diacid monomer serves as its own catalyst (autocatalytic activity) and the reaction is followed by measuring the rate of disappearance of carboxyl groups:


d½COOH ¼ k½COOH2 ½OH dt

ð3Þ

where one of the [COOH] represents the catalytic activity. If the starting concentrations of both functional groups (carboxyl and hydroxyl groups) are equal, the reaction can then be written, rearranged and integrated as


d½COOH ¼ k½COOH3 dt

2kt ¼

1 ½COOH2t

þ constant

ð4Þ ð5Þ

The extent of reaction (p) gives the fraction of functional groups that has reacted by time t. p¼

½COOHo
½COOHt ½COOHo

ð6Þ

Substitution of p into Eq. (4) and rearrangement yields: 1 ¼ 2k½COOH2o t þ constant ð1
pÞ2

ð7Þ

A plot of 1/(1
p)2 versus t has to be linear with a slope of 2k½COOH2o from which the rate constant, k, can be determined (Fig. 7)5 It was shown with experimentation that uncatalyzed esterification requires quite a long time to reach high degrees of polymerization. Higher rate is achieved by adding a small amount of acid catalyst to the system whose concentration is constant throughout the reaction. In this case, the constant concentration of the catalyst can be included in the rate constant (k0 ):


d½COOH ¼ k0 ½COOH½OH dt

ð8Þ

If the initial concentrations of carboxyl and hydroxyl groups are equal, then


d½COOH ¼ k0 ½COOH2 dt

½COOHo k0 t ¼

1 þ constant ð1
pÞ

ð9Þ ð10Þ

In the cases where only bifunctional reactants are present in the reaction system and no side reactions occur, the total number of molecules (N) in the reaction media gives the number of unreacted carboxyl groups. If both types of functional group are considered (eg, carboxyl and glycol structural units), the initial number of carboxyl groups is equal to the total number of

Fig. 7 Plot of 1/(1
p)2 versus t in the determination of rate constant of linear polycondensation.

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487

structural units, No. The number average degree of polymerization (X n ) is Xn ¼

1.22.2.2.1

Number of original molecules No ½COOHo 1 ¼ ¼ ¼ N ½COOHt Number of molecules at time t 1
p

ð11Þ

Molecular weight control in linear polycondensation

Molecular weight of polymers determines its mechanical as well as other properties. Therefore, it is important to control the polymer molecular weight during processing. One method of stopping the reaction at the desired molecular weight is shock cooling, but, this is not preferable since the polymer could restart growing upon subsequent heating due to the presence of unused functional groups. The easiest way to avoid this situation is to adjust the starting composition of the reaction mixture slightly different from stoichiometric equivalence. This can be done by adding either a slight excess of one of the bifunctional reactant or by adding a small amount of a monofunctional reactant into the reaction medium. Eventually, the monomer which is low in amount is completely used up and at all chain ends the excess group is present. If only bifunctional reactants are present and the numbers of the two types of groups initially present are NA and NB in a ratio of r ¼ NA/NB, the total number of monomers present is NA þ NB NA ð1 þ 1=rÞ ¼ 2 2

ð12Þ

At a given time, if p is the extent of reaction defining the fraction of reacted groups, (1
p) will represent the fraction of unreacted groups. Therefore, the total number of chain ends will be   1
rp ð13Þ NA ð1
pÞ þ NB ð1
rpÞ ¼ NA 1
p þ r Since each monomer is difunctional, the number of groups is twice the number of molecules present. Therefore, X n is Xn ¼

NA

ð1þ1r Þ

2 ð1
pþ1
rp r Þ NA 2

¼

1þr 1 þ r
2p

ð14Þ

This equation shows the variation of the degree of polymerization with the stoichiometric imbalance r and the extent of reaction p. When the two bifunctional monomers are present in equal amounts (r ¼1), the equation reduces to Xn ¼

1 ð1
pÞ

ð15Þ

On the other hand, for 100% conversion (p¼ 1), the X n becomes: Xn ¼

1þr 1þr ¼ 1þr
2 r
1

ð16Þ

In a polymerization reaction, p may approach, but never becomes equal to unity. This means there are always some functional groups left unreacted.5 Stoichiometric balance should be maintained in order to achieve high degrees of polymerization. Loss of one ingredient, side reactions, or the presence of monofunctional impurities may severely limit the degree of polymerization.6

1.22.2.3

Nonlinear Polycondensation and its Kinetics

Polyfunctional monomers having more than two functional groups on each molecule cause branching. The level of branching varies the properties of the end product. If monomers have functionality higher than two and if the amount of polyfunctional monomers in the reaction medium is high, branching will be high. In extreme cases where branches attach to each other, crosslinking will take forming an insoluble network structure. The structures of these nonlinear condensation polymers are more complex than those of linear ones. In this case, the polymer has an infinitely large molecular weight in the network structure. The sudden onset of gelation marks the division of the mixture into two parts: the gel (the insoluble part in nondegrading solvents), and the sol (part stays as soluble and can be removed from the gel by extraction). As the polymerization proceeds beyond the gel point, the amount of gel increases and the mixture rapidly changes from a viscous liquid to an elastic material of infinite viscosity. An important feature of the onset of gelation is that the number average molecular weight stays very low while the weight average molecular weight becomes infinite.7

1.22.2.3.1

Prediction of the gel point

In a polymerization reaction the gel point can be estimated from the average functionality of the monomers. Branching coefficient (a) is defined as the probability that a given functional group on a branch unit to connect to another branch unit. In cases where polyfunctional Af units are present with functionality, f, the criterion for gel formation is that, at least one of the functional group in the polyfunctional monomer should connect to another polyfunctional branching unit. Therefore, the critical value of a for gelation (ac) is given as ac ¼

1 f
1

ð17Þ

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Polymer Fundamentals: Polymer Synthesis

The gel point can also be observed experimentally when the polymerizing mixture suddenly loses fluidity. If the extent of reaction is followed as a function of time by determining the number of functional groups present, the value of p (extent of reaction) at the gel point can be experimentally determined.8

1.22.2.4

Mechanisms of Polycondensation

As was stated earlier, all condensation polymerizations take place either by using a monomer with two unlike groups suitable for polycondensation (AB type, eg, polycondensation of hydroxycarboxylic acids) or two different monomers, each having a pair of identical functional groups (AA and BB type, eg, polycondensation of diols with dicarboxylic acids). These monomers polymerize following different routes such as carbonyl addition–elimination, carbonyl addition–substitution, nucleophilic substitution, double bond addition, free radical coupling and aromatic electrophilic substitution reaction.5

1.22.2.4.1

Carbonyl addition–elimination mechanism

Carbonyl addition–elimination is the most important reaction used for polyamides, polyacetals, phenol-, urea-, and melamineformaldehyde polymer preparations. Some typical examples of this reaction are described below. 1.22.2.4.1.1 Direct reaction The reaction of a dibasic acid and a glycol (to form a polyester) or a dibasic acid and a diamine (to form a polyamide) are some examples of direct reaction. A strong acid or its salt is often used as a catalyst. The reaction may be carried out at elevated temperatures and water is removed to push the reaction towards product formation and increase molecular weight. 1.22.2.4.1.2 Interchange The reaction between a glycol and an ester yields polyesters and is preferred especially when the acid has low solubility. For example, in the production of poly(ethylene terephthalate) from ethylene glycol and dimethylterephthalate, generally methyl ester is used. The reaction between a carboxyl and an ester is much slower, but other interchange reactions, such as amine–amide, amine–ester, and acetal–alcohol are well known. 1.22.2.4.1.3 Acid chloride or anhydride Either of these molecules can react with a glycol or an amine. For example, polyamides are prepared by the reaction between an acid chloride and a diamine. 1.22.2.4.1.4 Interfacial condensation The reaction between an acid halide and a glycol or a diamine proceeds rapidly to form high molecular weight polymer chains when they react at the interface of two immiscible liquid containing or consisting of different monomers. In practice, an aqueous solution of the diamine or glycol and an acid acceptor is layered over an immiscible organic phase of the diacid chloride. The polymer forms at the interface and it can be pulled off in the form of a continuous fiber, film or filament. The method is applied in the synthesis of polyamides, polyurethanes and polyureas. Since it can be carried out at room temperature, it is useful in the preparation of heat sensitive polymers. 1.22.2.4.1.5 Ring versus chain formation Bifunctional monomers may react intramolecularly to produce a cyclic product. Thus, hydroxyacids may give either lactones or polymers on heating and amino acids may yield lactams or linear polyamides. The type of the product is generally dependent on the size of the ring that can be formed.

