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Hasirci V., Yilgor P., Endogan T., Eke G., and Hasirci N. (2011) Polymer Fundamentals: Polymer Synthesis. In: P. Ducheyne, K.E. Healy, D.W. Hutmacher, D.W. Grainger, C.J. Kirkpatrick (eds.) Comprehensive Biomaterials, vol. 1, pp. 349-371 Elsevier.
© 2011 Elsevier Ltd. All rights reserved. Author's personal copy
1.121. Polymer Fundamentals: Polymer Synthesis
V Hasirci, P Yilgor, T Endogan, G Eke, and N Hasirci, Middle East Technical University, Ankara, Turkey ã 2011 Elsevier Ltd. All rights reserved.
1.121.1. Introduction to Polymer Science 350 1.121.1.1. Classification of Polymers 351 1.121.1.2. Polymerization Systems 352 1.121.2. Polycondensation 353 1.121.2.1. Characteristics of Condensation Polymerization 353
1.121.2.2. Kinetics of Linear Polycondensation 354 1.121.2.2.1. Molecular weight control in linear polycondensation 355 1.121.2.3. Nonlinear Polycondensation and Its Kinetics 356 1.121.2.3.1. Prediction of the gel point 356 1.121.2.4. Mechanisms of Polycondensation 356
1.121.2.4.1. Carbonyl addition–elimination mechanism 356 1.121.2.4.2. Other mechanisms 356 1.121.2.5. Typical Condensation Polymers and Their Biomedical Applications 357 1.121.3. Addition Polymerization 357 1.121.3.1. Free Radical Polymerization 358
1.121.3.1.1. Initiation 358 1.121.3.1.2. Propagation 358 1.121.3.1.3. Termination 359 1.121.3.1.4. Kinetics of radical polymerization 359 1.121.3.1.5. Degree of polymerization 359
1.121.3.1.6. Thermodynamics of polymerization 360 1.121.3.2. Ionic Polymerization 360 1.121.3.2.1. Cationic polymerization 360 1.121.3.2.2. Anionic polymerization 360 1.121.3.3. Coordination Polymerization 360
1.121.3.4. Typical Addition Polymers and Their Biomedical Applications 361
1.121.3.5. Comparison of Addition and Condensation Polymerization 361 1.121.3.6. New Polymerization Mechanisms 361 1.121.3.6.1. Atom transfer radical polymerization 361 1.121.3.6.2. Nitroxide-mediated polymerization 362 1.121.3.6.3. Reversible addition–fragmentation chain transfer polymerization 362
1.121.4. Polymer Reactions 363 1.121.4.1. Copolymerization 363 1.121.4.1.1. Types of copolymerization 364 1.121.4.1.2. Effects of copolymerization on properties 365 1.121.4.1.3. Kinetics of copolymerization 365
1.121.4.2. Cross-Linking Reactions 367 1.121.4.2.1. Effect of cross-linking on properties 367 1.121.4.2.2. Cross-linking of biological polymers 367 1.121.4.2.3. Cross-linking agents 368 1.121.5. Conclusion 369
References 370
Glossary Cationic polymerization Polymerization initiated by Addition polymerization Rapid polymerization based cation and propagated by a carbonium ion. on initiation, propagation, and termination of double Condensation polymerization Polymerization in which bonded monomers and no small molecules are polyfunctional reactants produce larger units in a continuous, stepwise manner. eliminated. Anionic polymerization Polymerization initiated by Coordination polymers Polymers based on coordination a anion. complexes.
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350 Polymers
Copolymer Polymers composed of chains containing more Kinetic chain length Average length of the polymer than one monomer unit. chain initiated by one free radical. Degree of polymerization Average number of repeating Propagation Continuous successive chain extension in a units in main chains. chain reaction. Gelpoint Point at which cross-linking begins to Repeating unit Basic molecular unit that can represent a
produce polymer insolubility. polymer backbone chain. Glass transition temperature (Tg) Temperature at Tacticity Arrangement of the pendant groups in space; that which a polymer gains local or segmental is, isotactic, syndotactic, atactic. mobility. Termination Destruction of active growing chains in a Initiation Start of polymerization. chain reaction.
1.121.1. Introduction to Polymer Science solvent, the chains start to separate from each other and for
linear and branched polymers this separation leads to com-
A polymer is a macromolecule composed of a combination of plete solubility. The cross-linked network polymers, however, many small units that repeat themselves along the long mole- cannot dissolve in a solvent; they swell, forming gels. cule. The small starting molecules are called monomers, and The process of creating macromolecules from monomers is the unit which repeats itself along the chain is called the called polymerization. If only one type of monomer is used in repeating unit. In general, polymer chains have several thou- polymerization, there will be only one type of repeating unit sand repeat units. The length of the polymer chain is specified in the chain. In this case, the macromolecule is a homopoly- by the number of repeating units in the chains and this mer. If the polymer is formed from two different monomers number is called the degree of polymerization. Most of the (have two different repeating units), it is known as a copoly- monomers are composed of carbon, hydrogen, oxygen, and mer. If a chain is formed from only ethylene, the polymer is a nitrogen. Few other elements such as fluorine, chlorine, sul- homopolymer and named as polyethylene. On the other fur, etc. may also exist. Syntheses of polymers are carried out hand, the copolymer of ethylene and vinyl acetate has two in vessels or large reactors, sometimes with application of monomers and, therefore, has two different repeating units. heat and pressure, and the small monomeric units connect If three different monomers are used to produce a polymer, to each other through the chemical reactions. The chemical the product is a terpolymer. Biological polymers, such as process used for the synthesis of polymers is called the poly- enzymes, are formed from many different amino acids, and merization process. therefore, their structures contain a variety of repeating units.
Polymers which have the ability to melt and flow are used Since a large number of combinations of these molecules in manufacturing and are generally identified with the com- are available, it becomes possible to design and synthesize mon name, plastics. In general, plastic products contain other polymers with the desired properties ranging from fibers added ingredients such as antioxidants and lubricants to give to films, sponges to elastomers. This versatility makes them the desired properties to the object produced. essential materials to be used in various applications ranging
Most of the macrochains obtained in polymerization reac- from macro-sized products used in the households to nano- tions are linear polymers and are formed by the reactions of scale devices used in nanotechnological and biomedical monomers containing either carbon–carbon double bonds applications. or have two active functional groups or difunctionality. Polymers such as cellulose, silk, and chitin can be obtained Many monomers have different active groups on the same from natural sources and polymers such as polyethylene, poly- molecule such as one end of the monomer contains a carbox- styrene, and polyurethanes can be synthesized in the labora- ylic acid and the other end contains an alcohol, and the tories and plants. The macrochains such as DNA, RNA, and reaction of the acid group of one molecule with the alcohol enzymes have biological importance and are crucial for life. groupof the other forms polyesters. Polymerization reactions In general, the backbone of a polymer is formed mainly of also take place when one of the monomers contains two acid carbon atoms. These are called the organic polymers. There are groups and the other contains two alcohol or two amine also a few inorganic polymers, and the atoms in their back- groups. If there are some monomers which have more than bones are different than carbon. An example is silicone, the two functionalities (e.g., 3- or 4-functionality), their presence backbone of which is constituted of silicon and oxygen. in the chain cause the formation of extra chains linked to the One very important property which strongly influences main backbone. In this case, branched polymers are obtained. the mechanical strength of the polymer is its molecular weight.
If the extent of branching is very high and all the macrochains Hydrocarbon molecules with increasing number of carbons are connected to each other, then they form a highly cross- are methane, ethane, propane, etc. The ones containing up to linked, three-dimensional structure which is called a network. five carbons are in the gaseous state. As the number of carbons, These networks have infinite molecular weights since all and therefore, the molecular weight increases, they become chains are connected to each other. In a polymer structure, liquids, wax type solids, and eventually hard solids. The ones all chains are tangled around each other forming the bulk called polymers contain more than 100 carbons along the structure. At low temperatures they are solid, but in a good chain. Most polymers which are useful as plastics, rubbers,
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fibers, etc. have at least 50 repeating units and have molecular 4 6 1 weights between 10 and 10 g molÀ . Most of the properties of the polymers (plastics) are dependent on the chain length. As it increases, the softening point, melting point, or mechani- cal strength of the polymers also increase. Molecular weights of polymers are defined with average molecular weight values since there is always a distribution in chain lengths and no (a) R R RRRR constant length for chains during the 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:
MiNi Mn [1] ¼ N P i
2 PMi Ni (b) RR R RRR Mw [2] ¼ MiNi P P where Ni is the number of moles of molecules with a molecular weight of M . i The simplest polymer is polyethylene which has the repeat- ing unit of (–CH2–CH2–). The repeating units of polyethylene have high regularity and the chains come close to each other and cause high intermolecular interactions. If one of the (c) RRR RR R hydrogen atoms of polyethylene repeating unit is changed with a different atom or molecule such as a halogen atom Figure 1 Tacticity of vinyl polymers: (a) isotactic, (b) syndiotactic, and
(c) atactic. or R group, the arrangement of the chain may have differ- ent possibilities. The arrangement of atoms or groups fixed by chemical bonding in a molecule is called the configura- creates highly ordered organization of repeating units along the tion. Some examples are cis and trans isomers, and D and L chains, those polymers are more rigid with higher crystallinity forms of molecules. Chains may have different orientations and strength compared to atactic ones. Although this is the case arising from rotation of the chain about single bonds. These in the industry for most of the processes, atactic polymers are types of arrangements which are continuously changing preferred because of their ease of processing. are called conformations. A chain can have many different As defined previously, long chains are entangled with conformations. each other and stay together in a polymer structure forming In vinyl polymers isomerism is also defined with head- a solid mass. This type of polymers have no ordered inter- to-tail configuration. If there is a substitute attached to one molecular arrangements and are called amorphous polymers. carbon atom of the double bond, this carbon side can be The vinyl polymers which contain bulky substitutes such as named as the head, and the other carbon will then be the poly(methyl methacrylate) or polystyrene are amorphous tail. During polymerization, the carbon atoms containing a polymers. On the other hand, in some polymers, intermolec- substitute come together in either head-to-tail configuration ular attractions are very strong and many backbone chains or head-to-head and tail-to-tail configurations. form closely packed structure as a result of these strong Carbon atoms make four bonds in a tetrahedral geometry. intermolecular forces. In these cases, they form crystalline If the –C–C– main backbone which forms a zigzag structure polymers. Some polymers are partially crystalline, and some is assumed to be on a plane, the other two bonds of each regions of the different or the same chains are closely packed carbon, linked to an atom or a group, are either on one side or and have strong attractions. These highly ordered domains the other side of this plane. Depending on the organization of are distributed in the amorphous matrix. In this case, the the side groups linked to the adjacent chiral center carbons, a material is a semicrystalline polymer. Since crystallinity indi- stereochemistry is created and this is named tacticity. If cates highly ordered arrangement of macrochains with strong the polymer is isotactic, it means that all the substituted side intermolecular forces, these polymers are stronger and have groups on each successive chiral center are on the same side of higher mechanical and thermal properties compared to their the backbone plane and have the same stereochemical con- amorphous counterparts. figuration. For syndiotactic polymers, the side groups take place alternatingly on opposite sides of the backbone plane, 1.121.1.1. Classification of Polymers and each successive chiral center has the alternating stereo- chemical configuration. There is no regular arrangement of During the early years of polymer science, two types of classi- the subgroups in atactic polymers. The substituents are placed fications have come into use. One was based on polymer randomly along the chain. Different placements of substituent structure (backbone) and divided polymers into Condensa- group R in vinyl polymers are shown in Figure 1. Since tacticity tion and Addition polymers1 and the other was based on
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352 Polymers
polymerization kinetics and mechanism and divided polymer- 6. The molecular weight izations into Step and Chain polymerizations.2 Although these a. Oligomers: These are the polymers with a molecular 1 terms are often used interchangeably, because most condensa- weight in the range of 500–5000 g molÀ . tion polymers are produced by step polymerizations and most b. High polymers: These are the polymers used in the indus- addition polymers are produced by chain polymerizations, this try in the production of materials and have a molecular 4 6 1 is not always the case. weight in the range of 10 –10 g molÀ . Polymers can be synthesized from hundreds of monomers in 7. The thermal behavior numero us combinations in very different forms ranging from a. Thermoplastics: These are linear or slightly branched solid elastomers to fibers, from films to sponges, from tubes chains containing polymers and they soften and flow to gels. Therefore, they are very important in our daily life. when the temperature is increased. If they are loaded in
Polymers can be classified in many different ways depending a mold in this soft form and cooled, they solidify form- on their various properties. Some of them are given below. ing the product. Since there is no new chemical bond Polymer classification according to: formation during the heating and cooling, they can be reshaped with further application of heat and pressure. 1. The origin b. Thermoset polymers: During the processing of these poly-
a. Natural polymers: Proteins, starch, cellulose, natural mers, cross-linking reactions take place upon increase rubber, etc. are of natural origin. of temperature and they set in the shape of the mold b. Synthetic polymers:Theseareman-madepolymers they are in. Therefore, they cannot be melted and synthesized in the laboratories. reshaped with the application of heat. At high tempera- 2. The polymerization process tures, they decompose.
