Control The Polymerization Of Cyanoacrylate Biology Essay


Cyanoacrylates have generally been polymerised with uncontrolled systems, leading to polymers with a range of molecular weights (polydisperse). By controlling the polymerisations with RAFT, you can produce macromolecules with defined lengths and introduce functional groups to the ends of the chains. These can be utilised to attach further chemical units e.g. a drug molecule so that the polymers can be applied as drug carriers. The inherent biocompatibility of the polymers, coupled with their biodegradation, is advantageous for the field of drug delivery.

This project will initially look at finding the correct conditions (tempersature, solvent, concentrations), along with the correct RAFT agent (dithioester, trithiocarbonate or xanthate), in order to produce polymers with controlled and reproducible molecular weights with defined end groups.

Literature Review

1 Introduction to α-cyanoacrylate

Due to high reactivity and exceptional adhesive characteristics of poly (alkyl cyanoacrylate), alkyl cyanoacrylate monomers are very famous and widely used in chemical industry. On one hand, the short alkyl chain cyanoacrylates are usually used as glue for repairing and do-it-yourself activities. The typical example is Superglue manufactured by Henkel. On the other hand, longer alkyl chain cyanoacrylates are commonly employed in biomedical field, such as surgical glue for the closure skin wounds[7]-[13] and embolitic material for endovascular surgery.[10][11][14] As a matter of fact, many kinds of cyanoacrylates as commercial products have been widely applied in biochemical field, especially for tissue adhesive application. For example, methyl cyanoacrylate (MCA, Figure 1) composes the main part of Biobond tissue ashesive. N-butyl cyanoacrylate (nBCA, Figure 1) or octyl cyanoacrylate (OCA, Figure 1), which are in the category of longer alkyl ester chain cyanoacylates, were commercialized under the trademarks of Indermil, Liquidband, and Dermabond, respectively.

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Figure 1 Structure of alkyl cyanoacrylate: methyl cyanoacrylate (MCA), ethyl cyanoacrylate (ECA), n-butyl cyanoacrylate (nBCA), isobutyl cyanoacrylate (IBCA), isohexyl cyanoacrylate (IHCA), octyl cyanoacrylate (OCA), isostearyl cyanoacrylate (ISCA), hexadecyl cyanoacrylate (HDCA), and methoxypoly(ethylene glycol) cyanoacrylate (MePEGCA).

2 Synthesis of α-cyanoacrylate monomers

Since 1949, many patent papers have reported the synthesis process of alkyl cyanoacrylate monomers.[15]-[18] In general, there are two steps in the synthesis of α-cyanoacrylates. In the first place, corresponding alkyl cyanoacrylate reacts with formaldehyde with the presence of a kind of basic catalyst and then PACA oligmers are formed. This is so-called Knoevenagel condensation reaction. The catalyst can either be inorganic (e.g., sodium or potassium hydroxide, ammonia) or organic (e.g., quilonine, piperidine, dialkyl amines). In the second place, via a thermal depolymerization of oligmers produced in last step, pure alkyl cyanoacrylate monomer can be achieved. Beisides, it is necessary to add appropriate stabilizers loke protonic or Lewis acids and a small amount of a free-radical inhibitors which is used to prevent repolymerization. (Figure 2)

Figure 2 Synthesis of alkyl cyanoacrylate monomer via Knoeenagel condensation reaction (a) and subsequent thermal depolymerization (b).

Basically, this synthesis method remained almost unchanged except for some slight modification and improvement such as applying a transesterification approach to make cyanoacrylate bear longer alkyl ester chains, [21] or using a more efficient catalyst in the condensation step[22] and so on.