1.22.2.4.2

Other mechanisms

1.22.2.4.2.1 Carbonyl addition–substitution reactions Formation of polyacetals is an example and forms by the reaction of aldehydes with alcohols. There is addition followed by substitution reactions at the carbonyl group. 1.22.2.4.2.2 Nucleophilic substitution reactions This is a reaction between a donor of an electron pair (the nucleophile) and an acceptor of an electron pair (the electrophile). These reactions are used in the polymerization of epoxides. Nucleophiles attack the electrophilic C of the C–O bond of the epoxide and break it, causing ring opening. Epoxides are very reactive due to the strain in the 3-membered ring structure and opening of the ring relieves the strain, and therefore, epoxides can react with a large range of nucleophiles (eg, H2O, ROH, R-NH2). Nucleophilic substitution reactions are also the basis for the formation of natural polysaccharides and polynucleotides. 1.22.2.4.2.3 Double bond addition reactions Addition reactions are often associated with addition polymerization and especially free radical polymerization. Addition of the groups occurs to the double bonds. But, this is not always the case. The addition of diols to diisocyanates in

Polymer Fundamentals: Polymer Synthesis

489

the production of polyurethanes is a condensation polymerization without eliminating any small molecule (as water, ethanol, etc.). 1.22.2.4.2.4 Free radical coupling These reactions are used in the preparation of arylene ether polymers, polymers containing acetylene units and arylene alkylidene polymers. 1.22.2.4.2.5 Aromatic electrophilic substitution reactions This type of reactions including the use of Friedel–Crafts catalysts produces polymers by condensation polymerization.

1.22.2.5

Typical Condensation Polymers and Their Biomedical Applications

Polyesters, polyurethanes, polyamides, polyanhydrides, polycarbonates and polyureas are among the condensation polymers that find broad use in medical applications in various forms.1,2,9 Some natural polymers such as proteins (collagen, gelatin, silk fibroin) and polysaccharides (hyaluronic acid, cellulose) as well as bacterial polymers (polyhydroxyalkanoates, bacterial cellulose) are also condensation polymers and are widely used in medical applications especially as drug carriers in pharmacy and in the form of porous scaffolds for tissue engineering.10 Some typical examples of condensation polymers and their biomedical applications are listed in Table 1.

1.22.3

Addition Polymerization

Polymerization in which the polymer forms by addition of monomeric unit to the growing chain is called as addition polymerization. Generally, a monomer containing double bond and an initiator creates the first active unit; they are needed to start the chain growth. The active group, may be a free radical, an anion or a cation. In addition polymerization, the reaction takes place by opening of the double bond and the created active group adds the monomers at a very high rate so that high molecular weight polymer chains form in a very short time. The reaction medium therefore consists of large macromolecules and monomers unlike in condensation polymerization. Depending on the type of initiator, a radical, anion, or cation is created and depending on the chemistry, adds monomers either by radical or ionic mechanism, and eventually forms a large molecule. The molecular weight of the polymer chains is practically unchanged during polymerization, but in time more of the monomers is converted into polymers and the monomer concentration decreases.5 Monomers show varying degrees of preference with regard to the type of reactive center that leads to polymerization. A large number of monomers are polymerized by free radicals, but they are more selective of the ionic mechanisms. For example, acrylamide polymerizes anionic but not cationic routes, whereas N-vinylpyrrolidone polymerizes by cationic but not anionic.8 Free radical polymerization is possible for both monomers. Another type of polymerization is coordination polymerization in which special catalysts are used and highly ordered polymers with stereospecific properties are obtained. Table 1

Typical condensation polymers and their biomedical applications

Type

Characteristic linkage

Sample polymer

Biomedical application

Polyacetal

– O – CH – O –

Poly(ethyl glyoxylate)

Hard tissue replacement

Nylon

Intracardiac catheters, sutures, dialysis device components, heart mitral valves, hypodermic syringes

Bisphenol-A polycarbonate

Intraocular lenses, dialysis device components, heart/lung assist devices, blood collection, arterial tubules

Poly(lactic acid-co-glycolic acid)

Grafts, sutures, implants, prosthetic devices, micro and nanoparticles

Proteins, enzymes

Tissue engineering scaffolds, wound dressings

Polyisobutylene-based polyurea

Blood contacting surfaces

Poly(ether urethane)

Aortic patches, heart assist devices, adhesives, dental materials, blood pumps, artificial heart and skin

R O

Polyamide

– NH – C – O

Polycarbonate

– O – CO – Polyester

O – CO –

Polypeptides

O – NH – C –

Polyurea

O – NH – C – NH –

Polyurethane

O – O – C – NH –

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Polymer Fundamentals: Polymer Synthesis

Table 2

Types of addition polymerizations suitable for common monomers

Monomer

Ethylene Propylene and a-olefins Styrene Vinyl chloride Tetrafluoroethylene Acrylic and methacrylic esters Acrylonitrile

Polymerization mechanismsa Radical

Cationic

Anionic

Coordination

þ
þ þ þ þ þ

þ
þ







þ

þ þ

þ þ þ þ þ þ þ

a “ þ ” refers to high polymer formed, “
” refers to no reaction or oligomers only. Source: Modified from Billmeyer.5

Table 2 shows the types of initiation that polymerize various monomers. The reactions of polymerizations of the monomers given in Table 2 appears thermodynamically feasible because of the negative value of the Gibbs energy (ΔGo0), but polymerization practically is achieved only with a certain type of initiator. The key to this phenomenon lies in the polarity of the monomer and the strength of the ion formed. Monomers with electron donor groups (alkoxy, alkyl, alkenyl and phenyl) attached the carbons of the unsaturation, increase the electron density on the carbon–carbon double bond and when these electrons react with a cationic initiator, a stable carbenium ion forms on the growing unit. In this case chain polymerizes with cationic catalysts. On the other hand, monomers with electron withdrawing substituents (aldehyde, ketone, acid, ester, etc.) decrease the electron density on the double bond and facilitate the attack of anionic catalysts leading to anionic polymerization. Free radical polymerization takes place in most cases but may be considered to be an intermediate case and a radical created on the growing chain leads to the formation of macromolecules. Many monomers can polymerize by free radical mechanism in addition to an ionic mechanism.5,7

1.22.3.1

Free Radical Polymerization

Free radicals are unpaired electrons that are highly reactive and have short lifetimes. In free radical polymerizations each chain grows by adding monomers to the free radical end of the growing chain. When the monomer is added, the active free radical is transferred to the newly added group at the chain end. Free radical polymerization has the following three stages: initiation, propagation and termination.

1.22.3.1.1

Initiation

In the initiation step, free radicals are formed from the activation of the initiator and then the resultant free radicals attack a monomer. Initiators can be peroxides or azo compounds in which scission of a single bond creates radicals, or a redox reaction in which radicals are created by an electron transfer to or from an ion or molecule. Dissociation can be achieved by the application of heat or electromagnetic radiation (eg, UV, gamma). Peroxides and hydroperoxides are frequently used as initiators because of the instability of the peroxide (–O–O–) bond. In the case of azo compounds the process is driven by the release of N2. Redox reactions are preferred especially when the polymerization is needed to be carried out at low temperatures.8,12 Heat and electromagnetic radiations can also start polymerization by breaking the double bond of the monomeric units and creating two active radicals. In this case, chain adds to monomeric units from both ends. Some of the most widely used initiator systems are given in Table 3. The initiation step can be shown as follows: Dissociation of an initiator and combination of the radical to the monomer. Dissociation of an initiator (I) such as benzoyl peroxide yields two radicals (R  ). This step has a dissociation rate constant, kd. Then this radical attacks a monomer molecule to create the first M radical. This step has a rate constant of initiation, ki. Kd

I⟹2R  Ki

R  þ M⟹RM

1.22.3.1.2

ðviÞ ðviiÞ

Propagation

The free radicals formed are very active and immediately attack the monomer molecules leading to formation of growing macroradicals. Each addition creates a one monomer unit longer chain with a new radical that has the same reactivity as the previous one. In the polymerization mechanism it is assumed that all growing chains have the same propagation constant (kp). Propagation steps are fast and growth of the chain takes place in milliseconds. For most of the monomers the propagation rate constant, kp, is in the range 102–104 L mol
1 s
1. The successive additions may be represented as follows: Kp

Mn þ M⟹Mnþ1

ðviiiÞ

Polymer Fundamentals: Polymer Synthesis

Table 3

491

Free radical initiation reactions

1. Acyl peroxides, alkyl peroxides or hydroperoxides Benzoyl peroxide:

O

O

O

Ø–C–O–O–C–Ø

Δ →

2 Ø – C – O•

t-Butyl peroxide:

CH3

CH3

CH3 Δ →

H3C – C – O – O – C – CH3

2 H3C – C – O•

CH3

CH3

CH3

Cumyl hydroperoxide:

CH3

CH3

Ø – C – O – OH

Δ →

CH3

Ø – C – O•

+

•OH

CH3

2. Azo compounds 2,20 -Azobisisobutyronitrile (AIBN):

CH3

CH3

CH3

Δ H3C – C – N = N – C – CH3 →

2 H3C – C• + N2

CN

CN

CN

3. Redox systems H2 O2 þ Fe2þ -
OH þ Fe3þ þ \tf="Gvw" \char "B7O H 2
2þ 3þ þ SO
S2 O2
8 þ Fe -SO4 þ Fe 4 \tf="Gvw"\ \char\ "B7 4. Electromagnetic radiation (Photoinitiation) Styrene, benzoin:

H

H

H

Ø–C=C

Ø – C = C•

+

H•

H

H

H Ø•

+

C = C• H

O

H

H

Ø– C–C– Ø OH

1.22.3.1.3

H

O Ø – C•

+

•C – Ø OH

Termination

Termination step usually takes place by either combination or by disproportionation reactions. In case of combination, two growing chains are coupled to form a macro chain. Ktc

Mn þ Mm ⟹Mnþm where ktc is the rate constant for termination by combination.

ðixÞ

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Polymer Fundamentals: Polymer Synthesis

In case of disproportionation termination, there is a rearrangement of atoms where one hydrogen atom is exchanged between the growing chains. This results two terminated chains: Ktd

Mn þ Mm ⟹Mn þMm

ðxÞ

where ktd is the rate constant for termination by disproportionation. Termination by disproportionation forms one polymer molecule with a saturated end-group and another with an unsaturated end-group. Type of termination affects the molecular weight. If it is through combination, average molecular weight will be two times higher than that of polymers terminated by disproportionation. In general, both types of termination reactions take place in different proportions depending upon the monomer and the polymerization condition. For example, polystyrene chains terminate by combination whereas poly(methyl methacrylate) chains terminate by disproportionation, especially at temperatures above 60 1C.5

1.22.3.1.4

Kinetics of radical polymerization

In radical polymerization reactions, decomposition of the initiator (eg, peroxides, azo compounds) proceeds much more slowly than the reaction of the free radical with the monomer. This step is the rate-determining step. The rate of initiation (Ri) is   d½M  Ri ¼ ¼ 2fkd ½I ð18Þ dt i where f is the initiator efficiency and defines the fraction of the radicals that can bind the monomers and initiate polymerization. This step of initiator dissociation has the rate constant kd, and [I] is the concentration of the initiator. The constant 2 indicates that, each molecule of the initiator creates two radicals. The initiator efficiency is in the range 0.3–0.8 due to side reactions. The initiator efficiency decreases when side reactions terminate the radicals.8 For a redox initiation system, rate of initiation is given as   d½M  ¼ fk½Ox ½Red ð19Þ Ri ¼ dt i where [Ox] and [Red] are the concentrations of oxidizing and reducing agents and k is the rate constant. For photochemical initiation, intensity of light affects the rate and equation:   d½M  Ri ¼ ¼ 2FIabs dt i where Iabs is the intensity of the light absorbed and the constant F is the quantum yield. The rate of termination is represented as:   d½M  Rt ¼
¼ 2kt ½M 2 dt i

ð20Þ

ð21Þ

where kt is the overall rate constant for termination. The constant 2 shows two growing chains are terminated by each termination reaction. At the beginning of the polymerization, radical formation rate is higher than the termination rate. As the reaction proceeds, the rates of formation and loss of radicals by termination become equal and it can be stated that there is no change in the   concentration of M . This is the steady state (d½M dt ¼ 0). In steady state, the rates of initiation (Ri) and termination (Rt) are equal, leading to   fkd ½I 1=2 ½M  ¼ ð22Þ Kt The rate of propagation is represented as

 Rp ¼


d½M dt



¼ kp ½M ½M 

ð23Þ

t

and by using Eq. (22), Rp can be obtained as  Rp ¼ kp

fkd ½I kt

1=2 ½M

ð24Þ

If the initiator efficiency is high (close to 1) and f is independent of monomer, then the rate of polymerization is proportional to the first power of the monomer concentration. In chain polymerization, one important phenomenon is the “gel effect” or “Trommsdorff–Norrish effect” which is auto-acceleration of the polymerization. In these cases, viscosity of the reaction medium increases and the mobility of the growing chains are restricted. Chains continue to grow with addition of monomers, but they cannot terminate. Heat transfer is difficult and the system is not at steady state any more. Fast polymerization causes heat evolution and local hot spots cause crosslinking and gel formation.11

Polymer Fundamentals: Polymer Synthesis 1.22.3.1.5

493

Degree of polymerization

The number of monomer molecules added to every active center (created radicals) is defined as kinetic chain length ((n)). It is represented as Rp/Ri ¼ Rp/Rt. Therefore ðnÞ ¼

kp ½M 2kt ½M 

ð25Þ

and by using Eq. (23) it becomes ðnÞ ¼

k2p ½M2 2kt Rp

ð26Þ

The number average degree of polymerization, X n , and the kinetic chain length ((n)) may be same or not depending on the type of the termination reaction. If the propagating radicals terminate by combination, then X n ¼ 2ðnÞ, and if termination is by disproportionation, X n ¼ ðnÞ Chain transfer is the reaction of a growing chain with an inactive molecule to produce a new dead polymer chain and a new active molecule in the form of a radical. The transfer agent may be an initiator, monomer, polymer, solvent or even an impurity. When the transfer does not lead to new chain growth, it is called inhibition. If the newly formed radical is less reactive than the propagating radical, then it is called retardation.5

1.22.3.1.6

Thermodynamics of polymerization

Addition polymerizations of olefinic monomers have negative ΔH and ΔS. The polymerization reaction has exothermic nature because the process involves the formation of new bonds. The negative ΔS arises from the decreased degree of freedom of the polymer compared to the monomer. Gibbs free energy (ΔG) depends on both parameters and is given by DG ¼ DH
TDS

ð27Þ

The numerical value of ΔS is much smaller than ΔH. Therefore, ΔG is negative under ambient T conditions since |ΔH|4|TΔS|. Polymerization is thermodynamically favorable. However, thermodynamic feasibility does not mean that the reaction is practically feasible. For the polymerization reaction to take place at appreciable rates it may require specific catalyst systems. This is the case with the a-olefins which require Ziegler–Natta or Coordination-type initiators composed of alkyl halides of metals (groups I, II and III) and alkyl and halides of transition metals (groups IV–VIII).5

1.22.3.2

Ionic Polymerization

Addition polymerization of olefinic monomers can also be achieved with active centers possessing ionic charges. These can either be cationic or anionic polymerizations depending on the type of the chain carrier ion. The ionic charge of the active center causes these polymerizations to be more selective unlike in free radical polymerization. They proceed only with monomers that have substituent groups which can stabilize the active center. The activation energy required for ionic polymerizations is small allowing these reactions to occur at very low temperatures. This is a characteristic property of ionic polymerizations. For cationic active centers electron donating substituent groups are needed. For anionic polymerization, the substituent group must be electron withdrawing to stabilize the negative charge. Thus, most monomers can be polymerized either by cationic or by anionic polymerization but not both. Only when the substituent group has a weak inductive effect and is capable of delocalizing both positive and negative charges (eg, styrene and 1,3-dienes), both cationic and anionic polymerizations can be achieved. Another important difference between free radicalic and ionic polymerizations is that many ionic polymerizations proceed at much higher rates than free radical polymerization, mainly because the concentration of propagating chains is much higher (by a factor of 104–106). A further difference is that an ionic active center is accompanied by a counter ion of opposite charge. Both the rate and stereochemistry of propagation are influenced by the counter ion and the strength of interaction with the active center. Finally, termination does not occur by a reaction between two ionic active centers because they both have similar charges.11