a. Condensation polymers: These polymers are formed when 8. The arrangement of the repeating units two di- or polyfunctional molecules react and condense a. Homopolymers: They are formed from single type of forming macromolecules and with the possible elimina- monomers. tion of a small molecule such as water in the case of b. Copolymers: They are made of two or more types of polyester formation. All the natural polymers are con- monomers. The arrangements of the different repeating
densation polymers. units in the chain can be different, and therefore, copo-
b. Addition polymers: These polymers are produced by chain lymers can be further divided into groups as given below. reactions of double-bonded monomers in which the i. Alternating copolymers: the repeating groups of two chain carrier can be a radical or an ion. Free radicals are different monomers alternatingly follow each other usually formed by the decomposition of a relatively along the macrochain. unstable compound, called the initiator. ii. Random copolymers: there is no order in the positions
3. The structural forms of the chains of the repeating units of different monomers. a. Linear polymers: These polymers are composed of long iii. Block copolymers: in these polymers, one type of the chains and their monomers have only two functional monomer reacts and forms a long chain (a block) and groups if the polymer is a condensation polymer or a then reacts with the other type of monomer forming single double bond if it is an addition polymer. a different block. These block copolymers can be
b. Branched polymers: Similar to linear polymers, but they diblock copolymers which are formed as AB type have long chains with shorter side chains (branches) blocks, three-block copolymers which are formed caused by the presence of small amounts of tri- as ABA type blocks, or graft copolymers in which functional monomers for condensation or two unsa- the main chain is one type of block and the other turations for addition polymers. type is attached to the main chain as side chains.
c. Network polymers: These are cross-linked three-dimensional 9. The linkages repeating in the chains: These polymers are clas- polymers. They consist of long chains connected to each sified according to the chemical linkages between the other with multifunctional units and form a network. monomeric units which repeat along the chain. For exam- 4. The composition of the main backbone of the polymers ple, polyethers have ether linkages, polyesters have ester a. Homopolymers : These polymers contain only carbon– linkages, polyurethanes have urethane linkages, etc.
carbon bonds in their backbone.
b. Heteropolymers : These polymers contain atoms other than carbon in their main chain. The most common 1.121.1.2. Polymerization Systems noncarbon atoms are oxygen and nitrogen. Polymerization reactions are carried out in vessels or reactors 5. The structure generally with application of heat and with the addition of a. Organic polymers: These polymers contain mainly carbon different substituents. Depending on the phases that exist and atoms in their main chain. the forms of the medium, the polymerization processes are b. Inorganic polymers: The main chain of these polymers is classified as homogeneous and heterogeneous systems, which not composed of carbon but mainly of inorganic atoms include different techniques as given below: such as silicon in silicone rubbers. c. Coordination (chelate) polymers: In this type of polymers, 1. Homogeneous polymerization systems: All chemicals added into
a chelate ring is formed from an ion or metal and differ- the reaction medium create a homogeneous mixture in ent organic ligands which have donor–acceptor bonds which polymer formation occurs. These processes are either between. bulk or solution polymerization processes.
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a. Bulk polymerization: In these polymerizations, there are droplet the mechanism is very similar to bulk polymeri- only monomers and initiators in the reaction medium. zation. Size of the droplets is in the range of 0.01–0.50 cm These processes are generally used in the production and the polymer forms as dispersed solid particles of this of condensation polymers in which the reactions are size (Figure 5).
mildly exothermic, less viscous, and therefore, mixing, e. Emulsion polymerization: This system is similar to
heat transfer, and control of the process is easier com- suspension system, but the initiator is soluble in the pared to chain polymerization of vinyl polymers. aqueous phase. As the polymerization starts in the aque- b. Solution polymerization: A monomer and a initiator ous phase, emulsifier molecules surround the growing are added in a solvent and the reaction takes place in chain forming micelles. As the polymerization proceeds, this solution medium. This approach can be used for chains in the micelles elongate to get the monomer from
addition or condensation polymerizations since the the organic phase. Therefore, the monomer droplets get medium does not get too viscous which makes mixing, smaller and polymer micelles get larger. Still, these par- heat transfer, and control of the process easy. On the ticles are very small (about 0.1 mm) (Figure 6). other hand, it requires purification and removal of There are numerous types of synthetic polymers or copoly- the solvent. mers which are produced in the laboratories and every year 2. Heterogeneous polymerization systems: In these systems there new ones are added to the list. In addition, some new are more than one phase creating heterogeneous media biological polymers are also added to the list obtained by for the monomer, polymer, and initiator. some novel molecular techniques. These can be derived from a. Gas phase polymerization: In these systems, the monomer renewable biomass sources, such as vegetable oil, corn starch, is in gaseous form and the polymer formed is either or microbiota. Some examples for these polymers are starch- in liquid or solid form. Ethylene polymerization is an based polymers (used for the production of drug capsules in example (Figure 2). the pharmaceutical sector), polylactic acid (PLA; produced b. Precipitation polymerization: This is similar to bulk or from cane sugar or glucose, and used in the production of solution polymerization, but the polymer formed pre- foil, molds, tins, cups, bottles, and as bone plates in the medi- cipitates as soon as it forms. This polymer is not soluble cal sector), poly(3-hydroxybutyrate) (PHB; is biodegradable in its monomer and the solvent of the monomer is also and produced by certain bacteria), polyamide-11 (PA11; is not a solvent for the polymer (Figure 3). derived from natural oil and not biodegradable), bioderived c. Solid phase polymerization: Some solid crystalline olefins polyethylene (can be produced by fermentation of agricul- or cyclic monomers polymerize by solid state polymeri- tural feed stocks such as sugar cane or corn, and is chemically zation. In these systems, polymerization generally starts and physically identical to traditional polyethylene), and bio- with radiation such as X-rays or g-rays (Figure 4). plastics (produced by genetically modified organisms such as d. Suspension polymerization: In these systems, organic GM crops). phase containing monomer and initiator is dispersed as droplets in the aqueous phase containing the stabili- zers such as cellulose or polyvinyl alcohol. Initiator is 1.121.2. Polycondensation soluble in the monomer phase, and therefore, in the 1.121.2.1. Characteristics of Condensation Polymerization
Condensation polymerization is used for polymerization Monomer (gas) of monomers with functional groups and involves a series of
Liquid
hn Monomer (gas) Solid polymer Figure 2 Gas phase polymerization.
Solid crystal monomer Solid polymer
Figure 4 Solid phase polymerization.
Organic phase Aqueous Monomer Polymer Liquid Solid polymer phase droplets particles Figure 3 Precipitation polymerization. Figure 5 Suspension polymerization.
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Emulsifier Micelles
Organic phase
Aqueous Monomer Polymer phase droplets particles
Figure 6 Emulsion polymerization.