3 Polymerization of alkyl cyanoacrylate

Alkyl cyanoacrylate family, as the exotic class of representative vinyl monomers, have two powerful electro-withdrawing groups in the α-carbon of the double bond, ester (COOR) and cyano (CN). And because of that, with the presense of nudeophiles, like anions (hydroxide, iodide, alcoholate, etc.) or weak bases (alcohol, amine, etc.), alkyl cyanoacrylate monomers react remarkably and exhibit a high polymerization rate even if the content of above-mentioned additions is low. As a consequence, the pure alkyl cyanoacrylates are quite difficult to control and in order to keep these monomers stable, a small amount of acid stabilizers like SO2, sulfonic acid, etc. are necessary.[1]

There are three distinguished methods to synthesize poly (alkyl cyanoacrylate): (1) anionic, (2) zwitterionic, and (3) radical (Figure 3). As far as now, due to high reactivity of alkyl cyanoacrylate derivates, anionic and zwitterionic polymerization are considered as two predominant methods especially under traditional experiment conditions due to a pure radical process.

Figure 3 Initiation and propagation steps involved during anionic (a), zwitterionic (b) and radical (c) polymerization of alkyl cyanoacrylate monomer initiated by a base (B-), a nucleophile (Nu), and a radical (Pâ-), respectively.

3.1 Synthesis of Homopolymers

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In this field, Peter and his team accomplished an extensive work in order to get a better understanding of affects of experiment conditions on polymerization results. [23]-[26] As a matter of fact, simple anions (CH3COO_, CN_, I_, etc.) or covalent organic bases (Et3N, pyridine, etc.) can initiate the homopolymerization of ethyl cyanoacrylate (ECA, Figure 1) and n-butyl cyanoacrylate (nBCA, Figure 1) in solution, resulting in anionic or zwitterionic polymerization respectively. [23] Regarding zwitterionic polymerization of nBCA, the nature properties of initiator and other reaction surroundings can influence the main characteristics of the polymer product like number-average molecular weight and molecular weight distribution as well as polymerization kinetics such as monomer conversion, polymerization rate and so forth. With respect to anionic polymerization, the same research group accomplished the polymerization of nBCA at 20-40℃ in tetrahydrofuran (THF), using tetrabutyl ammonium salts (hydroxide, bromide, acetate, and substitute acetates) as the initiators. And they reported a nearly ideal living polymerization can be achieved with the presence of hydroxide-based initiator. [31]-[33]

Although anionic and zwitterionic polymerization are more likely to happen for the polymerization of alkyl cyanoacrylates, free-radical polymerization is considered as the main approach to extend polymeric chain during homopolymerization. [34]-[37] and copolymerization. [37][38] in bulk with a suitable inhibitor in the reaction medium. It is noteworthy that anionic polymerization still cannot be inhibited completely even under such a specific inhibition condition, but it can be neglected with respect to the timescale of the polymerization reaction. In 1960, Canale et al. [34], using boron trifluoride-acetic acid compound as inhibitor, successfully accomplished free-radical polymerization of MCA at 60â-¦C initiated by azobisisobutyronitrile (AIBN). Bevington et al. [36] used propane-1,3-sultone as inhibitor for the free-radical polymerization of MCA in bulk or in 1,4-dioxane at 60â-¦C, initiated by AIBN or benzoylperoxide (BPO). In 1983, Yamada et al. [37] polymerized ECA in bulk at 30â-¦C with a small amount of acetic acid or propane-1,3-sultone and they reported a very high propagation rate constants: kp = 1622 l mol−1 s−1 in the presence of acetic acid and kp = 1610 l mol−1 s−1 in the presence of propane-1,3-sultone. As a comparison, methyl methacrylate (MMA) which is considered as a highly reactive monomer gave kp = 450 l mol−1 s−1 at 30â-¦C. [39]