1.22.3.2.1

Cationic polymerization

Typical catalysts for cationic polymerization are strong electron acceptors such as Lewis acids, Friedel–Crafts halides, Brönsted acids and stable carbenium ion salts. Most of the cationic polymerizations require a co-catalyst, usually a proton donor, to initiate polymerization. The monomers having electron donating 1–1-substituents form stable positively charged carbenium ions and polymerize by cationic mechanisms. For these systems the polymerization rate is very high; for isobutylene initiated by AlCl3 or BF3, in a few seconds at
100 1C, chains of several million Daltons can form. Both the reaction rate and the chain length decrease with temperature.7 In certain cationic polymerizations, a distinct termination step may not happen; therefore, the polymers formed are called “living” cationic polymers. However, chain transfer to a monomer, polymer, solvent, or counterion can take place and these would terminate the growth of the chains. Cationic polymerizations are usually conducted in solution, at low temperature, typically
80 1C to
100 1C. The solvent is important because it determines the activity of the ion at the end of the growing chain. The polymer chain length increases linearly and polymerization rate increases exponentially as the dielectric strength of the solvent used increases.12

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Polymer Fundamentals: Polymer Synthesis

1.22.3.2.2

Anionic polymerization

The initiator in an anionic polymerization needs to be a strong nucleophile, such as Grignard reagents and other organometallic compounds (eg, n-butyl lithium). When the starting reagents are pure and there are no traces of oxygen and water in the polymerization reactor, the chain can grow until all the monomer molecules are used up. That is why anionic polymerization is sometimes also called “living” polymerization. Termination step can occur only by intentional introduction of oxygen, carbon dioxide, methanol or water into the reactor. In the absence of a termination mechanism, the number average degree of polymerization, X n , is Xn ¼

½Mo ½Io

ð28Þ

where [M]o/[I]o is the ratio of the initial concentrations of the monomer to the initiator. The absence of termination in this polymerization method allows the formation of a very narrow molecular weight distribution and a heterogeneity index (HI) very close to 1 (eg, 1.06), whereas it is as high as 2 with free radical polymerization.12

1.22.3.3

Coordination Polymerization

Coordination polymerizations are used to obtain polymers with very high stereospecificity. For this purpose, very special catalysts may be used. For example, special Ziegler–Natta catalysts are used in the polymerization process to synthesize isotactic polypropylene (i-PP) and high density polyethylene (HDPE). Catalysts lead to coordination type mechanism during polymerization. Ziegler–Natta catalysts consist of a complex between the cation from groups I to III in the Periodic Table, (eg, Al(C2H5)3), and a halide of transition metal from groups IV to VIII, (eg, TiCl4). In the preparation of high density polyethylene (HDPE) ethylene gas is bubbled in a suspension containing Al(C2H5)3 and TiCl4 in hexane at room temperature. It is proposed that the metal atom of the catalyst is bound to the growing polymer chain and during monomer insertion coordination of the monomer with the metal atom takes place. The coordination of the monomer and the metal atom is the cause of the stereospecificity of the forming polymer. These coordination polymerizations can be terminated by the presence of water, hydrogen, aromatic alcohol or metals.12

1.22.3.4

Typical Addition Polymers and Their Biomedical Applications

Addition polymers such as polyethylene, polypropylene, polystyrene, and polyacrylates can be easily fabricated in many forms such as fibers, textiles, films, rods and viscous liquids, and they are used in a variety of biomedical applications. Some are given in Table 4.13,14 Table 4

Some addition polymers used in biomedical applications

Synthetic polymers

Monomeric Unit

Applications

Polyethylene (PE)

½
CH2
CH2
n

Pharmaceutical bottles, nonwoven fabrics, catheters, pouches, flexible containers, orthopedic implants (eg, hip implants) Contact lenses, surface coatings, drug delivery systems

Poly(2-hydroxyethyl methacrylate) (PHEMA)

CH3 −CH2−C−n COOCH2CH2OH

Poly(methyl 2-cyanoacrylate)

CN

Surgical adhesive

−CH2−C−n COOCH3 Poly(methyl methacrylate) (PMMA)

CH3 −CH2−C−n

Blood pumps and reservoirs, membranes for dialyzers, intraocular lenses, bone cement, drug delivery systems

COOCH3 Polypropylene (PP)

−CH2−CH−n CH3

Polystyrene (PS)

Poly(tetrafluoro ethylene) (PTFE) Poly(vinyl chloride) (PVC)

−CH2−CH− n C6H5 −CF2−CF2−n −CH2−CH− n Cl

Disposable syringes, blood oxygenator membranes, sutures, nonwoven fabrics, artificial vascular grafts, reinforcing meshes, catheters Tissue culture flasks, roller bottles, filters Catheters, artificial vascular grafts, various separator sheets Blood bags, surgical packaging, i.v. sets, dialysis devices, catheter bottles, connectors, cannulas

Polymer Fundamentals: Polymer Synthesis 1.22.3.5

495

Comparison of Addition and Condensation Polymerization

The main difference between step polymerization and chain polymerization is that in the step polymerization the reaction can occur between any different sized species. The size of the polymer molecules increases at a slow rate and the monomers disappear early in the reaction. In case of chain polymerization the monomer concentration decreases gradually (in the medium there are long chains and monomers till the end of the reaction) and growth occurs very rapidly by addition of single monomeric units to the end of the growing chains. Longer polymerization durations are essential in obtaining high molecular weight condensation polymers whereas with chain polymers long reaction times increase the yield without affecting the molecular weight significantly. In the case of chain polymerizations, continuous increase of terminated polymer chains are observed as the reaction goes on. On the other hand, in step polymerizations high molecular weight polymer can be obtained only at or near the end of the reaction (at 98% conversion).3,15,16

1.22.3.6 1.22.3.6.1

Other Polymerization Techniques Atom transfer radical polymerization

Atom transfer radical polymerization (ATRP) is a controlled living polymerization method which yields well defined polymers or copolymers with predetermined molecular weight, narrow molecular weight distribution, and a high degree of chain end functionality. ATRP has been used in the preparation of polymers with precisely controlled functionalities, topologies (linear, star/ multi-armed, comb, hyperbranched and network polymers), and compositions (homopolymers, block copolymers, gradient copolymers, graft copolymers, etc.). Monomers, initiators with a transferable atom (generally a halogen), and catalysts (transition metals with suitable ligands) are the main constituents of ATRP. In some cases an additive (metal salt in a higher oxidation state) may be used. Solvents used and temperatures applied are important parameters for a successful ATRP. The most commonly used monomers are styrenes, methacrylates, methacrylamides, dienes, and acrylonitriles. Atom transfer step is the main reaction that leads to uniform growth of the polymer chains. In ATRP, radicals are formed as a result of a reversible redox reaction of a transition metal complex, Mtn
Y/Ligand, where Mt is a transition metal and Y is another ligand or a counterion. Transfer of X (usually a halogen) from a dormant specie to the metal leads to an oxidized metal complex (X
Mtn þ 1
Y/Ligand which is the persistent specie) and a free radical (R). Activation and deactivation reactions occur with rate constants of kact and kdeact, respectively (Fig. 8). Even if same ATRP conditions (same catalyst and initiator) are used, each monomer has its own atom transfer equilibrium constant for its active and dormant species. The rate of polymerization depends on the equilibrium constant Keq, which is the ratio of the activation and deactivation rate constants (Keq ¼ kact/kdeact). If it is too small, the polymerization reaction will occur slowly, and if it is too large, due to the high radical concentration, termination will occur and polymerization will be uncontrolled. The new radical can initiate the polymerization by addition to a monomer with the rate constant of propagation, kp. Also termination reactions with termination rate constant, kt also occur in ATRP reactions. Terminations may occur by combination or disproportionation, or the active species is reversibly deactivated by the higher oxidation state metal complex. In a well-controlled ATRP reaction, only a small percent of the chains undergo termination. During the initial, short, non-stationary stage of the polymerization the concentration of radicals decays by irreversible self-termination, while the oxidized metal complexes increase steadily as the persistent species. As the reaction proceeds, the decrease in the concentration of the radicals causes a decrease in self termination and cross reaction with persistent species towards the dormant species. The decrease in the stationary concentration of growing radicals minimizes the rate of termination. The stabilizing group (eg, phenyl or carbonyl) on the monomers produces sufficiently large atom transfer equilibrium constant. Typically, alkyl halides (RX) are used as the initiator. The halide group (X) rapidly and selectively migrates between the growing chain and the transition-metal complex to form polymers having similar chain length and with narrow molecular weight distributions. Catalyst on the other hand determines the position of the atom transfer equilibrium and the dynamics of exchange between the dormant and active species. A variety of transition metal complexes have been used as ATRP catalysts such as transition metal complexes of copper, ruthenium, palladium, nickel and iron. Polymerization is carried out in bulk or in solvents (eg, benzene, water, etc.) at moderate temperatures (70–130 1C).17,18

Fig. 8 General mechanism of ATRP.

496

Polymer Fundamentals: Polymer Synthesis

Fig. 9 General mechanism of NMP.