chemical condensation reactions progressing generally with The polymerization proceeds in this stepwise manner with the elimination of side products with low molar weight, such the molecular weight of the polymer gradually increasing as water, alcohol, or hydrogen. with time. Condensation polymerizations are characterized In condensation polymers, the elemental composition of by the disappearance of monomer early in the reaction for the repeating unit differs from that of the two monomers by before the production of any polymer of sufficiently high the elements of the eliminated small molecule. Condensation molecular weight to be of practical use. polymers can, therefore, be degraded to their monomers upon The rate of a condensation polymerization is the sum the addition of the eliminated small molecules. of the rates of reactions between molecules of various sizes. The kinetics of such a situation with innumerable separate reactions is normally very difficult to analyze. However, it is 1.121.2.2. Kinetics of Linear Polycondensation generally assumed that the rate of reaction of a group is inde- The type of product formed in a condensation reaction is pendent of the size of the molecule to which it is attached; determined by the functionality of the monomers, that is, by in other words, the functional group reactivity is assumed to the number of reactive functional groups per monomer. be independent of the molecular weight. These simplifying assumptions, often referred to as the concept of equal reactiv- Bifunctional monomers form long linear polymers but mono- functional monomers when used with bifunctional monomers ity of functional groups, make the kinetics of condensation form only low molecular weight products. polymerization identical to those for the analogous small 4 The monomers can have the same type or different type of molecule reaction. There is both theoretical and experimen- 2 functional groups, and in the former case, two different difunc- tal justification of these simplifying assumptions. The kinetics of condensation polymerization can be tional monomer types are necessary for product formation. explained by taking the formation of a polyester from a diol Polyesters are formed by typical condensation reactions with the elimination of water. If a polyester is synthesized from a and a diacid as a model system. Condensation polymerization diol and a diacid, the first step is the reaction of the diol and typically involves equilibrium reactions of the type diacid monomers to form a dimer: kf 1 A B ⇄ C D[V] HO R OH HOOC R COOH þ kr þ w w þ w w ! 1 HO R OCO R COOH H2O [I] and the rates of the forward and reverse reactions are w w w w þ kf[A][B] and kr[C][D], respectively. At equilibrium these rates The dimer then might form a trimer by reaction with a diol are equal, therefore monomer:
kf C D 1 K ½½ [3] HO R OCO R COOH HO R OH ¼ k ¼ A B w w w w þ w w ! r ½½ HO R OCO R1 COO R OH H O [II] w w w w w w 2 If the system is not at equilibrium, as in the initial stages þ or with a diacid monomer: of polymerization, the reverse reaction is negligibly slow and changes in the concentrations of the reactants may be HO R OCO R1 COOH HOOC R1 COOH considered to result from the forward reaction alone. This w w w w þ w w ! 1 1 reaction is normally catalyzed by acids, however, in the HOOC R COO R OCO R COOH H2O [III] w w w w w w þ absence of a strong acid, the diacid monomer acts as its own
Dimer could also react with itself to form a tetramer: catalyst for the esterification reaction and the reaction is fol- lowed by measuring the rate of disappearance of carboxyl 2HO R OCO R1 COOH HO R OCO R1 groups: w w w w ! w w w w 1 COO R OCO R COOH H2O [IV] w w w w þ d COOH 2 ½k COOH OH [4] The tetramer and trimer proceed to react with themselves, À dt ¼ ½½ with each other, with the monomer and the dimer.3 where one of [COOH] represent the catalysis phenomenon.
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If the starting concentrations of carboxyl and hydroxyl are defined as structural units, the initial number of carboxyls groups are equal present is equal to the total number of structural units present N0. The number average degree of polymerization, Xn, is: d COOH ½k COOH 3 [5] À dt ¼ ½ Number of original molecules N0 COOH o 1 Xn ½ ¼ Number of molecules at time t ¼ N ¼ COOH t ¼ 1 p rearrangement and integration gives: ½À [12] 1 2kt constant [6] 2 ¼ COOH t þ ½ 1.121.2.2.1. Molecular weight control in linear The extent of reaction, p, is defined as the fraction of func- polycondensation tional groups that has reacted at time t. Therefore, It is important to control the change in polymer molecular weight with reaction time since molecular weight determines
COOH o COOH t the properties of the polymer. One method of stopping the p ½À ½ [7] ¼ COOH reaction at the desired molecular weight is cooling. But, this is ½o not preferable since the polymer could restart growing upon Substitution of p into eqn [6] and rearrangement gives: subsequent heating because the ends of the polymer molecules 1 contain unused functional groups. 2k COOH 2t constant [8] 2 o The easiest way to avoid this situation is to adjust the 1 p ¼ ½þ ðÞÀ starting composition of the reaction mixture slightly away 2 or a plot of 1/(1 p) versus t should be linear with a slope of from stoichiometric equivalence, by adding either a slight 2 À 2k COOH from which k can be determined (Figure 7).3 excess of one bifunctional reactant or by introducing a small ½ o It was shown with experimentation that uncatalyzed ester- amount of a monofunctional reagent. Eventually, the mono- ifications require quite long times to reach high degrees of mer which is low in amount is completely used up and all polymerization. Greater success is achieved by adding a small chain ends consist of the excess group. If only bifunctional amount of acid catalyst to the system, whose concentration is reactants are present and the two types of groups are initially constant throughout the reaction. In this case, the concentra- present in numbers N and N with a ratio r N /N , the total A B ¼ A B tion of the catalyst has to be included in the rate constant (k0): number of monomers present is
d COOH N N N 1 1=r ½k0 COOH OH [9] A þ B AðÞþ [13] À dt ¼ ½½ 2 ¼ 2
If the initial concentrations of carboxyl and hydroxyl At a given time, if p is the extent of reaction defining the groups are equal, fraction of reacted groups, (1 p) will show the fraction of À unreacted groups. Therefore, the total number of chain ends d COOH 2 ½k0 COOH [10] will be À dt ¼ ½
1 1 rp 0 NA 1 p NB 1 rp NA 1 p À [14] COOHo k t constant [11] ðÞÀ þ ðÞÀ ¼ À þ r ½¼ 1 p þ ðÞÀ If only bifunctional reactants are present in the reaction Since each monomer is difunctional, the number of system and no side reactions occur, the number of unreacted groups is twice the number of molecules present. Therefore,
Xn will be carboxyl groups equals the total number of molecules (N)in the system. If acid or glycol groups separately (not in pairs) 1 1 þr NA ðÞ2 1 r X n 1 rp þ [15] 1 p À ¼ À þ r ¼ 1 r 2p NA ðÞ2 þ À
This equation shows the variation of the degree of polymeriza- tion with the stoichiometric imbalance r and the extent of reaction p. When the two bifunctional monomers are present in equal amounts (r 1), the equation reduces to
2
) ¼
p 2 - Slope = 2k[COOH]0 1 Xn [16]
1/(1 ¼ 1 p ðÞÀ
On the other hand, for 100% conversion the Xn becomes
1 r 1 r X n þ þ [17] ¼ 1 r 2 ¼ r 1 þ À À t In actual practice, p may approach but never becomes equal Figure 7 Plot of 1/(1 p)2 versus t in the determination of rate to unity. This means there are always some functional groups À 5 constant of linear polycondensation. that are left unreacted.
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Stoichiometric balance should be precisely maintained in 1.121.2.4.1. Carbonyl addition–elimination mechanism order to obtain high degrees of polymerization. Loss of one Carbonyl addition–elimination is the most important reaction ingredient, side reactions, or the presence of monofunctional which has been used for the preparation of polyamides, poly- impurities may severely limit the degree of polymerization.6 acetals, phenol–, urea–, and melamine–formaldehyde poly-
mers. Some typical examples of this reaction include: 1.121.2.3. Nonlinear Polycondensation and Its Kinetics Direct reaction: The reaction of a dibasic acid and a glycol (to
Polyfunctional monomers with more than two functional form a polyester) or a dibasic acid and a diamine (to form a groups per molecule yield branched or hyperbranched conden- polyamide) are some examples of direct reaction. A strong sation polymers. With certain monomers, cross-linking will acid or acidic salt often serves as a catalyst. The reaction may also take place with the formation of network structures in be carried out by heating the reactants together and remov- ing water (to draw the reaction toward product formation) which branches from one polymer molecule become attached to other molecules and eventually yield insoluble molecules. usually by applying vacuum in the later stages. The structures of these nonlinear condensation polymers Interchange: The reaction between a glycol and an ester yields are more complex than those of linear ones. Nonlinear poly- polyesters and is preferred especially when the dibasic acid condensation occurs with gelation, the formation of essentially has low solubility. Frequently the methyl ester is used, as in the production of poly(ethylene terephthalate) from eth- infinitely large polymer networks. The sudden onset of gela- ylene glycol and dimethyl terephthalate. The reaction tion marks the division of the mixture into two parts: the gel, which is insoluble in all nondegrading solvents; and the sol, between a carboxyl and an ester is much slower, but other whichremains soluble and can be extracted from the gel. As the interchange reactions, such as amine–amide, amine–ester, polymerization proceeds beyond the gel point, the amount of and acetal–alcohol are well known. Acid chloride or anhydride: Either of these can be reacted with a gel increases at the expense of sol and the mixture rapidly glycol or an amine. Polyamides are prepared by the reaction transforms from a viscous liquid to an elastic material of infinite viscosity. An important feature of the onset of gelation of an acid chloride with a diamine. is that the number average molecular weight stays very low Interfacial condensation: The reaction of an acid halide with a while the weight average molecular weight becomes infinite.7 glycol or a diamine proceeds rapidly to high molecular weight polymer if carried out at the interface between two immiscible liquid phases each containing one of the reac- 1.121.2.3.1. Prediction of the gel point In order to calculate the point in the reaction at which gela- tants. Very high molecular weight polymers can be prepared. Typically, an aqueous phase containing the diamine or glycol tion takes place, a branching coefficient (a)isdefinedasthe probability that a given functional group on a branch unit to and an acid acceptor is layered at room temperature over connect to another branch unit. In the case where polyfunc- an organic phase containing the acid chloride. The polymer formed at the interface can be pulled off as a continuous film tional Af units are present with functionality f,thecriterion for gel formation is that at least one of the f 1segments or filament. The method is applied to the formation of poly- À radiating from the end of a segment is in turn connected to amides, polyurethanes, and polyureas. It is particularly useful for preparing polymers which are unstable at the higher another branch unit. Therefore, the critical value of a for temperatures. gelation (ac) is given as: Ring versus chain formation: Bifunctional monomers may react
1 intramolecularly to produce a cyclic product. Thus, hydro- ac [18] ¼ f 1 xyacids may give either lactones or polymers on heating À and amino acids may give lactams or linear polyamides. The gel point can also be observed experimentally when The type of the product is generally dependent on the size the polymerizing mixture suddenly loses fluidity. If the of the ring that can be formed. extent of reaction is followed as a function of time by deter- mining the number of functional groups present, the value of p (extent of reaction) at the gel point can be experimentally 1.121.2.4.2. Other mechanisms determined. 8 Carbonyl addition–substitution reactions: The reaction of aldehydes
with alcohols involving addition followed by substitution
at the carbonyl group leads to the formation of polyacetals. 1.121.2.4. Mechanisms of Polycondensation Nucleophilic substitution reactions: Nucleophilic substitution is As was stated earlier, all condensation polymerizations take the reaction of an electron pair donor (the nucleophile) place either by using a monomer with two unlike groups with an electron pair acceptor (the electrophile). These reac- suitable for polycondensation (AB type, e.g., polycondensation tions are used in the polymerization of epoxides. Nucleo- of hydroxycarboxylic acids) or two different monomers, each philes attack the electrophilic C of the C–O bond causing it possessing a pair of identical reactive groups that can react with to break, resulting in ring opening. Opening the ring relieves each other (AA and BB type, e.g., polycondensation of diols the ring strain and epoxides can react with a large range with dicarboxylic acids). of nucleophiles (such as H2O, ROH, R–NH2). Nucleophilic These monomers polymerize following different routes substitution reactions are also the basis for the formation such as carbonyl addition–elimination, carbonyl addition– of natural polysaccharides and polynucleotides. substitution, nucleophilic substitution, double bond addition, Double bond addition reactions: Although addition reactions or free radical coupling.5 at double bonds are often associated with addition
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polymerization, this is not always the case. The ionic addi- medium consists of large polymers and monomers unlike in tion of diols to diisocyanates in the production of polyur- condensation polymerization. Depending on the type of initi- ethanes is an example of condensation polymerization. ator a radical, anion, or cation is created and depending on Free radical coupling: These reactions are used in the preparation the chemistry, adds monomers and eventually form a large
of arylene ether polymers, polymers containing acetylene molecule. The molecular weight of the polymer chains is
units, and arylenealkylidene polymers. practically unchanged during polymerization, but in time Aromatic electrophilic substitution reactions: This type of reactions more of the monomer is converted into polymers and mono- including the use of Friedel–Crafts catalysts produces poly- mer concentration decreases.3 mers by condensation polymerization. Monomers show varying degrees of selectivity with regard to the type of reactive center that will lead to polymerization.