3.2 Synthesis of Copolymers

Via a free radical Process (using trifluoride-acetic acid complex as an efficient inhibitor against anionic polymerization), alkyl cyanoacrylates copolymerize with more 'common' vinyl monomers to produce a wide range of copolymers, depending on the nature properties of comonomer. [38] The studies have reported that random copolymers with MMA were achievable in bulk while alternating copolymers with styrene were obtained in benzene solution at 60 using AIBN as initiator. With respect to the nature of bulk, random copolymers with 10% MMA show similar properties to PMCA homopolymer, on the contrary, alternating copolymers with styrene showed an improved thermal stability comparing to radam copolymers. Hall et al., who previously researched the reactions of electron-rich olefins with electron-poor olefins, [40]-[42] proved the alternating copolymers starting from a styrene and MCA mixture with a 1:1 proportion, either produced under AIBN initiation and UV light at 40 in benzene solution or produced spontaneously at room temperature. [43] However, when copolymerize MMA with other comonomers such as isobutyl vinyl ether, p-methoxystyrene or -bromostyrene resulted in mixtures of (co)polymers and/or small adducts. [43] In 1978, Buck proposed a comprehensive synthetic strategy of bis(alkyl cyanoacrylate)s starting from anthancene adducts. [44] The copolymerizations of these difunctional alkyl monomers based on cyanoarylates with monofunctional alkyl cyanoacrylates like MCA and siobutyl cyanoacrylate (IBCA, Figure 1) lead to crosslinked macromolecular adhesive compositions showing excellent mechanical properties under both dry and wet environments compared with noncrosslinked counterparts which could be desirable applied as pit and fissure sealant in density.

Like poly(ethylene glycol) (PEG) and PACA blocks which have more complicated macromolecular architectures like diblock and triblock copolymers were also produced in homogeneous media through zwitterionic polymerization. [45] The synthesis involved the preparation of triphenylphosphine end-capped monohydroxyl and dihydroxyl PEGs, offering corresponding monofunctional and difunctional macrozwitterionic initiator. In the subsequent step, the polymerization of IBCA was initiated by every macroinitiator in THF at room temperature to achieve PIBCA-b-PEG diblock and PIBCA-b-PEG-b-PIBCA triblock copolymers with tuneable compositions in good match with the initia stochiometry.

Peracchia et al. have reported the synthesis process of poly[(hexadecyl cyanoacrylate)-co-methoxypoly(ethylene glycol) cyanoacrylate] [P(HDCA-co-MePEGCA)], which is a kind of comb-like copolymers showing amphiphilic properties. [46] hexadecyl cyanoacrylate and PEG monomethyl ether cyanoacrylate react with formaldehyde via Knoevenagel condensation reaction in the presence of dimethylamine as the catalyst (Figure 4). Due to the slow, in situ formation of the cyanoacrylate monomers, the polymerization is easier and better to be controlled than a direct ionic polymerization. What's more, by changing the initial cyanoacrylates feed ratio, the composition of the copolymer (and thus its hydrophilicity/hydrophobicity) can be adjusted easily. [æ-‡ç« æœ¬èº« 17页]

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Figure 4 Synthesis of random, comb-like poly[(hexadecyl cyanoacrylate)-co-methoxypoly(ethylene glycol) cyanoacrylate] [P(HDCA-co-MePEGCA)] copolymer via knoevenagel condensation reaction.

4 Biocompatibility and Biodegradation of Poly(alkyl cyanoacrylate) Polymers

The biocompatibility and biodegradation of poly(alkyl cyanoacrylate) nanoparticles play a quite significant role on its biomedical applications due to the fact that the drug carrier applied in vivo application must be made of biocompatible, biodegradable or at least excretable materials. In general, poly (alkyl cyanoacrylate) can be used as drug carrier are because of its distinguished strategies to degradation. In this field, many studies have reported mechanisms and details so far. (Figure 5).

By hydrolysing side chain ester function of poly (alkyl cyanoacrylate), [1]-[3] corresponding alkyl alcohol and poly (cyanoacrylate acid) are produced as degradable products according to the latter compound has water-soluble property and can be eliminated by kindney filtration (Figure 5(a)). This strategy plays a predominant role on degradation of poly (alkyl cyanoacrylate). It is noteworthy that the length of alkyl side chains and the reaction surroundings can influence the hydrolysis directly. The longer the alkyl side chains, the lower the toxicity and the slower htdrolysis. [1][5][6] And the surrounding environment can be strongly catalysed by esterases from serum, lysosomes and pancreatic juice. [7][8] However, only low-molecular-weight PACA polymers, typically below 10,000 can be eliminated from body totally.

It has been postulated that 'unzipping' depolymerisation reaction which can be started by a base is another degradation strategy of PACA. [66] Consequently, it is more likely to occur in a biologic media where can offer amino acids of proteins as inducers for reaction (Figure 5(b)). After the depolymerisation of parent polymers, repolymerization occur immediately and then lower-molecular-weight polymers are formed. So far, the detailed mechanism description has not been reported possible because the occurrence is too fast to be unambiguously observed.