1.22.3.6.2

Nitroxide mediated polymerization

Nitroxide mediated polymerization (NMP) is another controlled radical polymerization method. It allows the preparation of welldefined polymers with controlled molecular weight and narrow distribution and to extend chains with different monomers to produce multi-block copolymers. A combination of a nitroxide and a free radical initiator or alkoxyamine serves both as initiators and controlling agents. NMP is based on a reversible recombination of propagating species (P ) and nitroxide (R2NO , R¼alkyl group) that form alkoxyamine (R2NOP), results in a low radical concentration and decreases the irreversible termination reactions. Polymer chains with equal chain lengths and reactive chain ends can be obtained because a majority of dormant living chains can grow until the monomer is fully consumed. A typical mechanism is given in Fig. 9. NMP is metal free and not colored, and polymer does not require any purification after synthesis. The main limitation of NMP is the availability of a range of monomers that can be effectively controlled. Some alkoxyamines and nitroxides are able to control most of the conjugated vinyl monomers. Some of these double bonded polymers are styrene and derivatives, acrylates (including some functional acrylates), acrylamides, acrylonitrile, and methacrylates (with some limitations) and also some dienes such as isoprene.19,20

1.22.3.6.3

Reversible addition
fragmentation chain transfer polymerization

Reversible addition
fragmentation chain transfer polymerization (RAFT) is one of the most versatile methods of controlled radical polymerization. It allows the use of a wide range of monomers and solvents, including aqueous solutions. The method is relatively new for the synthesis of living radical polymers and may be more versatile than ATRP or NMP. Thiocarbonylthio compounds, (eg, dithioesters, dithiocarbamates, trithiocarbonates, xanthates) are used in RAFT polymerization. The technique is also versatile because it is applicable to a wide range of monomers (eg, methacrylates, methacrylamides, acrylonitrile, styrene, butadiene, vinyl acetate, N-vinylpyrrolidone). Due to its exceptional effectiveness, the broad range of monomers and solvents, highly organized polymers production with highly controlled molecular weight and molecular weight distribution, RAFT polymerization has become an extremely important polymerization technique. A RAFT polymerization medium consists of an initiator, monomer, chain transfer agent and solvent. The control of temperature is critical. It is performed by adding a certain amount of a suitable RAFT agent (ie, a thiocarbonylthio compound) to a conventional free radical polymerization medium. The initiators creating radicals, such as azobisisobutyronitrile (AIBN) and 4,40 -azobis(4-cyanovaleric acid) (ACVA), are commonly used as initiators in RAFT polymerizations. There are 4 steps in a typical RAFT polymerization: initiation, addition–fragmentation, reinitiation, and equilibration (Fig. 10). Initiation step starts by radical initiators (I). The reaction of initiator with monomer create an active radical specie which is capable to start polymerization by forming active polymer chains (Pn ). Addition–fragmentation step takes place between the active chain (Pn ) and the RAFT agent and this reaction releases the homolytic leaving group (R  ). This is a reversible step and the active intermediate (Pn ) can lose either active group (R  ) or the polymeric chain. Reinitiation can start between the leaving group radical and another monomer and starts the formation of another active polymer. This active chain (Pm ) goes through the addition–fragmentation or equilibration steps. RAFT agents behave as chain transfer agents, and they are thiocarbonylthio compounds having Z and R groups. The Z group mainly controls the type of the radical specie that can add to the C ¼ S bond. The R group is a good homolytic leaving group, and it is able to initiate new polymer chains. There is a continuous equilibrium in the RAFT reactions and this controls the reaction between the active propagating species and the dormant thiocarbonyl compound. Active polymer chains (Pm and Pn ) are in equilibrium between the active and dormant stages. In the process, when one polymer chain is in the dormant stage (bound to the thiocarbonyl compound), the other chain is active in polymerization.21,22 RAFT process allows the synthesis of polymers with specific macromolecular architectures such as block, gradient, statistical, linear block, comb/brush, star, hyperbranched and network copolymers and dendrimers.23 Examples of architectures that can be synthesized by RAFT are given in Fig. 11.

1.22.3.6.4

Click polymerization

Click polymerization is a technique applied to obtain specially designed polymers under mild conditions. In general, click reactions are 1,3-dipolar cycloaddition reactions of azides and terminal alkynes with possible catalytic effect of metals such as

Polymer Fundamentals: Polymer Synthesis

Fig. 10 General mechanism of RAFT.

Fig. 11 Examples of complex architectures prepared by RAFT.

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Fig. 12 Thermally activated and metal mediated click polymerization.

copper. Click reactions have a high thermodynamic driving force; they avoid side product formation or contamination leading to highly pure products. Since the reactions are quite simple and efficient, they are called “click” reactions.24 One example is alkyneazide click reactions for the synthesis of polytriazoles (PTAs) with linear and hyperbranched structures.25 The PTAs show some unique functional properties, such as luminescence, chromism, fluorescence imaging, emission superquenching, chain helicity, optical nonlinearity, light refractivity, photovoltaic effect, cytocompatibility and biodegradability. The process catalyzed by Cu(I) or Ru(II) and form 1,4- and 1,5-regioregular PTAs, respectively, is shown in Fig. 12. In the literature there are examples of the applications of the azide-alkyne click chemistry into the conjugation of polymers with biological molecules such as nucleic acids, peptides, sugars, proteins, viruses, and cells which find use in pharmaceutics and drug discovery, and also as model for the area of polymer and material sciences.26 Atom transfer radical polymerization (ATRP), nitroxide-mediated polymerization (NMP) and reversible addition–fragmentation transfer polymerization (RAFT) are controlled radical polymerization (CRP) techniques and they are all very suitable for the preparation of functional polymers. Polymers synthesized with these techniques have at the end a “dormant” unit such as a halogen atom in ATRP, an alkoxyamine moiety in NMP, a dithioester moiety in RAFT. These end groups can be transformed into a variety of functional groups after polymerization and can be used in the preparation of complex materials.27,28

1.22.4

Polymer Reactions

1.22.4.1

Copolymerization

Copolymers are polymers formed from two or more monomeric units. The repeating units can be arranged in various ways along the chain. Some copolymers have only two repeating units, however, proteins and some polysaccharides are copolymers of a number of different monomers. Copolymers constitute the vast majority of commercially important polymers. In general, the properties of copolymers depend on the amounts of the constituents present in the structure. The composition may vary by adding either very small percentage of one component or adding comparable proportions. Such a wide variation in composition leads to variety in the properties of the products. Crosslinking or vulcanization can be obtained by adding sulfur, dienes or trifunctional monomers. By changing the composition, the desired properties such as product solubility, dyeability, or strength can be obtained.12

1.22.4.1.1

Types of copolymerization

In free radical polymerization, reactivity ratios of the monomers, r1 and r2, are of great importance. Reactivity ratios represent the relative affinity of a given radical to its own monomer over the other monomer. r1 ¼

k11 k12

r2 ¼

k22 k21

ð29Þ

where k11 and k22 are the rate constants for the radicals adding their own type of monomer and k12 and k21 are the rate constants for them adding the opposite kind. Depending on the r values, copolymerization reactions can form ideal, random, alternating or block copolymers. Another type is graft copolymers. In ideal copolymerization, the growing chain end reacts with one of the monomeric units with a statistically possible preference. The multiplication of reactivity ratios should be unity. When, r1.r2 ¼ 1 then, r1 ¼

1 r2

or

k11 k21 ¼ k12 k22

ð30Þ

The composition and the relative amounts of the reacting monomeric groups in the polymer chain are determined by the reactivity of the monomer and the initial (feed) composition of the reaction medium.