Most monomers are polymerized by free radicals, but they are 1.121.2.5. Typical Condensation Polymers and Their more selective to the ionic mechanisms. For example, acrylam- Biomedical Applications ide polymerizes anionically but not cationically, whereas Polyesters, polyurethanes, polyamides, polyanhydrides, poly- N-vinyl pyrrolidone polymerizes by cationic but not anionic carbonates, and polyureas are among the condensation route.6 For both monomers, free radical polymerization is polymers that find broad use in medical applications in vari- possible. Another type of polymerization is coordination poly- ous forms. Some naturally occurring polymers such as proteins merization in which special catalysts are used and highly (collagen) and polysaccharides (hyaluronic acid) as well as ordered polymers with stereospecific properties are obtained. bacterial polyesters (polyhydroxyalkanoates) are classified Table 2 shows the types of initiation that polymerize as condensation polymers, since their synthesis from their various monomers. Although the polymerization of the mono- 3,9 reactants are achieved by the elimination of water. Some mers in Table 2 is thermodynamically feasible by having typical examples of condensation polymers and their biomed- DG < 0, practically polymerization is achieved only with a ical applications are listed in Table 1. certain type of initiator.3 The key to this phenomenon lies in the polarity of the monomer and the strength of the ion formed. Monomers with electron-donating groups (alkoxy,
1.121.3. Addition Polymerization alkyl, alkenyl, and phenyl) attached the carbons of the unsa-
turation, increase the electron density on the carbon–carbon Polymerization in which the polymer forms by addition of double bond and when these electrons react with a cationic monomeric unit to the growing chain is called as addition poly- initiator, a stable carbenium ion forms on the growing unit. merization. Generally, a monomer containing double bond In this case, chain polymerizes with cationic catalysts. On the and an initiator creates the first active unit; they are needed to other hand, monomers with electron-withdrawing substitu- start the chain growth. The active group, which is the chain ents (aldehyde, ketone, acid, ester) decrease the electron den- carrier group, may be a free radical, an anion, or a cation. sity on the double bond and facilitate the attack of anionic In addition polymerization reaction takes place by opening catalysts leading to anionic polymerization. Free radical poly- of the double bond and the created active group adds the merization takes place in most cases but may be considered to monomer at a very high rate so that immediately high be an intermediate case and a radical created on the growing molecular-weight polymer chains form. Therefore, the reaction chain leads to the formation of macromolecules. Many
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
R Polyamide O Nylon Intracardiac catheters, sutures, dialysis device components, heart mitral valves, hypodermic syringes – NH – C – Polycarbonate O Bisphenol-A polycarbonate Intraocular lenses, dialysis device components, heart/lung assist devices, blood collection, arterial tubules – O – CO – Polyester O Poly(lactic acid-co-glycolic acid) Grafts, sutures, implants, prosthetic devices, micro and nanoparticles – CO – Polypeptides O Proteins, enzymes Tissue engineering scaffolds, wound dressings
– NH – C – Polyurea O Polyisobutylene-based polyurea Blood contacting surfaces
– NH – C – NH – Polyurethane O Poly(ether urethane) Aortic patches, heart assist devices, adhesives, dental – O – C – NH – materials, blood pumps, artificial heart and skin
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Table 2 Types of addition polymerization suitable for common Table 3 Free radical initiation reactions monomers 1. Acyl peroxides, alkyl peroxides or hydroperoxides
Benzoyl peroxide: Polymerization mechanism
O O O Monomer Radical Cationic Anionic Coordination D Æ – C – O – O – C – Æ ® 2Æ – C – O• Ethylene þþ Àþ Propylene and a-olefins ÀÀ Àþ t-butyl peroxide: Styrene þþ þþ Vinyl chloride CH3 CH CH3 þÀ Àþ 3 Tetrafluoroethylene þÀ Àþ D Acrylic and methacrylic H3C – C – O – O – C – CH3 ® 2H3C – C – O• þÀ þþ esters CH CH CH Acrylonitrile 3 3 3 þÀ þþ , high polymer formed; , no reaction or oligomers only. Cumyl hydroperoxide: þ À Modified from Billmeyer, F.W. Textbook of Polymer Science, Wiley: New York, 1984. CH 3 CH3 D Æ – C – O – OH ® Æ – C – O• + •OH monomers can polymerize by free radical mechanism in addi- CH CH tion to an ionic mechanism.3,5 3 3
2. Azo compounds
1.121.3.1. Free Radical Polymerization 2,2Ј-Azobisisobutyronitrile (AIBN):
Free radicals are unpaired electrons that are highly reactive and CH3 CH3 CH3 have short lifetimes. In free radical polymerizations, each poly- D mer chain grows by addition of monomer to the free radical H3C – C – N = N – C – CH3 ® 2H3C – C• + N2 of the growing chain. Upon addition of the monomer, the CN CN CN free radical is transferred to the new chain end. Free radical polymerization has three stages: initiation, propagation, and termination. 3. Redox systems 2+ – 3+ H2O2 + Fe ® OH + Fe + •OH 1.121.3.1.1. Initiation 2− 2+ 2− 3+ –• S2O8 + Fe ® SO4 + Fe + SO4 In the initiation step free radicals are formed from an initiator and then these free radicals bind to a monomer. Initiators can be peroxides or azo compounds in which scission of a single 4. Electromagnetic radiation (photoinitiation) bond creates radicals, or a redox reaction in which radicals are Styrene, Benzoin: created by an electron transfer to or from an ion or molecule. H H H Dissociation can be affected by the application of heat or hn electromagnetic radiation (e.g., UV, g). Peroxides and hydro- Æ – C = C Æ – C = C• + H• peroxides are frequently used as initiators because of the H instability of the O–O bond. In the case of azo compounds, H the process is driven by the release of N2. Redox reactions are hn preferred especially when the polymerization is needed to be H 6,10 carried out at low temperatures. Heat and electromagnetic radiations can also start polymerization by breaking the dou- Æ• + C = C• ble bond of the monomeric units and creating two active H radicals. In this case, the chain adds to monomeric units H from both ends. Some of the most widely used initiator sys-
O H O H tems are given in Table 3. hn The free radical initiation step can be shown as follows: Æ – C – C – ÆÆ – C• + •C – Æ
Dissociation of an initiator (I) such as benzoyl peroxide yields OH OH two radicals (R) with a dissociation rate constant kd:
k I d 2R [VI] ! This radical then attacks to a monomer molecule to create the 1.121.3.1.2. Propagation first radical M. The free radicals formed are very active and immediately add
on monomer molecules leading to growing macroradicals. ki R M RM [VII] þ ! Each addition creates a new radical that has the same identity where ki is the rate constant of initiation. as the previous one, except that it is larger by one monomer
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unit. In the polymerization mechanism, it is assumed that all For photochemical initiation, intensity of light affects the growing chains have the same propagation constant (kp). The rate and equation is given as successive additions may be represented by: dM Ri ½ 2FIabs [21] kp ¼ dt i ¼ Mn M Mn 1 [VIII] þ ! þ Propagation with growth of the chain takes place in milli- where Iabs is the intensity of the light absorbed and the con- stant F is called quantum yield. seconds and kp for most monomers is in the range of 2 4 1 1 3 The rate of termination is represented as 10 –10 l molÀ sÀ .