At last, based on the inverse Knoevenagel condensation reaction, PACA can be degraded and produces corresponding alkyl cyanoacrylate and formaldehyde (Figure 5(c)). Although the formaldehyde might also form from hydrolysis of -hydroxyl functions of polymer chains, provided the hydroxyl ions have been initially used as an initiator (Figure 5(d)). [69] However, the inverse Knoevenagel condensation reaction in aqueous solution at physiological PH has been less reported, possibly because it is much slower than above-mentioned enzyme-catalyzed hydrolysis mechanism. [118]-[120]

Figure 5 Possible degradation pathways for poly (alkyl cyanoacrylate) (PACA) polymers: hydrolysis of ester functions (a), 'unzipping' depolymerisation reaction (b), the inverse Knoevenagel condensation reaction (c), and release of formaldehyde from hydrolysis of the -hydroxyl functions (d).

5 RAFT polymerization

Reversible addition-fragmentation chain transfer (RAFT) polymerization is one kind of living radical polymerization (LRP) techniques and more versatile than other living radical polymerizations, like atom transfer radical polymerization (ATRP) or nitroxide-mediated polymerization (NMP). It was first reported in 1998 by CSIRO. RAFT polymerization adds a chosen quality of thiocarbonylthio compounds as RAFT agent like dithioester, dithiocarbamates, trithiocarbonates and xanthates to a conventional living radical polymerization in order to mediate the polymerization through a reversible chain-transfer process. This is the main difference from conventional living radical polymerization.

The Z and R group of RAFT agent play a different role in RAFT polymerization (Figure 6). [2] The Z group greatly affect the stability of the thiocarbonyl-thio radical intermediate. Consequently, the strong stabilizing groups help to form intermediate, contributing to a high reactivity of C=S bond toward radical addition. The R group must be a good leaving group comparing to the growing polymeric chain in order to initiate new polymer chains. Radical initiators, such as azobisisbutyronitrile (AIBN) and 4,4'-Azobis(4-cyanovaleric acid) (ACVA) are widely used. Because the concentration of RAFT agent is low in reaction system, the concentration of the initiator is usually lower than that in conventional radical polymerization.

Figure 6 Generic structure of RAFT agents.

According to outstanding effectiveness and wide range of applicable monomers, RAFT polymerization has become a quite popular polymerization technique. What's more, the molecular weight of polymer can be easily determined before reaction and the molecular weght distribution can be controlled pretty good. Polydispersity indexes are controlled in a narrow and expecting rang. Additionally, RAFT polymerization is useful to design polymers with desirable architectures such as linear block polymer, star copolymer, grafting polymer and so forth.

The transfer of the CTA between growing radical chains, present at a very low concentration, and dormant polymeric chains, present at a higher concentration, will regulate the growth of the molecular weight and limit the termination reactions. The mechanism of RAFT/MADIX polymerization, as it is generally accepted, is depicted in Scheme 3.24-26

5.1 Mechanism of RAFT polymerization

During reaction, the concentration of transfer of the CTA between growing radical chains is very low, on contrary, the concentration of dormant polymeric chain is at a higher value in order to control the growth of molecular weight and restrict termination reaction. In general, the process of RAFT polymerization is comprised of five steps (Figure 7). [24]-[26]

Step (: Initiation

The reaction is initiated by initiators, such as Azobisisobutyronitrile (AIBN) or 4,4'-Azobis(4-cyanovaleric acid) (ACVA). In this step, the initiator (I) reacts with the monomer (Ki) in order to create a radical species which starts an active polymerizing chain.

Step (II): Addition-Fragmentation

The active chain (Pm) quickly reacts with the reactive C=S bond of the chain transfer agent (CTA) (7) (Kadd) and then kicks out a re-initiating group (R). In this step, a radical intermediate (8; prior to reacting with any monomer, the active initiator may add onto the CTA immediately) can be formed. And due to its ability to losing either the leaving group (R) and a macro chain-transfer agent (macro-CTA; 9)(Kβ) or the radical species (Pm), the fragmentation of the intermediate is reversible.