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r1.r2 ¼1 occurs under two conditions: iÞ

r1 41 and

r2 o1

or

r1 o1

and

r2 41

Here, one either r1 or r2 is more reactive than the other. Therefore, the final product will be rich in the active monomer and will contain a greater proportion of it. The sequence is random along the chain. In this case, to obtain copolymers with significant quantities of both monomers is difficult and become more difficult if the difference in the reactivities of the two monomers increases. iiÞ

r1 ¼ r2 ¼ 1

In the cases where reactivity ratios of both monomers are equal, the growing radicals cannot make a choice since they have similar activity for both monomers. The composition of the copolymer is the same as that of the input concentrations and the monomers are arranged randomly along the chain. These copolymers show properties of both homopolymers of its constituents. Random copolymers are formed when r values of both monomers are close to each other. Two or more monomers are polymerized in one process. The sequence and the arrangement of the monomers in the chain is determined by kinetic factors. If the reacting monomers are shown as A and B, the sequence will have no order, such as —AABBAAABABAA—. Random copolymers tend to average the properties of the constituent monomers in proportion to the relative abundance of the co-monomers. In the alternating copolymerization, r values of both monomers are equal to zero (r1 ¼ r2 ¼ 0 or r1.r2 ¼ 0). This means each radical exclusively reacts with the other monomer and has no affinity for the monomers similar to itself. This means one type of radical can regenerate itself. This leads an alternating organization along the chain. These types of copolymers are called alternating copolymers and can be shown as —ABABAB—. Polymerization continues until one of the monomers is used up. Perfect alteration occurs when both r1 and r2 are zero. In the cases where r1r2 approaches zero, there is an increasing tendency toward alternation, but it may not cause perfect alternating copolymers. The values of r1r2 close to zero leads copolymers with appreciable amounts of both monomers.14 Alternating copolymers, while relatively rare, are characterized by combining the properties of the two monomers along with structural regularity. Crystalline polymers can be obtained if a very high degree of regularity (stereoregularity extending along the all configuration of the repeat units) exists. In the preparation of block or segmented copolymers usually multi-step processes are used. The blocks may be a homopolymer or may themselves be copolymers. Diblock can be shown as —AAAABBB— and triblock as —AAABBBBAAAA—. In multiblock copolymers the A and B segments repeat themselves many times along the chain. Block copolymers are generally prepared by sequential addition of monomers to living polymers (rather than by depending on the improbable r1r241 criterion in monomers).8 Graft copolymers and branched copolymers are formed by copolymerization of macromonomers and can form as a consequence of intramolecular rearrangement. In general, the backbone chain is formed from one type of monomer, and the chains of the other type are attached as branches. This can be shown as

Special classes of branched copolymers are star polymers, dendrimers, hyperbranched copolymers and microgels.29

1.22.4.1.2

Effect of copolymerization on properties

Copolymer synthesis enables us to modify the properties of a homopolymer in the desired direction by introducing an appropriate repeating unit. Since the homopolymers are combined in the same molecule, copolymer demonstrates the properties of both homopolymer. Properties such as crystallinity, flexibility, melting point (Tm), and glass transition temperature (Tg) can be altered in this way. Also, arrangement of the units (either random, alternating or block) changes in the properties. In general copolymers having stereoregular orientations have regular arrangements and may form crystalline structures. Meanwhile if it is random copolymer, crystallinity is even lower than that of the respective homopolymers. For random copolymers, if there is crystallinity, Tm is usually lower than that of either homopolymer. The Tg value will be in between the values of two homopolymers. In case of alternating copolymers, organization is regular, and therefore can easily crystallize if there are not rigid, bulky, or excessively flexible chain segments in the repeating units. Tm and Tg values are in between the corresponding values of the corresponding homopolymers. On the other hand, block copolymers having long blocks of different homopolymers demonstrate similar crystallinity, Tm and Tg as the corresponding homopolymers. They may have two different Tm and Tg values belonging to each homopolymer segments separately.

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Table 5 Reaction mechanisms, rate constants and rate equations of copolymerization Reaction

Rate constant

Rate equation

M1 þ M1 -M1 M1 M1 þ M2 -M1 M2 M2 þ M2 -M2 M2 M2 þ M1 -M2 M1

k11 k12 k22 k21

k11[M1 ][M1] k12[M1 ][M2] k22[M2 ][M2] k21[M2 ][M1]

Most commercially used copolymers are either random or block copolymers. In case of random copolymers, in general the two repeating units possess the same functional groups. There are only few commercial random copolymers having two repeating units with different functional groups. For block copolymers the two repeating units have different functional groups.30

1.22.4.1.3

Kinetics of copolymerization

1.22.4.1.3.1 Kinetics of addition copolymerization Kinetics of copolymerization reactions is very complicated. The copolymerization between two different monomers can be described using four reactions: two homopolymerizations and two cross-polymerization additions. Reaction mechanism is given in Table 5. The specific rate constants for the different reaction steps described are assumed to be independent of chain length.11 At steady state, the concentrations of M1 and M2 are assumed to remain constant. Therefore, the rate of conversion of M1 and  M2 necessarily equals that of conversion of M2 to M1 . Thus, k21 ½M2 ½M1  ¼ k12 ½M1  ½M2 

ð31Þ

The rate of polymerization can be expressed with the rates of disappearance of monomers M1 and M2 as shown below:


  d½M1  ¼ k11 M1 ½M1  þ k21 M2 ½M1  dt

ð32Þ




  d½M2  ¼ k12 M1 ½M2  þ k22 M2 ½M2  dt

ð33Þ

The division of the two equations yields the copolymer equation. The ratio d[M1]/d[M2] gives the monomer ratios present in the polymer chain.   d½M1  ½M1  r1 ½M1  þ ½M2  ¼ ð34Þ ½M2  ½M1  þ r2 ½M2  d½M2  Rates of the reactions are effected by the presence of bulky groups causing steric hindrance. Especially, in case of 1,2-disubstituted vinyl monomers, steric hindrance reduce the reactivity of the monomer or radical due to the steric effect of the 2-bulky substituent on the attacking radical and the monomer. Meanwhile, there is no 2- or b-substituent when the attacking radical is styrene, and copolymerization is possible.12 The effect of steric hindrance in reducing reactivity may also be demonstrated by comparing the reactivities of 1,1 and 1,2 disubstituted olefins with reference radicals. The addition of a second 1-substituent usually increases reactivity 3- to 10-fold; however, the same substituent in 2-position usually decreases reactivity by 2- to 20-fold. The extent of reduction in reactivity also depends on energy differences between cis and trans forms.5 1.22.4.1.3.2 Kinetics of condensation copolymerization Condensation polymerization reactions are the ones that take place with reactions of functional groups of the monomers. In general, monomers have different chemistries and this leads to different organizations as summarized below:

•

Random copolymers: In the cases where the mixture of more than 2 types of monomers is copolymerized, it generally leads to formation of random copolymers. For instance, if there are 4 different monomer going into polymerization reaction, the result is random copolymer having all groups in the structure (as XWYV). Formation of alternating or block copolymer is very unlikely since the reactivities of these different monomers would be different and would not lead formation of regular orientation. 9 ðX Þ HOOC2R 1 2COOH > > > > ðY Þ HOOC2R 2 2COOH = ðW Þ H2 N2R 3 2NH2 > > > > ; ðVÞ H2 N
R 2
NH2

HOOC2R 1 2CONH2R 3 2NHCO2R 2 2CONH2R 4 2NH2 Copolymer XWYV

In a step polymerization, if the initially present active groups have a stoichiometric ratio, the overall composition of the product copolymer will also have this ratio. The final product will have the all monomers randomly distributed in its structure.

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This random distribution is the result of similar reactivities of the functional groups on different monomers. Even in cases where there are only one diacid (R1) with two amines (R3 and R4); or one diamine (R3) with two acids (R1 and R2), they can still produce a copolymer with random structure (eg, –R1–R3–R1–R4–R1–R3–R1–R3–R1– or –R1–R3–R2–R3–R1–R3–R1–R3–R2–) with no sequence along the chain.31

•

Alternating Copolymers: It is possible to synthesize an alternating copolymer in which R1 ¼ R2 and R3 ¼ R4, by using a two-stage process. In the first stage, a diamine is reacted with an excess of diacid to form acid ended trimer. nHOOC2R 1 2COOH þ nH2 N2R 3 2NH2 -nHOOC2R 1 2CONH2R 3 2NHCO2R 1 2COOH

ðxiÞ

In the second stage the trimer is reacted with an equimolar amount of a second diamine: nHOOC2R 1 2CONH2R 3 2NHCO2R 1 2COOH þ nH2 N2R 4 2NH2 -HO2 ðCO2R 1 2CONH2R 3 2NHCO2R 1 2CONH2R 4 2NHÞn 2H þ ð2n
1ÞH2 O

ðxiiÞ

Alternating copolymers with two different functional groups are similarly synthesized by using preformed reactants.32,33 OCN2R 1 2CONH2R 3 2OSiðCH3 Þ3

HF

⟹


ðCH3 Þ3 SiF

2ðCO2NH2R 1 2CO2NH2R 3 2OÞn 2

ðxiiiÞ

OCN2R 1 2CONH2R 3 2NHCO2R 1 2NCOþ HF

HO2R 2 2OH⟹2ðCONH2R 1 2CONH2R 3 2NHCO2R 1 2NHCOO2R 2 2OÞn 2

ðxivÞ

The silyl ether derivative of the alcohol is used in reaction (xiii). In this reaction, the corresponding alcohol OCN–R1–CONH–R3–OH cannot be isolated because of the high reactivity of the alcohol groups to isocyanate groups.