dM 2 Rt ½ 2kt M [22] 1.121.3.1.3. Termination ¼À dt ¼ ½ i Termination usually occurs by combination or disproportion- where kt is the overall rate constant for termination. The con- ation reactions. Combination is coupling of two growing stant 2 shows that the two growing chains are terminated by chains to form a single polymer molecule. each termination reaction. ktc At the start of the polymerization, the rate of formation of Mn Mm Mn m [IX] þ ! þ radicals greatly exceeds the rate of termination. As the reaction where ktc is the rate constant for termination by combination. proceeds, the rate of formation and the rate of loss of radicals
In disproportionation reaction, a hydrogen atom is by termination becomes equal and it can be stated that there is abstracted and exchanged between the growing chains leaving no change in the concentration of M. This is the steady state behind two terminated chains: (d[M]/dt 0). At steady state, the rates of initiation (Ri) and ¼ termination (Rt) are equal, leading to ktd Mn Mm Mn Mm [X] þ ! þ 1=2 fkd I where ktd is the rate constant for termination by M ½ [23] ½¼ kt disproportionation. Termination by disproportionation forms one polymer The rate of propagation is represented as molecule with a saturated end-group and another with dM an unsaturated end-group. Type of termination affects the R ½ k M M [24] p ¼À dt ¼ p½½ molecular weight. If it is through combination, average molec- t ular weight will be two times higher than that of polymers so using eqn [23], Rp can be obtained as terminated by disproportionation. In general, both types of 1=2 termination reactions take place in different proportions fkd I R k ½ M [25] depending upon the monomer and the polymerization condi- p ¼ p k ½ t tion. For example, polystyrene chains terminate by combina- tion whereas poly(methyl methacrylate) chains terminate by If the initiator efficiency is high (close to 1) and if f is indepen- 10 dent of monomer, rate of polymerization is proportional to the disproportionation, especially at temperatures above 60 C. first power of the monomer concentration. In chain polymerization, one important phenomenon is
1.121.3.1.4. Kinetics of radical polymerization ‘gel effect’ or ‘ Trommsdorff – Norrish effect’ which is autoac-
In radical polymerization reactions, decomposition of the celeration of the polymerization. In these cases, viscosity of the initiator (such as peroxides and azo compounds) proceeds reaction medium increases and the mobility of the growing much more slowly than the reaction of the free radical with chains are restricted. Chains continue to grow with addition the monomer. This step is therefore the rate-determining step. of monomers, but they cannot terminate. Therefore, the system The rate of initiation (Ri)is is no longer in steady state. Fast polymerization causes heat
dM evolution and local hot spots, leading to cross-linking and gel R ½ 2fk I [19] 11 i ¼ dt ¼ d½ formation. i where f is the initiator efficiency, the fraction of the radicals 1.121.3.1.5. Degree of polymerization successful in initiating chains, k is the rate constant for Kinetic chain length n is defined as the number of monomer d initiator dissociation, and [I] is the concentration of the initi- molecules used per active center. It is, therefore, represented as ator. The constant 2 defines that two radicals are formed from R /R R /R . Therefore, p i ¼ p t one initiator molecule. The initiator efficiency is in the range kp M of 0.3–0.8 due to side reactions. The initiator efficiency n ½ [26] ¼ 2k M decreases when side reactions terminates the radicals.6 t½
using eqn [24], For a redox initiation system, rate of initiation is given as 2 2 dM kp M Ri ½ fkOx Red [20] ½ [27] ¼ dt ¼ ½½ n i ¼ 2ktRp where [Ox] and [Red] are the concentrations of oxidizing and The number average degree of polymerization, Xn, is the reducing agents and k is the rate constant. average number of monomer molecules added to the polymer
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360 Polymers
molecule. If the propagating radicals terminate by combi- interaction with the active center. Finally, termination does not nation Xn 2n, and if termination is by disproportionation occur by a reaction between two ionic active centers because ¼ 10 Xn n. they are of similar charge. ¼ Chain transfer is the reaction of a growing chain with an inactive molecule to produce a dead polymer chain and 1.121.3.2.1. Cationic polymerization a molecule with a radical. The transfer agent may be the Typical catalysts for cationic polymerization are strong electron initiator, monomer, polymer, solvent, or an impurity. When acceptors and include Lewis acids, Friedel–Crafts halides, the transfer does not lead to new chain growth, it is called Bro¨nsted acids, and stable carbenium-ion salts. Many of inhibition. If the newly formed radical is less reactive than them require a cocatalyst, usually a proton donor, to initiate the propagating radical, then it is called retardation.3 polymerization. Those monomers with electron donating 1-1-substituents that can form stable carbenium ions are 1.121.3.1.6. Thermodynamics of polymerization polymerized by cationic mechanisms. For these systems, Addition polymerizations of olefinic monomers have negative the polymerization rate is very high; for isobutylene initiated
DH and DS. The exothermic nature of polymerization arises by AlCl3 or BF3, in few seconds at 100 C, chains of several À because the process involves the formation of new bonds and million daltons can form. Both the rate and the molecular the negative DS arises from the decreased degree of freedom of weight decrease with temperature and are much lower at 5 the polymer compared to the monomer. DG depends on both room temperature. parameters and is given by In certain cationic polymerizations, a distinct termination
step may not take place; therefore ‘living’ cationic polymers DG DH T DS [28] ¼ À are formed. However, chain transfer to a monomer, polymer, solvent, or counterion can terminate the growth of chains. The numerical value of DS is much smaller than DH. Therefore
G is negative under ambient T conditions since | H| > |T S|. Cationic polymerizations are usually conducted in solution, D D D at low temperature, typically 80 to 100 C. The solvent is Polymerization is thermodynamically favorable. However, À À important because it determines the activity of the ion at the thermodynamic feasibility does not mean that the reaction is practically feasible. For the polymerization reaction to end of the growing chain. There is a linear increase in polymer take place at appreciable rates, it may require specific catalyst chain length and an exponential increase in polymerization rate as the dielectric strength of the solvent increases.12 systems. This is the case with the a-olefins, which require 3 Ziegler–Natta or coordination-type initiators. 1.121.3.2.2. Anionic polymerization The initiator in an anionic polymerization needs to be a strong 1.121.3.2. Ionic Polymerization nucleophile, including Grignard reagents and other organome-
tallic compounds like n-butyl (n-C4H9) lithium. When the Addition polymerization of olefinic monomers can also be starting reagents are pure and the polymerization reactor is achieved with active centers possessing ionic charges. These free of traces of oxygen and water, the chain can grow until can be either cationic polymerizations or anionic polymeriza- all the monomer is consumed. For this reason, anionic poly- tions depending on the type of the chain carrier ion. The ionic merization is sometimes called ‘living’ polymerization. Ter- charge of the active center causes these polymerizations to be mination occurs only by the deliberate introduction of more selective unlike free radical polymerization. They proceed oxygen, carbon dioxide, methanol, or water. In the absence only with monomers that have appropriate substituent groups of a termination mechanism, the number average degree of which can stabilize the active center. Since the required activa- polymerization, X ,is tion energy for ionic polymerization is small, these reactions n may occur at very low temperatures. High rate of polymerization M o at low temperatures is a characteristic of ionic polymerizations. Xn ½ [29] ¼ I o For cationic active centers, electron-donating substituent groups ½ are needed. For anionic polymerization, the substituent group where [M]o and [I]o are the initial concentrations of the mono- must be electron withdrawing to stabilize the negative charge. mer and the initiator, respectively.
Thus, most monomers can be polymerized either by cationic or The absence of termination during a living polymerization leads to a very narrow molecular weight distribution with a by anionic polymerization but not by both. Only when the substituent group has a weak inductive effect and is capable of heterogeneity index (HI) as low as 1.06, whereas for free radical 12 delocalizing both positive and negative charges (e.g., styrene polymerization polydispersities as high as 2 were reported. and 1,3-dienes) both cationic and anionic polymerization can be achieved. 1.121.3.3. Coordination Polymerization Another important difference between free radicalic and ionic polymerizations is that many ionic polymerizations pro- Use of some special catalysts may lead to the formation of very ceed at much higher rates than free radical polymerization, orderly structured polymers with high stereospecificity. For mainly because the concentration of propagating chains is example, the processes used in the polymerization of both much higher (by a factor of 104–106). Another difference is isotactic polypropylene (i-PP) and high density polyethylene that an ionic active center is accompanied by a counter ion of (HDPE) employ transition-metal catalysts called Ziegler–Natta opposite charge. Both the rate and stereochemistry of propa- catalysts, which utilize a coordination type mechanism during gation are influenced by the counter ion and the strength of polymerization. In general, a Ziegler–Natta catalyst is an
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organometallic complex with the cation from Groups I to III the monomers disappear early in the reaction unlike chain in the Periodic Table, (e.g., Al(C2H5)3), a hallide of transi- polymerization where the monomer concentration decreases tion metal from Groups IV to VIII, (e.g., TiCl4). HDPE can gradually (medium generally contains long and dead chains be prepared by bubbling ethylene gas into a suspension and monomers) and growth occurs very rapidly by addition of Al(C H ) and TiCl in hexane at room temperature. of one unit at a time to the end of the growing chain. 2 5 3 4 Although the exact mechanism is still unclear, it is proposed Longer polymerization durations are essential in obtaining that the growing polymer chain is bound to the metal atom high molecular weight condensation polymers whereas with of the catalyst and that monomer insertion involves a coordi- chain polymers long reaction times give high yields but do nation of the monomer with the atom. It is this coordina- not affect the molecular weight significantly. tion of the monomer that results in the stereospecificity The typical step and chain polymerizations differ signifi- of the polymer. Coordination polymerizations can be termi- cantly in the relationship between polymer molecular weight nated by introduction of water, hydrogen, aromatic alcohol, and the percent conversion of monomer. The chain polymeri- or metals. 12 zation will show the presence of high molecular weight polymer molecules at all percent of conversions. There are no intermediate sized molecules in the reaction mixture 1.121.3.4. Typical Addition Polymers and Their Biomedical (only monomer and high polymer). The only change that Applications occurs with conversion is the continuous increase in the num- Addition polymers such as polyethylene, polypropylene, poly- ber of polymer molecules. On the other hand, high molecular styrene, polyacrylates can be easily fabricated in many weight polymer is obtained in step polymerizations only near forms such as fibers, textiles, films, rods, and viscous liquids the very end of the reaction (at 98% conversion).3,15,16 and they are used in a variety of biomedical applications. Some are given in Table 4.13,14 1.121.3.6. New Polymerization Mechanisms
1.121.3.6.1. Atom transfer radical polymerization 1.121.3.5. Comparison of Addition and Condensation Atom transfer radical polymerization (ATRP) is a controlled/ Polymerization living polymerization technique which is highly effective in
The main characteristic of step polymerization that distin- obtaining well-defined polymers or copolymers with predeter- guishes it from chain polymerization is that the reaction mined molecular weight, narrow molecular weight distribu- occurs between any of the different sized species present in tion, and a high degree of chain end functionality. ATRP has the reaction system. In step polymerization, the size of the been used in the preparation of polymers with precisely con- polymer molecules increases at a relatively slow pace and trolled functionalities, topologies (linear, star/multiarmed,
Table 4 Some additional polymers used in biomedical applications
Synthetic polymers Monomeric unit Applications
Polyethylene (PE) −CH2−CH2− Pharmaceutical bottles, nonwoven fabrics, catheters, pouches, flexible n containers, orthopedic implants (e.g., hip implants) Poly(2-hydroxyethyl methacrylate) CH3 Contact lenses, surface coatings, drug delivery systems (PHEMA) −CH2−C− n COOCH2CH2OH Poly(methyl 2-cyanoacrylate) CN Surgical adhesive
−CH2−C−n COOCH 3 Poly(methyl methacrylate) (PMMA) CH3 Blood pumps and reservoirs, membranes for dialyzers, intraocular lenses, bone −CH −C− cement, drug delivery systems 2 n COOCH3
Polypropylene (PP) −CH −CH− Disposable syringes, blood oxygenator membranes, sutures, nonwoven 2 n fabrics, artificial vascular grafts, reinforcing meshes, catheters
CH3
Polystyrene (PS) −CH −CH− Tissue culture flasks, roller bottles, filterwares 2 n
C6H5
Poly(tetrafluoro ethylene) (PTFE) −CF2−CF2− Catheters, artificial vascular grafts, various separator sheets n Poly(vinyl chloride) (PVC) Blood bags, surgical packaging, i.v. sets, dialysis devices, catheter bottles, −CH2−CH− n connectors, and cannulae Cl
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kact n n+1 R-X + Mt -Y/Ligand X-Mt -Y/Ligand + R• k deact kp P1•
Monomer kt
Termination
Figure 8 General mechanism of ATRP.