Step (III): Reinitiation

The R group then re-initiate the polymerization (Kre-in) by means of reacting with the monomers and starting a new polymer chain which is then able to propagate (Kp) or react back with the macro-CTA(Kβ). When the initial CTA is finished up, the macro-CTA presents uniquely in the reaction medium and goes to the next step - equilibrium.

Step (IV): Equilibrium

This is the fundamental step in the RAFT process. Active and dormant (thiocarbonyl-thio capped) chains exchange quickly ensuring equal probability for all chains to grow. As a consequence, the resulting polymers all have a narrow molecular weight distribution. The intermediate radicals 8 and 10 were first observed via electron spin resonance (ESR) by the CSIRO group[27] and have since been confirmed by many other research groups.[27]-[35] Such radical intermediates may also be involved in a variety of side reactions during polymerization, including termination with a propagating polymeric chain.

Step (V): Termination

The termination of reaction is inevitable and occurs in all free-radical polymerization systems by means of either combination (Ktc) or disproportionation (Ktd). However, the final resulting polymer is comprised of a large majority of polymeric chains showing the re-initiating group (R) at one end and the thiocarbonyl-thio groups at the other by reason of the termination reactions are controlled under a minimum. This structure has been proved by various analytical techniques, such as 1H NMR, UV spectroscopy and showed in many reports. What's more, these studies also have reported that a small number of chains terminated by the thiocarbonyl- thio moiety have been initiated by the free-radical initiator.[36][37]

Figure 7 Proposed general mechanism of RAFT polymerization

According to the mechanism, the following remarks can be concluded:

The mechanism of RAFT polymerization is quite different from that of ATRP or NMP, because the chain grows depending on the cooperative chain transfer between polymeric chains (bimolecular reactions) rather than reversible radical capping (monomolecular reaction).

The source of radicals triggers the degenerative chain transfer, leading to the growth of polymeric chains. With the increasing concentration of radical, the rate of polymerization will increase but the probability of chain termination will also increase which may cause a higher molecular weight distribution of product polymers.

The majority of the polymeric chains are initiated by the CTA re-initiating group (R group) and terminated by the thiocarbonyl-thio group (Figure 8).

The molecular weight increases linearly with conversion and can be predicted, if we assume that all CTAs have reacted and neglect the chains initiated by the source of radicals, by the following equation:

Mn,theo - the theoretical number-average molecular weight

[Monomer] and [CTA] - the concentration of the monomer and CTA, respectively

FW(CTA) and FW(CTA) - the monomer and CTA formula weight, repectively

c - the fractional conversion (Figure 9).

Figure 8 Overall reaction in RAFT polymerization

Figure 9 Evolution of Mn and PDI with the monomer conversion in the bulk polymerization of methyl acrylate at 60 mediated by PEDB in the following concentrations: (â-²), (â-), (â- ), (â-¼).

5.2 RAFT Polymerization Processes

A representative advantage of RAFT polymerization is the polymerization process. Comparing to conventional free radical polymerization, RAFT polymerization only need the involvement of a CTA which means, under the same reaction conditions, the RAFT polymerization does not need any modification of existing setups and this makes large-production a more satisfactory result. By far, RAFT polymerization can be conducted in all kinds of process, such as bulk, solution, emulsion and miniemulsion, in ionic liquids and supercritical carbon dioxide, and at high pressure.

5.2.1 Bulk

Up to date, bulk polymerization is the simplest process for RAFT polymerization. However, during the polymerization process, the viscosity increases when conversion rate reaches a high value, leading to a negative effect on the processing of final resulting polymer. In general, polymerization in bulk is faster than that in solution. For instance, Zhu etal. [193] reported that at 60, the polymerization of glycidyl metharylate reached 96.7% conversion in bulk and 64.3% in benzene comparing to 50% conversion of monomer for the same reaction time. But the polymerization in bulk does not lead to a higher polydispersity. For example, under the same experiment conditions, the polymers produced by 4-acetoxystyrene and isobutyl methacrylate in the bulk both have a narrower polydispersities than those produced from solution or emulsion. [194][195]

5.2.2 Solution

Solution polymerization solves the problem for high glass-transition temperature polymers in bulk that the viscosity increases under a high conversion rate, but it is slower and can result in a little high polydispersity than that if bulk polymerization.[194][195] One dominant merit of solution polymerization is that it allows the copolymerization of monomers that are not miscible.