•

Block Copolymers: Block copolymers can generally be synthesized by two methods. These are either one-prepolymer or twoprepolymer methods. The reactions below are given for the block copolymers having repeating units with different functional groups. They are also applicable to block copolymers with similar functional groups in the two repeating units. In twoprepolymer method, two different prepolymers with enough chain length are synthesized separately. Then, these two prepolymers each containing appropriate end groups, put into the same reaction vessel and the end groups react forming the block copolymer. A glycol-terminated polyester prepolymer may be synthesized from the monomeric units of HO–R–OH and HOOC–R1–COOH in the presence of excess of diol. An isocyanate-terminated polyurethane prepolymer is synthesized from OCN–R2–NCO and HO–R3–OH using an excess of the diisocyanate. Then, these two macro prepolymers (glycol terminated dihydroxypolyester and isocyanate terminated diisocyanate polyurethane) are subsequently polymerized with each other to form the block copolymer. The length of the blocks can be controlled and adjusted using the calculated stoichiometric amounts of each reactant. In general each prepolymer have molecular weights in the range 500–6000 Da. H2ðO2R 1 2OOC2R 3 2COÞn 2OR 1 2OH þ OCN2ðR 2 2NHCOO2R 4 2OOCNHÞm 2R 2 2NCOh 2 ðO2R 1 2OOC2R 3 2COÞn 2OR 1 2OOCNH2ðR 2 2NHCOO2R 4 2OOCNHÞm 2R 2 2NHCOp


ðxvÞ

A coupling agent can be used to connect the two-prepolymer. For example, a diacyl chloride can be added to join two different macrodiols or two different macrodiamines or two different macrodiamines or a macrodiol with a macrodiamine. The oneprepolymer method involves one of the above prepolymers with two “small” reactants. The macrodiol is reacted with a diol and diisocyanate. H2ðO2R 1 2OOC2R 3 2COÞn 2OR 1 2OH þ ðm þ 1ÞOCN2R 2 2NCO þ mHO2R 4 2OHh 2 ðO2R 1 2OOC2R 3 2COÞn 2OR12OOCNH2ðR 2 2NHCOO2R 4 2OOCNHÞm 2R 2 2NHCOp


ðxviÞ

The chain lengths of each block and the final copolymer can be determined by controlling the polymerization conditions of each prepolymer synthesis and its subsequent polymerization. In polyurethane synthesis via one-prepolymer method uses macrodiol with excess diisocyanate and form isocyanate terminated prepolymer. Then, a small molecular weight diol (named as chain extender) can be added to join isocyanate groups to each other. Principle the same final block copolymer is obtained in both one- and two-prepolymer methods, but the dispersity of the polyurethane block length is usually narrower in the two-prepolymer method.33

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Polymer Fundamentals: Polymer Synthesis

1.22.4.2

Crosslinking Reactions

Crosslinking is the predominant reaction following irradiation of many polymers. It involves attachment of polymeric chains to each other. When each molecule is bound at least once, the whole system becomes insoluble. This is accompanied by the formation of a gel and ultimately by the insolubilization of the specimen. Crosslinking has, therefore, a beneficial effect on the mechanical properties of polymers. In commercial practice crosslinking reactions take place during the fabrication of articles made with thermosetting resins. The crosslinked network is stable against heat and does not flow or melt. Most linear polymers are thermoplastic. They soften and take on new shapes upon the application of heat and pressure.7 Crosslinking can be achieved by the action of electromagnetic radiation, heat or catalysts and results in the opening of unsaturated groups on chains and reaction of multifunctional (42) groups. Control of crosslinking is critical for processing. The period after the gel point, when all the chains are bonded at least to one other chain is usually referred to as the curing period.

1.22.4.2.1

Effect of crosslinking on properties

The change in some properties of a polymer is determined by the extent of crosslinking. Lightly crosslinked polymers swell extensively in solvents in which the uncrosslinked material dissolves, but covalently (irreversibly) crosslinked polymers cannot dissolve but only swell in the solvent of the uncrosslinked form. Upon extensive crosslinking, the sample may even not swell appreciably in any solvent. Crosslinking has a significant effect on viscosity; it becomes essentially infinite at the onset of gelation. The effect of chain branching and crosslinking on Tg are explained in terms of free volume. A high amount of branches increase the free volume and lower the Tg, whereas crosslinking lowers the free volume and raises the Tg. The addition of crosslinks leads to stiffer, stronger, tougher products, usually with enhanced tear and abrasion resistance. However, extensive crosslinking of a crystalline polymer leads to a loss of crystallinity, and this might decrease mechanical properties. When this occurs, the initial trend of properties may be toward either enhancement or deterioration depending on the degree of crystallinity of the unmodified polymer and the method of formation and location (crystalline or amorphous regions) of the crosslinks.7

1.22.4.2.2

Crosslinking of biological polymers

1.22.4.2.2.1 Crosslinking of proteins Proteins are found to be chemically (permanent) or physically (reversibly) crosslinked. These crosslinks can be intra or intermolecular. For example, the triple helix of collagen has intermolecular crosslinking whereas many reversible crosslinks are observed in the secondary and tertiary structure of the proteins. Proteins are crosslinked for various applications (biotechnological, biomedical, etc.). Physical crosslinking methods include drying, heating or exposure to electromagnetic radiation such as gamma

Fig. 13 Mechanism of protein crosslinking using carbodiimide (EDC) and N-hydroxy succinimide (NHS).

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503

or UV. The main advantage of these methods is that they cause less harm compared to chemical methods. However, the limitation of these methods is that getting the required amount of crosslinking is difficult. In chemical crosslinking methods, crosslinkers are generally used to bind the functional groups of amino acids. In recent years there has been an increase in the use of physical crosslinking methods. The main reason is to avoid using chemical crosslinking agents because most have some toxic effects. However, the degree of crosslinking is considerably lower and crosslinks are weaker than obtained by chemical methods.

Fig. 14 Mechanism of protein crosslinking using Genipin. (A) Protein binding to the ester group (outside the ring structure) of genipin and crosslinking, (B) Protein binding to the ring structure of genipin and crosslinking.

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Collagen is the major protein component of bone, cartilage, skin and connective tissue and also the major constituent of all the extracellular matrices in animals. Collagen can be chemically crosslinked by various compounds including glutaraldeyde, carbodiimide, genipin and transglutaminase.34,35 1-Ethyl-3-diaminopropyl carbodiimide (EDC) and N-hydroxysuccinimide (NHS) catalyze covalent binding of carboxylic acid and amino groups and make crosslinking of collagen possible (Fig. 13). Furthermore, similar extracellular matrix components such as glycosaminoglycans (GAGs) which carry carboxyl groups, are also crosslinked with EDC/NHS approach.36 1.22.4.2.2.2 Crosslinking of polysaccharides Both chemical and physical methods can be used in the crosslinking of polysaccharides. In physical crosslinking, polysaccharides form networks crosslinked with the counterions on the surface. High counterion concentration requires long reaction times for complete chemical crosslinking of the polysaccharides. Chemical crosslinking of polysaccharides leads to products with high mechanical stability. During crosslinking, counterions used in the crosslinking process diffuse into the polymer and react forming intermolecular or intramolecular linkages. Main factors which affect chemical crosslinking are the concentration of the crosslinking agents and the reaction duration. High concentrations of crosslinking agents induce rapid crosslinking. Like physical crosslinking, high counterion concentrations require long reaction times to achieve complete crosslinking of the polysaccharides. Polysaccharides can be chemically crosslinked with either addition or condensation reactions. For addition polymerization, the network properties can be easily controlled by the concentration of the polysaccharide and the crosslinker. These reactions are preferably carried out in organic solvents in order to prevent water from interfering with the crosslinking process. Polysaccharides can be crosslinked through condensation using 1,6-hexamethylene diisocyanate (HDI), 1,6-hexanedibromide or other reagents. Condensation crosslinking can also be done by carbodiimide which induces crosslinks as mentioned above. The commonly used carbodiimide is 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) which is water soluble. EDC crosslinking involves the activation of the carboxylic acid groups such as those of aspartic acid (Asp) or glutamic acid (Glu) residues by EDC to form O-acylisourea groups. NHS is also used in these reaction to suppress side reactions of O-acylisourea groups. NHS converts the O-acylisourea group into an activated carboxylic acid group, which is very reactive towards amine groups of hydroxylysine, yielding a so called zero length crosslink, because neither EDC nor NHS take part in the final product.15