comb, hyperbranched, and network polymers), and composi- distributions. Catalyst is an important component of ATRP tions (homopolymers, block copolymers, statistical copoly- since it determines the position of the atom transfer equilib- mers, gradient copolymers, graft copolymers). rium and the dynamics of exchange between the dormant and Monomer, initiator with a transferable atom (halogen), and active species. A variety of transition metal complexes have catalyst (transition metal with suitable ligands) are the main been used as ATRP catalysts such as transition metal complexes components of ATRP. In some cases, an additive (metal salt in of copper, ruthenium, palladium, nickel, and iron. Polymeri- a higher oxidation state) may be used. Type of solvent and level zation is conducted either in bulk or in solvents (benzene, 17–21 of temperature are important parameters for a successful ATRP. water, etc.) at moderate temperatures (70–130 C). The most commonly used monomers are styrenes, methacry-
1.121.3.6.2. Nitroxide-mediated polymerization lates, methacrylamides, dienes, and acrylonitriles. Atom transfer step is the key elementary reaction leading Nitroxide-mediated polymerization (NMP) is another con- to the uniform growth of the polymeric chains. In ATRP, trolled radical polymerization method. NMP allows the radicals are formed by a reversible redox reaction of a transi- preparation of very well-defined polymers with controlled n tion metal complex, M -Y/ligand, where Mt is transition metal molecular weight and narrow molecular weight distribution t and Y may be another ligand or a counterion. Transfer of an X and to extend chains with different monomers to obtain atom (usually halogen) from a dormant species to the metal multiblock copolymers. Combination of a nitroxide and a n 1 results in an oxidized metal complex (X-Mt þ -Y/ligand which free radical initiator or alkoxyamines serving as both initiators is the persistent species) and a free radical (R). Activation and and controlling agents are used in this technique. deactivation processes occur with rate constants of kact and NMP is based on a reversible recombination between pro- k , respectively (Figure 8). pagating species (P) and nitroxide (R NO,R alkyl group) deact 2 ¼ Even when the same ATRP conditions (same catalyst and with the formation of alkoxyamine (R2NOP), resulting in a initiato r) are used, each monomer has its own unique atom low radical concentration and decreases the irreversible termi- transfer equilibrium constants for its active and dormant species. nation reactions. Polymer chains with equal chain lengths and The rate of polymerization depends on K (K k /k ). reactive chain ends can be obtained because a majority of eq eq ¼ act deact If it is too small, polymerization reaction will occur slowly, dormant living chains can grow until the monomer is fully and if it is too large, due to the high radical concentration, consumed. termination will occur and polymerization will be uncontrolled. NMP is metal free and not colored, and polymer does not The new radical can initiate the polymerization by addition require any purification after synthesis. The main limitation of to a monomer with the rate constant of propagation kp. Termi- NMP is the range of monomers that can be effectively con- nation reactions (rate constant is k ) also occur in ATRP, by trolled. Some efficient alkoxyamines and nitroxides are able t combination or disproportionation, or the active species is to control most of the conjugated vinyl monomers such as reversibly deactivated by the higher oxidation state metal com- styrene and derivatives, acrylates (including some functional plex. In a well-controlled ATRP, no more than a few percent of acrylates), acrylamides, acrylonitrile, and methacrylates (with the polymer chains undergo termination. During the initial, some limitations) and also some dienes such as isoprene.22,23 short, nonstationary stage of the polymerization, the concen- tration of radicals decays by the unavoidable irreversible self 1.121.3.6.3. Reversible addition–fragmentation chain termination, whereas, the oxidized metal complexes increase transfer polymerization steadily as the persistent species. As the reaction proceeds, Reversible addition–fragmentation chain transfer polymeriza- the decreasing concentration of radicals causes a decrease in tion (RAFT) is one of the most versatile methods of controlled self-termination and cross-reaction with persistent species radical polymerization because it allows a wide range of func- toward the dormant species. The decrease in the stationary tionalities in the monomers and solvents, including aqueous concentration of growing radicals minimizes the rate of termi- solutions. The method is relatively new for the synthesis of nation which has a key role in the first-order kinetic. living radical polymers and may be more versatile than ATRP The stabilizing group (e.g., phenyl or carbonyl) on the or NMP. RAFT polymerization uses thiocarbonylthio com- monomers produces a sufficiently large atom transfer equilib- pounds, such as dithioesters, dithiocarbamates, trithiocarbo- rium constant. Typically, alkyl halides (RX) are used as the nates, and xanthates in order to mediate the polymerization via initiator. The halide group (X) must rapidly and selectively a reversible chain-transfer process. The technique is applicable migrate between the growing chain and the transition-metal to a wide range of monomers including methacrylates, metha- complex to form polymers with narrow molecular weight crylamides, acrylonitrile, styrene and derivatives, butadiene,
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vinyl acetate, and N-vinyl pyrrolidone. As a result of its excep- active species (Pn). Reinitiation occurs with the reaction tional effectiveness and the wide range of monomers and between the leaving group radical and another monomer spe- solvents, RAFT polymerization has developed into an cies, starting another active polymer chain. This active chain extremely versatile polymerization technique. Especially, the (Pm) then goes through the addition–fragmentation or equili- molecular weight of the polymer can be predetermined and the bration steps. Equilibration is a fundamental step in the RAFT molecular weight distribution can be controlled fairly well. process which traps the majority of the active propagating Typically, a RAFT polymerization system consists of species into the dormant thiocarbonyl compound. This limits an initiator, monomer, chain transfer agent, and solvent. The the possibility of chain termination. Active polymer chains (Pm control of temperature is crucial. It can be performed by simply and Pn) are in an equilibrium between the active and adding a certain quantity of an appropriate RAFT agent (i.e., a dormant stages. While one polymer chain is in the dormant thiocarbonylthio compound) to a conventional free radical stage (bound to the thiocarbonyl compound), the other is 24–28 polymerization medium. Radical initiators such as azobisiso- active in polymerization. butyronitrile (AIBN) and 4,40-azobis(4-cyanovaleric acid) RAFT process allows the synthesis of polymers with spe- (ACVA) are widely used as initiators in RAFT polymerizations. cific macromolecular architectures such as block, gradient, RAFT agents (also called chain transfer agents) must be thio- statistical, linear block, comb/brush, star, hyperbranched, and carbonylthio compounds where the Z and R groups perform network copolymers and dendrimers. Examples of architec- different functions (Figure 9). The Z group primarily controls tures that can be synthesized by RAFT are given in Figure 11. the effectiveness with which radical species can add to the C S ¼ bond. The R group must be a good homolytic leaving group which is able to initiate new polymer chains. 1.121.4. Polymer Reactions
There are four steps in a typical RAFT polymerization: initi- 1.121.4.1. Copolymerization ation, addition–fragmentation, reinitiation, and equilibration (Figure 10 ). Copolymers are polymers formed from two or more mono- In the initiation step, the reaction is started using radical meric units. The arrangement of repeating units can be in initators (I) such as AIBN. The initiator reacts with a monomer various ways along the chain. Some copolymers are very simi- to create a radical species which starts an actively polymerizing lar to homopolymers, because they have one type of repeating chain. During addition–fragmentation step, the active chain units. But proteins and some polysaccharides are copolymers (Pn) reacts with the dithioester, which releases the homolytic of a number of different monomers. leaving group (R). This is a reversible step, with an intermedi- Copolymers constitute the vast majority of commercially ate species capable of losing either the leaving group (R) or the important polymers. Compositions of copolymers may vary from only a small percentage of one component to comparable
proportions of both monomers. Such a wide variation in com- S position permits the production of polymer products with vastly different properties for a variety of end uses. The minor C constituent of the copolymer may, for example, be a diene R introduced into the polymer structure to provide sites for Z S such polymerization reaction as vulcanization; it may also be Figure 9 General structure of RAFT agents. a trifunctional monomer incorporated into the polymer to
Initiation:
P • I• n
Addition–fragmentation: Addition Fragmentation
P • + S S S S S +SR• n • R R C Pn C Pn C Z Z Z
Reinitiation:
R• + Monomer (M) Pm•
Equilibration:
Pm• + S S S S S +SPn• • M P P C P P C M C n m m m Z Z Z Figure 10 RAFT mechanism.
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364 Polymers
B B reactive monomer in the random sequence of monomer B B A-A-A-A-A units. In this case, production of copolymers with signifi- B B B B B cant quantities of both monomers will be more difficult as A-A-A-B-B-B A B B B the difference in reactivities of the two monomers increases. B B B B B B 2. r r 1. B 1 2 B B ¼ ¼ Under these conditions, the growing radicals cannot distin-
Block copolymer Star polymer Comb polymer guish between the two monomers. The composition of the
A-A-A copolymer is the same as that of the input concentrations B B B B and the monomers are arranged randomly along the chain. B B These copolymers show properties of both homopolymers B B B B B B of its constituents. A A BBB Random copolymers are formed when r values of both A-A-A A-A-A A A BBB A A monomers are close to each other. A mixture of two or more BB B B B monomers is polymerized in one process and where the BB B B B arrangement of the monomers within the chains is determined B B A-A-A by kinetic factors. If the reacting monomers are shown as A and
Dumbbell (pom-pom) Ring block B, the sequence will have no order in the chain, such AB2 star as –AABBAAABABAA–. Figure 11 Examples of complex architectures prepared by RAFT. Random copolymers tend to average the properties of the constituent monomers in the proportion to the relative abun- dance of the comonomers. ensure cross-linking, or possibly it may be a monomer contain- In the alternating copolymerization, r values of both ing carboxyl groups to enhance product solubility, dyeability, monomers are equal to zero. When r1 r2 0 (or r1r2 0), or some other desired properties.12 ¼ ¼ ¼ each radical reacts exclusively with the other monomer; that is, neither radical can regenerate itself. Consequently, 1.121.4.1.1. Types of copolymerization the monomer units are arranged alternately along the chain. These are called alternating copolymers and can be shown In free radical polymerization, reactivity ratios of the mono- as –ABABAB–. mers, r 1 and r2, should be considered. Reactivity ratios repre- sent the relative preference of a given radical that is adding Polymerization continues until one of the monomers is its own monomer to the other monomer. used up and then it stops. Perfect alternation occurs when both r1 and r2 are zero. As the quantity r1r2 approaches zero,
k11 there is an increasing tendency toward alternation. This has r1 [30] k practical significance because it enhances the possibility of ¼ 12 producing polymers with appreciable amounts of both mono- where k and k are the rate constants for radicals adding 12 11 22 mers from a wider range of feed compositions. Alternating their own type of monomer and k12 and k21 are the rate con- copolymers, while relatively rare, are characterized by combin- stants for adding the opposite kind. ing the properties of the two monomers along with structural regularity. Crystalline polymers can be obtained if a very high k22 r2 [31] degree of regularity (stereoregularity extending along the all ¼ k21 configuration of the repeat units) exists. Depending on the r values, copolymerization reaction can Block or segmented copolymers are usually prepared by form ideal, random, alternating, or block copolymers. Another multistep processes. The blocks may be a homopolymer or type is graft copolymers. may themselves be copolymers. Diblock can be shown as
In ideal copolymerization (r1r2 1), the growing chain –AAAABBB– and triblock can be shown as –AAABBBBAAAA–. ¼ end reacts with one of the monomeric unit with a statistically In multiblock copolymers, the A and B segments repeat them- possible preference. The multiplication of reactivity ratios selves many times along the chain. should be equal to 1. Block copolymers are generally prepared by sequential
When r1r2 1 then, addition of monomers to living polymers, rather than by ¼ 6 depending on the improbable r1r2 > 1 criterion in monomers. 1 k11 k21 Graft copolymers and branched copolymers are formed by r1 or [32] ¼ r2 k12 ¼ k22 copolymerization of macromonomers and can form as a con-