5.2.3 Emulsion

Emulsion polymerization is a well-studied process for the industrial-scale production of polymers and provides good heat transfer as the viscosity of the system remains low, even at high polymer loadings.210 Emulsion polymerization mediated by the RAFT process was first reported by the CSIRO group, with the polymerization of butyl methacrylate,12 and was further applied to the polymerization of styrene and MMA.25 Much has now been written on RAFT polymerization in emulsion and mini-emulsion conditions. Our first communication on RAFT polymerization briefly mentions the successful emulsion polymerization of butyl methacrylate with cumyl dithiobenzoates as a stable entry. [13] Additional examples and discussion of some significant factors for successful RAFT polymerization in emulsion and mini-emulsion were showed in a subsequent paper. [9] Many studies have reported the choice of RAFT agent and polymerization conditions play decisive roles on the success of RAFT polymerization. [9][175-183] Most researches have paid attention to polymerization of styrene while some focus on polymerization of BA [178] and methacrylates. [9][13] Using cumyl dithiobenzoate 22 as RAFT agent in ab initio emulsion polymerization of styrene is not recommended. [9] The emulsion recipes have been reported were feed process in which conversion of monomer into polymer was maintained at a high level (often 90%). The first step was to synthesize a low-molecular-weight polymeric RAFT agent. Control for this step was not always good. But the poor polydispersity achieved in this stage does not affect control exerted during the later stages of polymerization.

In recent years, a new method to RAFT emulsion polymerization has been reported. [103][181] In the first place, polymerizing a water-soluble monomer (AA) in the water phase to a low degree of polymerization in order to produce a macro-RAFT agent. Then, a hydrophobic monomer(BA) was added at a controlled feed ratio to provide oligomers which were used to form rigid micelles. These comprise a RAFT-containing seed. Continued controlled feed of hydrophobic monomer may be used to continue the emulsion polymerization. This process is similar to the 'self-stabilizing lattices' process we have previously introduce in macro-monomer RAFT polymerization which involves sequential polymerization of methacrylic acid and non-polar methacrylates. [184] These two processes both can alow emulsion polymerization with no surfactant adding.

RAFT polymerization in mini-emulsion has also been reported. [9][68][82][102][185]-[195] The polystyrene with a narrow polydispersity can be produced via RAFT polymerization in mini-emulsion in a batch process. [9] Some retardation is found with dithiobenzoate RAFT agents. [9][82] However, when using dithioesters [82] or trthiocarbonate RAFT agents [102], the retardation reduces remarkably. In conventional mini-emulsion polymerization, the high concentration of surfactant and co-stabilizer which is typically used is a important issue should be noted. Recently, Pham et al. [102] have reported surfactant-free mini-emulsion polymerization. The process used amphipathic macro-RAFT agents as sole stabilizer which is synthesized in situ via polymerization of AA. This approach eliminated secondary nucleation of new particles and contributed to a latex without labile surfactant and good particle size control.

5.3 Application of RAFT polymerization

5.3.1 Block copolymers

5.3.2 Star copolymers

Many studies have reported the synthesis process of star (co)polymer by means of RAFT polymerization using a variety of multifunctional CTAs. It is important to note that by functionalization of either R substituents (Scheme 1) or the Z substituents (Scheme 2), the core of star can be formed and this is the main reason for the the RAFT process is different from other living radical polymerization like ATRP or NMP.

The use of the R group from CTA produces a similar structure of star (co)polymer comparing to those gained from ATRP or NMP (the so-called attached-to or R approach technique, as the polymeric arms grow away from the core). As a general rule, since the main termination way of monomers' polymerization is through combination, the conversions should be controlled under a low value in order to avoid star-star coupling. What's more, aiming to keep the number of dead linear polymeric chains to a minimum, the concentration of radicals which are used to initiate the AFCT reactions should be maintained at a very value. When these factors are considered, polydispersities ranging from 1.1 to 1,4 can be obtained.