1.22.4.2.3

Crosslinking agents

Crosslinkers (CL) are either bi- or more functional reagents permitting the establishment of inter- and intramolecular crosslinkages. Homo-bifunctional reagents, specifically reacting with primary amine groups (ie, e-amino groups of lysine residues) have been used extensively as they are soluble in aqueous solvents and can form stable inter- and intra-subunit covalent bonds. Genipin is a naturally occurring crosslinking agent that has significantly low toxicity. It can form stable crosslinked products which resist enzymatic degradation and in that aspect it is comparable to glutaraldehyde. Genipin reacts in a similar manner to glutaraldehyde, but unlike glutaraldehyde it can bind to only one other genipin molecule. Even though the definite crosslinking mechanism of genipin is not known some mechanisms are proposed as presented in Fig. 14(a) and (b). In scheme (A) the NH2 group of the protein binds to the ester group (outside the ring structure) which then reorganizes by releasing a methanol group and achieves the binding. Then two protein-bound genipins interact to create the crosslinkage. In scheme (B) the reaction begins with an initial nucleophilic attack of a primary amine group of the protein on the C3 carbon atom of genipin to form an intermediate aldehyde group. Opening of the dihydropyran ring is followed by an attack on the resulting aldehyde group by the secondary amine formed in the first step. The predominant chemical agent that has been investigated for the treatment of collageneous tissues is glutaraldehyde, which yields a high degree of crosslinking when compared to formaldehyde, epoxy compounds, cyanamide and the acylazide method. Glutaraldehyde, a popular and classical crosslinking reagent, has been used in a variety of applications such as those where the maintenance of structural rigidity of protein is important. It covalently binds amino groups to each other, but it can also bind to other glutaraldehyde molecules. Glutaraldehyde crosslinking reactions have been extensively used and studied (Fig. 15). Proposed reaction is taking place in between aldehyde groups of glutaraldehyde and amine groups of proteins yielding a Schiff base. Meanwhile, a mixture of free aldehyde and mono- and dihydrated glutaraldehyde, and monomeric and polymeric hemiacetals are always present in an aqueous solution of glutaraldehyde, and this makes it difficult to understand the actual crosslinking

Fig. 15 Crosslinking mechanism with glutaraldehyde. (A) Glutaraldehyde activated chitosan, (B) Glutaraldehyde crosslinked chitosan.

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505

Fig. 16 Crosslinking of alginic acid with calcium ions.

mechanism. Depolymerization of polymeric glutaraldehyde crosslinks has been reported and this leads to the release monomeric glutaraldehyde and subsequent toxicity. Calcium ions may be used as a crosslinker especially for alginates which are water soluble polysaccharides. When a sodium alginate solution is added to a solution containing calcium ions, each calcium ion replaces two sodium ions crosslinking the chains. The alginate molecule contains large amounts of hydroxyl groups that can be crosslinked with cations (Fig. 16).5,11

1.22.5

Conclusion

In brief, polymers are very complex molecules owing to the large variety preparation conditions and mechanisms involving initiators, catalysts and monomers. This enables us to produce very large numbers of different polymers with very diverse properties and this is precisely why polymers play a very important role as a source for materials needed to satisfy human needs. They can be made flame retardant, conductive, bio- or hemocompatible, inert or reactive, stable or degradable, very tough or soft as jelly. The biomedical field benefits from this diversity immensely since the physical and chemical properties of polymers resemble that of the tissues of the human body more than any other material type such as metals or ceramics. With the developments in biotechnology, nanotechnology and nanomedicine, polymers will keep getting better and more useful for human wellbeing.

References 1. Hasirci, V.; Vrana, E.; Zorlutuna, P.; et al. J. Biomater. Sci. Polym. Ed. 2006, 17 (11), 1241–1268. 2. Hasirci, N. Micro and Nano Systems in Biomedicine and Drug Delivery. In Nanomaterials and Nanosystems for Biomedical Applications; Mozafari, M. R., Ed.; Springer: Dordrecht, Netherlands, 2007; pp. 1–26.

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3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36.

Polymer Fundamentals: Polymer Synthesis

Flory, P. J. Principles of Polymer Chemistry; Cornell University Press: Ithaca, NY, 1953. Odian, G. Principles of Polymerization, 4th ed.; Wiley-Interscience: New York, 2004. Billmeyer, F. W. Textbook of Polymer Science; John Wiley & Sons: New York, NY, 1984. Hiemenz, P. C.; Lodge, T. P. Polymer Chemistry, 2nd ed.; CRC Press: Boca Raton, FL, 2007. Chanda, M. Introduction to Polymer Science and Chemistry; CRC Press: Boca Raton, FL, 2006. Ebewele, R. O. Polymer Science and Technology; CRC Press: Boca Raton, FL, 2000. Kara, F.; Aksoy, A. E.; Calamak, S.; Hasirci, N.; Aksoy, S. J. Bioactive Compatible Polym. 2016, 31 (1), 72–90. Endogan, T. T.; Hasirci, V.; Hasirci, N. Polym. Compos. 2015, 36 (10), 1917–1930. Young, R. J.; Lovell, P. A. Introduction to Polymers, 2nd ed.; Chapman & Hall: London, 1995. Carraher, C. E. Polymer Chemistry, 7th ed.; CRC Press: Boca Raton, FL, 2008. Endogan, T.; Kiziltay, A.; Torun Kose, G.; Comunoglu, N.; Beyzadeoglu, T.; Hasirci, N. J. Appl. Polm. Sci. 2014, 131 (3), 39662. Park, J. B.; Bronzino, J. D. Biomaterials: Principles and Applications; CRC Press: Boca Raton, FL, 2003. Shi, D. Introduction to Biomaterials; Tsinghua University Press: Beijing, 2006. Braun, D.; Cherdron, H.; Rehahn, M.; Ritter, H.; Voit, B. Polymer Synthesis: Theory and Practice, Fundamentals, Methods, Experiments, 4th ed.; Springer: Berlin, Heidelberg, New York, 2005. Moad, G.; Solomon, D. H. The Chemistry of Radical Polymerization, 2nd ed.; Elsevier: Oxford, 2006. Matyjaszewski, K.; Tsarevsky, N. V. Nat. Chem. 2009, 1, 276–288. Tsarevsky, N. V.; Matyjaszewski, K. Chem. Rev. 2007, 107, 2270–2299. Detrembleur, C.; Debuigne, A.; Jerome, C.; Phan, T. N. T.; Bertin, D.; Gigmes, D. Macromolecules 2009, 42, 8604–8607. Guillaneuf, Y.; Gigmes, D.; Marque, S. R. A.; Tordo, P.; Bertin, D. Macromol. Chem. Phys. 2006, 207, 1278–1288. Lubnin, A.; O’Malley, K.; Hanshumaker, D.; Lai, J. Eur. Polym. J. 2010, 46 (7), 1563–1575. West, A. G.; Barner-Kowollik, C.; Perrier, S. Polymer 2010, 51 (17), 3836–3842. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004–2021. Qin, A.; Lam, J. W. Y.; Tang, B. Z. Macromolecules 2010, 43, 8693–8702. Droumaguet, B. L.; Velonia, K. Macromol. Rapid Commun. 2008, 29, 1073–1089. Lutz, J. F.; Börner, H. G.; Weichenhan, K. Macromol. Rapid Commun. 2005, 26 (7), 514–518. Kelly, A. R.; Wei, J. Q.; Kesavan, S.; et al. Org. Lett. 2009, 11, 2257–2260. Herman, F. M.; Alfrey, T. Annu. Rev. Phys. Chem. 1950, 1, 337–346. Ahluwalia, V. K.; Mishra, A. Polymer Science: A Textbook; CRC Press: Boca Raton, FL, 2007. Jackson, W. J.; Morris, J. C. J. Polym. Sci. Polym. Chem. Ed. 1988, 26, 835. Gopal, J.; Srinivasan, M. Makromol. Chem. 1986, 187 (1), 1–7. Liou, G. S.; Hsiao, S. H. J. Polym. Sci. Polym. Chem. Ed. 2001, 39 (10), 1786–1799. Ber, S.; Kose, G. T.; Hasirci, V. Biomaterials 2005, 26 (14), 1977–1986. Ulubayram, K.; Aksu, E.; Gurhan, S.; Deliloglu, I.; Serbetci, K.; Hasirci, N. J. Biomater. Sci. Polym. Ed. 2002, 13 (11), 1203–1219. Kalbitze, L.; Franke, K.; Möller, S.; Schnabelrauch, M.; Pompe, T. J. Mater. Chem. B 2015, 3, 8902–8910.