The relative amounts of the monomer units in the chain are sequence of intramolecular rearrangement. In general, the backbone and the chain is formed from one type of monomer, determined by the reactivities of the monomer and the feed and the chains of other type are attached as branches. This can composition of the reaction medium. r r 1 occurs under two conditions: be shown as 1 2 ¼ –AAAAAAAA– 1. r1 > 1 and r2 < 1orr1 < 1 and r2 > 1. BB One of the monomers is more reactive than the other. The BB copolymer will contain a greater proportion of the more BB
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Special classes of branched copolymers are star polymers, Table 5 Reaction mechanism, rate constants, and rate equation or dendrimers, hyperbranched copolymers, and microgels.29 copolymerization
1.121.4.1.2. Effects of copolymerization on properties Reaction Rate constant Rate equation
Copolymer synthesis offers the ability to alter the properties of M1 M1 M1M1 k11 k11[M1 ][M1] þ ! homopolymer in the desired direction by the introduction M1 M2 M1M2 k12 k12[M1 ][M2] þ ! of an appropriately chosen second repeating unit. Since the M M M M k k [M ][M ] 2 þ 2 ! 2 2 22 22 2 2 homopolymers are combined in the same molecule, copoly- M M M M k k [M ][M ] 2 þ 1 ! 2 1 21 21 2 1 mer demonstrates the properties of both homopolymers. Prop- erties, such as crystallinity, flexibility, T , T can be altered by m g forming copolymers. The magnitudes and sometimes even the of M1 to M2 necessarily equals that of conversion of M2 directions of the property alteration differ depending on to M1. Thus, whether random, alternating, or block copolymer is involved. k M M k M M [33] The crystallinity of a random copolymer is lower than that of 21½2 ½¼1 12½1 ½2 either of the respective homopolymers (i.e., the homopoly- The rate of polymerization can be given with the rates of mers corresponding to the two different units) because of the disappearance of monomers M1 and M2 as shown below: decrease in structural regularity. The melting temperature of dM any crystalline material formed is usually lower than that À ½1 k M M k M M [34] dt ¼ 11½1 ½þ1 21½2 ½1 of either homopolymer. The Tg value will be in between those for the two homopolymers. dM2 À ½k11 M1 M2 k22 M2 M1 [35] Alternating copolymers have a regular structure, and their dt ¼ ½½þ ½½ crystallinity may not be significantly affected unless one of the repeating units contains rigid, bulky, or excessively From the division of the two equations, the copolymer equa- tion is obtained. The ratio of d[M1]/d[M2] gives the monomer flexible chain segments. The Tm and Tg values of an alternating copolymer are in between the corresponding values for ratios present in the polymer chain. the homopolymers. Block copolymers show the properties d M M r M M 1 1 1 2 2 [36] (e.g., crystallinity, Tm, Tg) present in the corresponding homo- ½½½þ½ d M2 ¼ M2 M1 r2 M2 polymer as long as the block lengths are not too short. This ½½½þ½ behavior is typical since A blocks from different polymer mole- Here, r1 and r2 are monomer reactivity ratios and are defined by cules aggregate with each other and separately, B blocks from k11 different polymer molecules aggregate with each other. This r1 [37] ¼ k12 offers the ability to combine the properties of two very differ- ent polymers into the one block copolymer. The exception and, to this behavior occurs infrequently when the tendency for k cross-aggregation between A and B blocks is the same as for r 22 [38] 2 ¼ k self-aggregation of A blocks with A blocks and B blocks with 21
B blocks. Monomer-radical reaction rates are also affected by steric Most commercial utilization of copolymerization falls into hindrance. The role of steric hindrance in the reduction of the one of the two groups. One group consist of various random reactivity of 1,2-disubstituted vinyl monomers can be illu- copolymers in which the two repeating units posses the same strated by the fact that while these monomers undergo copoly- functional groups. The other groups of commercial copoly- merization with other monomers (e.g., styrene), they do not mers consist of block copolymers in which two repeating tend to homopolymerize. Homopolymerization is prevented units have different functional groups although only few because of the steric effect of the 2-substituent on the attacking commercial random copolymers in which the two repeating radical and the monomer. On the other hand, there is no 2- or units have different functional groups exist. The reason for the b-substituent when the attacking radical is styrene; conse- situation probably lies in the difficulty of finding one set of quently, copolymerization is possible.12 reaction condition for simultaneously performing two differ- The effect of steric hindrance in reducing reactivity may also 30 ent reactions. be demonstrated by comparing the reactivities of 1,1- and 1,2 disubstituted olefins with reference radicals. The addition of a 1.121.4.1.3. Kinetics of copolymerization second 1-substituent usually increases reactivity three to ten- 1.121.4.1.3.1. Kinetics of addition copolymerization fold; however, the same substituent in the 2-position usually
Kinetics of copolymerization reactions are very complicated. decreases reactivity 2- or 20-fold. The extent of reduction in
The copolymerization between two different monomers can be reactivity also depends on the energy differences between cis 5 described using four reactions, two homopolymerizations and and trans forms. two cross-polymerization additions. Reaction mechanism is given in Table 5. The specific rate constants for the different 1.121.4.1.3.2. Kinetics of condensation copolymerization: reaction steps described are assumed to be independent of • Random copolymers: The copolymerization of a mixture of 11 chain length. monomers offers a route to random copolymers; for instance, At steady state, the concentrations of M1 and M2 are a copolymer of overall composition XWYV is synthesized assumed to remain constant. Therefore the rate of conversion by copolymerizing a mixture of the four monomers.
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366 Polymers
cannot be isolated because of the high degree of reactivity of (X) HOOC—R—COOH isocyanate and alcohol groups toward each other. (Y) HOOC—R —COOH 2 HOOC—CONH—R —NHCO—R —CONH—R —NH 1 2 3 2 • Block copolymers: There are two general methods for (W) H2N—R1—NH2 Copolymer of XWYV synthesizing block copolymers. These two methods, the one (V) H N—R —NH 2 3 2 prepolymer and the two prepolymer methods, are described below for block copolymers containing different functional
groups in the repeating units. They are equally applicable It is highly unlikely that the reactivities of the various to block copolymers containing the same functional monomers would be such that block or alternating copolymers groups in the two repeating units. The two prepolymer are formed. The overall composition of the copolymer method involves the separate synthesis of two different obtained in a step polymerization will almost always be prepolymers, each containing appropriate end groups, the same as the composition of the monomer mixture since followed by the polymerization of two polymers via these reactions are carried out to essentially 100% conversion reaction of their end groups. Consider the synthesis of (a necessity for obtaining high molecular weight polymer). In apolyester-block-polyurethane.Aisocyanate-terminated the step copolymerization of monomer mixtures, one often polyester prepolymer is synthesized from HO–R –OH observes the formation of random copolymers. This occurs 3 and HOOC–R –COOH using an excess of diol reactant. either because there are no differences in the reactivities of 1 An isocyannate-terminated polyurethane prepolymer the functional groups existing on different monomers or the is synthesized from OCN–R –NCO and HO–R –OH polymerization under reaction conditions where there is 2 3 using an excess of the diisocyanate reactant. The extensive interchange. The use of only one diacid or diamine a,o-dihydroxypolyester and a,o-diisocyanatapolyurethane would produce a variation on the copolymer structure with prepolymers, referred to as macrodiol and macrodiiso- either R R or R R .31 ¼ 2 1¼ 3 cyanate, respectively, are subsequently polymerized with Statistical copolymers containing repeating units each each other to form the block copolymer: with a different functional group can be obtained using appropriate mixture of monomers. For example, a polyester- amide can be synthesized from a ternary mixture of a diol, H O R OCC R1 CO n O ROH wðw w w w w wÞ w w diamine, and diacid or binary mixture of a diacid and OCN R2 NHCOO R3 OOCNH m R2 NCO amine–alcohol. þ wðw w w w Þ w w H O R OOC R CO O RO OCNH R ! wðw w w w 1w wÞnw w w w 2w • Alternating copolymers: It is possible to synthesize an alter- NHCOO R3 OOCNH R2 m NCO nating copolymer in which R R2 by using a two-stage ð w w w wÞ w ¼ process. In the first stage, a diamine is reacted with an excess [XV] of diacid to form a trimer: The block lengths n and m can be varied by adjusting
nHOOC R COOH mH N R NH the stoichiometric ratio r of reactants and conversion in w w 2 w 1w 2 þ each prepolymer synthesis. In typical systems, the prepoly- mHOOC R CONH R NHCO R COOH [XI] ! w w w 1w w w mers have molecular weights in the range of 500–6000Da. Avariationofthetwo-prepolymermethodinvolvestheuse The trimer is then reacted with an equamolar amount of a of a coupling agent to join the prepolymers. For example, a second diamine in the second stage: diacyl chloride could be used to join together two different nHOOC R CONH R NHCO R COOH nH N R NH macrodiols or two different macrodiamines or a two differ- w w w 1w w w 2 w 3w 2 þ ent macrodiamines or a macrodiol with a macrodiamine. HO CO R CONH R NHCO R CONH R NH H ! ðw w w w 1w w w w 3w Þnw The one-prepolymer method involves one of the above
2n 1 H2O prepolymers with two ‘small’ reactants. The macrodiol is þ ðÞ À [XII] reacted with a diol and diisocyanate
Alternating copolymers with two different functional groups H O R OOC R CO OR OH 32–35 w w w w w 1w n w are similarly synthesized by using preformed reactants. ð Þ m 1 OCN R NCO mHO R OH þð þ Þ w 2w þ w 3w HF [XVI] nOCN R CONH R1 OSi CH3 3 H O R OOC R1 CO OR OOCNH w w w w ðÞCHÀ!3 SiF n ÀðÞ3 ! wð w w w w Þ w w
HF CH3 3SiF CO NH R CO NH R1 O n [XIII] R2 NHCOO R3 OOCNH m R2 NCO wðÞð w w w w w w Þ ðw w w w Þ w w
HF The block lengths and the final polymer molecular nOCN R CONH R1 NHCO R NCO HO R2 OH w w w w w w þ w w ! weights are again determined by the details of the prepolymer HF CONH R CONH R NHCO R NHCOO R O wð w w w 1w w w w 2w Þn synthesis and its subsequent polymerization. An often-used [XIV] variation of the one-prepolymer method is to react the macrodiol with excess diisocyanate to form an isocyanate-
The silyl ether derivative of the alcohol is used in reac- terminated prepolymer. The latter is then chain-extended tion [XIII].ThecorrespondingalcoholOCN R CONH R OH (i.e., increased in molecular weight) by reaction with a diol. w w w 1w
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The one- and two-prepolymer methods can in principle yield are observed in the secondary and tertiary structure of exactly by the same final block copolymer. However, the dis- the proteins. Proteins are also cross-linked for various applica- persity of the polyurethane block length is usually narrower tions (biotechnological, biomedical, etc.). when the two-prepolymer method is used.32,35 Physical cross-linking methods include drying, heating, or
exposure to or UV radiation. The primary advantage of g physical methods is that they do not cause harm. However, 1.121.4.2. Cross-Linking Reactions the limitation of such methods is that obtaining the desired Cross-linking is the predominant reaction upon irradiation of amount of cross-linking is difficult. In chemical cross-linking many polymers. It involves attachment of polymeric chains methods, cross-linkers are generally used to bond the func- tional groups of amino acids. In recent years, there has been to each other. When each molecule is bonded at least once, then the whole sample becomes insoluble. It is accompanied an increase in interest in physical cross-linking methods. by the formation of a gel and ultimately by the insolubiliza- The main reason is that use of cross-linking agents is avoided tion of the specimen. Cross-linking has a beneficial effect on because most cause some toxic effects. However, the degree of the mechanical properties of polymers. cross-linking is considerably lower and cross-links are weaker than obtained by chemical methods. In commercial practice, cross-linking reactions take place during the fabrication of articles made with thermosetting Collagen is the major protein component of bone, resins. The cross-linked network is stable against heat and cartilage, skin, and connective tissue and also the major con- does not flow or melt. Most linear polymers are thermoplastic. stituent of all extracellular matrices in animals. Collagen
They soften and take on new shapes upon the application of can be chemically cross-linked by various compounds 5 including glutaraldeyde, carbodiimide, genipin, and transglu- heat and pressure. Cross-linking can be achieved by the action of electromag- taminase. 1-Ethyl-3-diaminopropyl carbodiimide (EDC) and netic radiation, heat, or catalysts and results in opening of N-hydroxysuccinimide (NHS) catalyze covalent bindings unsaturated groups on chains and reaction of multifunctional between carboxylic acid and amino groups; thus, cross-linking (>2) groups. Control of cross-linking is critical for processing. between collagen structures is possible (Figure 12). Furthermore, other extracellular matrix components containing carboxyl 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 groups, such as glycosaminoglycans, can also be cross-linked 36,37 period. with this approach.