On contrary, the use of Z group for the star (co)polymers gives a unique and special result to RAFT polymerization. In this way, the polymeric arms are detached from the core as they grow and then react back onto the core for the chain-transfer reaction. This approach is called the away-from process or Z approach. Coupling happens not between stars but between arms. As a cresult, the polydispersity of star (co)polymers is quite narrow as the PDI value is around 1.1, a quite excellent result. The conversion of polymerization is higher than that in the growing approach. Stetic hindrance, however, may play a negative role on arms by means of a high molecular weight since it is difficult for chains to react back on the thiocarbonyl-thio moiety attached to the core. Furthermore, it is worth noting that in this type of architecture, the thiocarbonyl-thio is the key part for arms attaching to the core as well as the integrated part as a consequence.

5.3.3 Grafting polymers

Introducing grafted polymers onto a polymer bead through non-controlled radical polymerization can lead to a broad molecular weight distribution and high polydispersity. Even using other controlled radical polymerization techniques like ATRP and NMP, polymeric microspheres would often require derivitization. By employing RAFT polymerization, grafting from these microspheres become a one step process. Furthermore, the grafted polymer would have a FRAT end group, leading to the possibility of reinitiating the chains to form block copolymer shells.

Barner, L. (2003). "Surface Grafting via the Reversible Addition-Fragmentation Chain-Transfer (RAFT) Process: From Polypropylene Beads to Core-Shell Microspheres". Aust. J. Chem. 56: 1091. doi:10.1071/CH03142.

5.4 Reaction Conditions (Temperature, Pressure, Solvent, Lewis Acids)

So far, the detailed studies of the influences of temperature on the process of RAFT polymerization have not been reported. Temperatures reported about RAFT polymerization range from ambient temperature to 140. There are some data shows that the molecular-weight distribution of resulting polymer is narrower when RAFT polymerization is processed at a higher temperature. [7] Besides, at higher temperatures, the retardation with dithiobenzoates is less. Regarding MMA polymerization with trithiocarbonate RAFT agent 1 (Figure ), the temperature has little influences on molecular-weight distribution. (Figure 15). However, it is worth noting that the higher temperature provide higher rates of polymerization which means in a shorter reaction time a given conversion is achievable.

Figure Trithiocarbonate RAFT agent 1

The studies for RAFT polymerization under high pressure have been reported. [161]-[163] The termination of RAFT polymerization is in the form of radical-radical termination, allowing polymer products have higher molecular weight and higher polymerization rates comparing to that achieved under ambient pressure. [æ-‡ç« æœ¬èº«]

The RAFT polymerization is compatible with a variety of reaction media containing protic solvents like alcohols and water [13][14][164][165] and less traditional solvents like ionic liquids [166] and supercritical dioxide. [167] In aqueous media, polymers have been polymerized successfully via RAFT polymerization. However, attention should be paid to the hydrolytic sensitivity of some RAFT agents. [243] The roughly relationship between RAFT agents have been found (dithiobenzoates trithiocarbonates aliphatic dithioesters). [æ-‡ç« æœ¬èº«]

RAFT polymerization can be processed in the presence of Lewis acids. There are many studies about attempted tacticity control homopolymers [91][168-170] to polymerize stereoblock copolymers. [171] and control alternating tendency for polymerization with Lewis acids as additives. [172][173] Take MMA polymerization as an example, by adding Lewis acids scandium triflate, Sc(OTf)3, the fraction of isotactic triads increases and the rate of polymerization in traditional radical [174] and RAFT course [168][170][171] improves apparently. Molecular weight and polydispersity are poor controlled by using dithiobenzoate RAFT agent 8 [170] or 22 [168][170][171]and Sc(OTf)3. By NMR analysis, [170] the reasons to poor results can be found that Lewis acid causes degradation of the dithiobenzoate RAFT agents. In addition, further studies show that the trithiocarbonates are substantially more stable. Therefore, the polymers produced with trithiocarbonate RAFT agent 58 have narrow molecular-weight distributions (). In addition, the molecular weights as well as effect on tacticity are achieved expectedly.