1.121.4.2.2.2. Cross-linking of polysaccharides 1.121.4.2.1. Effect of cross-linking on properties Chemical and physical methods are used for cross-linking of The change in properties is determined by the extent of cross- polysaccharides. Physical cross-linking is achieved by physical linking. Lightly cross-linked polymers swell extensively in interaction between different polymer chains. solvents in which the uncross-linked material dissolves, but In physical cross-linking, polysaccharides form cross- covalently (irreversibly) cross-linked polymers cannot dissolve linked networks with the counterions on the surface. High but only swell in the solvent of the uncross-linked form. Upon counterion concentration requires long exposure times to extensive cross-linking, the sample may even not swell appre- achieve complete cross-linking of the polysaccharides. Chemi- ciably in any solvent. cal cross-linking of polysaccharides leads to products with Cross-linking has a significant effect on viscosity; it good mechanical stability. During cross-linking, counterions becomes essentially infinite at the onset of gelation. The effect diffuse into the polymer and reacts with polysaccharides of chain branching and cross-linking on Tg are explained in forming intermolecular or intramolecular linkages. Factors terms of free volume. A high amount of branches increase the which affect chemical cross-linking are the concentration of free volume and lower the Tg, whereas cross-linking lowers the cross-linking agents and the cross-linking duration. High the free volume and raises the Tg. concentration of cross-linking agent induces rapid cross- The addition of cross-links leads to stiffer, stronger, tougher linking. Like physical cross-linking, high counterion concen- products, usually with enhanced tear and abrasion resistance. tration require longer exposure times to achieve complete However, extensive cross-linking of a crystalline polymer leads cross-linking of the polysaccharides. to a loss of crystallinity, and this might decrease mechanical Polysaccharides can be chemically cross-linked with either properties. When this occurs, the initial trend of properties addition or condensation cross-linking mechanism. For addi- may be toward either enhancement or deterioration, depend- tion polymerization, the network properties can be easily ing on the degree of crystallinity of the unmodified polymer tailored by the concentration of the dissolved polysaccharide and the method of formation and location (crystalline or and the amount of cross-linking agent. These reactions are 5 amorphous regions) of the cross-links. preferably carried out in organic solvents because water can
also react with the cross-linking agent. 1.121.4.2.2. Cross-linking of biological polymers Polysaccharides can be cross-linked through condensation 1.121.4.2.2.1. Cross-linking of proteins using 1,6-hexamethylene diisocyanate or 1,6-hexanedibromide Proteins are found to be chemically (permanent) or physically or other reagents. Condensation cross-linking can also be done (reversibly) cross-linked. These cross-links can be intra or inter- by carbodiimide which induces cross-links between carboxylic molecular. For example the triple helix of collagen is intermo- acid and amine groups without itself being incorporated. lecularly cross-linked whereas many reversible cross-links The commonly used carbodiimide is a water-soluble
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O R RЈ HO N N O NH (NHS) O p COOH + C p C OO C
N N
R R (EDC)
O O O H N p O 2 O
HO N + p C HN p p C O N + R NH C NH R
O O
R = H C CH CH 2 2 3 CH 3 + RЈ = H2C CH2 CH2 CH2 NH2 – Cl CH 3
Figure 12 Mechanism of protein cross-linking using carbodiimide (EDC).
carbodiimide called 1-ethyl-3-(3-dimethyl aminopropyl) car- structure) which then reorganizes by releasing a methanol bodiimide (EDC). EDC cross-linking involves the activation of group and achieves the binding. Then two protein-bound gen- the carboxylic acid groups of aspartic acid (Asp) or glutamic ipins interact to create the cross-linkage. In scheme (b), the acid (Glu) residues by EDC to give O-acylisourea groups. reaction begins with an initial nucleophilic attack of a primary Besides EDC, another reagent, N-hydroxysuccinimide (NHS) amine group of the protein on the C3 carbon atom of genipin is used in the reaction for the purpose of suppressing side to form an intermediate aldehyde group. Opening of the reactions of O-acylisourea groups such as hydrolysis and dihydropyran ring is then followed by an attack on the result- the N-acyl shift. NHS can convert the O-acylisourea group ing aldehyde group by the secondary amine formed in the into a NHS activated carboxylic acid group, which is very first step of the reaction. reactive toward amine groups of hydroxy lysine, yielding a so The predominant chemical agent that has been investigated called zero length cross-link. In this cross-linking process, nei- for the treatment of collageneous tissues is glutaraldehyde, ther EDC nor NHS is incorporated in the matrix. which yields a high degree of cross-linking when compared
to formaldehyde, epoxy compounds, cyanamide, and the acy- 1.121.4.2.3. Cross-linking agents lazide method. Glutaraldehyde, a popular reagent, has been Cross-linkers (CL) are either homo- or hetero-bifunctional used in a variety of applications where maintenance of struc- reagents permitting the establishment of inter- as well as intra- tural rigidity of protein is important. It covalently binds molecular cross-linkages. Homo-bifunctional reagents, specifi- to amino groups, but can also bind to other glutaraldehyde cally reacting with primary amine groups (i.e., -amino groups molecules. e of lysine residues) have been used extensively as they are The glutaraldehyde cross-linking reactions have been exten- soluble in aqueous solvents and can form stable inter- and sively studied (Figure 14). In general, it is believed that alde- intrasubunit covalent bonds. hydes react with the amine groups of proteins, yielding a Genipin is a naturally occurring cross-linking agent that Schiff base. However, the exact cross-linking structure is still has significantly low toxicity. It can form stable cross-linked not clear because a mixture of free aldehyde and mono- and products with resistance against enzymatic degradation that is dehydrated glutaraldehyde and monomeric and polymeric comparable to that of glutaraldehyde-fixed tissue. Genipin hemiacetals is always present in a glutaraldehyde aqueous reacts in a similar manner to glutaraldehyde, but can only solution. However, depolymerization of polymeric glutar- bind to one other genipin molecule. aldehyde cross-links has been reported. This depolymeri- Even though the definite cross-linking mechanism of zation leads to the release monomeric glutaraldehyde and genipin is not known some mechanisms are proposed as pre- subsequent toxicity. sented in Figure 13(a) and 13(b). In scheme (a) NH2 group Calcium ions may also be used as a cross-linker for alginates of the protein binds to the ester group (outside the ring which are water soluble polymers. When a sodium alginate
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H N p 2 + H N p – 2 HN p H – O O O OCH O OCH3 N p OCH3 3 C C C C
+ CH3OH O O O O
CH2OH OH CH2OH OH CH2OH OH CH2OH OH p H O N p O NH C C CH3
p 2
O O O NH C CH CH OH OH OH 2 O (a)
p: protein CH3 OH
O OCH 3 O OCH C O O OCH3 3 OCH3 C C C
H2N p C NH p O H O N N p p
CH OH OH 2 CH OH OH CH OH CH2OH 2 2
O OCH3 H CO O C 3 CH3
2 N N O p OCH3 p CH
CH2OH
N p: protein + p
CH3 (b)
Figure 13 Mechanism of protein cross-linking using Genipin. a) Protein binding to ester group (outside the ring structre) of genipin and crosslinking, b) Protein binding to ring structure of genipin and crosslinking.
RNH2 + HOC-CH2-CH2-CH2-CHO R-N=CH-CH2-CH2-CH2-CHO
(a) Glutaraldehyde
2RNH2 + HOC-CH2-CH2-CH2-CHO R-N=CH-CH2-CH2-CH2-CH=N-RNH2 Glutaraldehyde
RNH2 : Chitosan
(b)
Figure 14 Cross-linking mechanism with glutaraldehyde. (a) Glutaraldehyde activated chitosan and (b) Glutaraldehyde cross-linked chitosan. solution is dipped into a solution containing calcium ions, 1.121.5. Conclusion each calcium ion replaces two sodium ions. The alginate mol- ecule contains plenty of hydroxyl groups that can be coordi- In brief, polymers are very complex molecules owing to the large 3,11 nated to cations (Figure 15). variety of initiators, catalysts, monomers, and mechanisms
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– – O O O OH O OH O HO O O CaCl2 O OH O O HO r.t. O O OH OH O O– OH O n O– Alginic acid (Alg)
O– O–
O OH O OH O HO O O O O OH O HO O O OH OH O – O OH O 2+ Ca n – O –O
O Ca2+ HO –O O
OH HO O O OH O HO O O O O OH O
HO O HO O – O –O
n Alg gels
Figure 15 Cross-linking of alginic acid with calcium ions.
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