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CHAPTER 1
The History of Nitroxide-mediated Polymerization
GRAEME MOAD AND EZIO RIZZARDO
1.1 Introduction
This chapter traces the early history of nitroxide-mediated polymerization (NMP) during its first ~15 years. It begins with a short prehistory of observations made during studies on defining initiation mechanisms using nitroxide radical trapping that can be seen to have inspired the initial experiments. The main part of the chapter is devoted to an account of the discovery of NMP in the early 1980s and research carried out in the period through to 1993, which saw most aspects of the mechanism defined and the process exploited at CSIRO, mainly in the synthesis of acrylic block copolymers. Many nitroxides for NMP were evaluated, including TEMPO (1.1). However, those found to be more effective and which were most used were 1,1,3,3-tetraethylisoindolin-N-oxyl (1.2) and di-t-butyl nitroxide (1.3) (Figure 1.1). We also provide a brief summary of developments in both the patent and open literature during the period 1993–2000 when the process came to the attention of the wider polymer community, mainly for the TEMPO-mediated polymerization of styrenics. The end of this period saw the discovery of nitroxides such as SG1 (1.4) and TIPNO (1.5) (Figure 1.2), which provided utility and versatility to NMP.
The term "nitroxide" is discouraged in IUPAC nomenclature, which instead recommends the term "aminoxyl". The IUPAC recommended term for "nitroxide-mediated polymerization" (NMP) is "aminoxyl-mediated radical polymerization" (AMRP). However, in keeping with the historical context, the terms in common use are used throughout this chapter.
1.2 Radical Polymerization
Over the past 20 years, radical polymerization has proved to be one of the most active and fertile fields for research into polymer synthesis. The growth of interest in radical polymerization over this period can be largely attributed to the development of techniques for reversible deactivation radical polymerization (RDRP), which impart living character to the process. These techniques include nitroxide-mediated polymerization (NMP — vide infra), atom transfer radical polymerization (ATRP), reversible addition-fragmentation chain transfer (RAFT), and tellurium-mediated radical polymerization (TERP). Papers on these methods now account for more than two-thirds of all papers on radical polymerization.
NMP was discovered at CSIRO, in the then Division of Applied Organic Chemistry, and lodged as an Australian patent application Alkoxyamines useful as initiators in 1984. The first publication on NMP was a European patent application, Free radical polymerization and the produced polymers, which appeared in 1985. In these documents, the process was described as a method for controlled-growth radical polymerization. The introduction states "The present invention relates generally to improved processes for free radical polymerization, particularly to improved processes in which it is possible to control the growth steps of the polymerization to produce relatively short chain length homopolymers and copolymers, including block and graft copolymers, and further relates to new initiators which find particular application in the improved processes," and goes on to define suitable alkoxyamine initiators. The process was said to have living character and be particularly suited for the preparation of well-defined short-chain or oligomeric chains with Mn in the range 500–5000. However, the preparation of higher molecular weight polymers was also outlined.
NMP was briefly described in our review entitled Other initiating systems, which appeared in Comprehensive Polymer Science in 1989. However, the origins of the process at CSIRO are given little mention in most reviews of NMP. Some details of the discovery are revealed in articles by Solomon and Rizzardo and Solomon.
In the 1980s, radical polymerization was possibly the most widely used processes for the commercial production of high molecular weight polymers. Radical polymerization provides the ability to polymerize a vast array of monomers. This versatility can be attributed to the technique's tolerance of unprotected functionality in monomer and solvent, its compatibility with a variety of reaction conditions, and the relative simplicity and low cost of implementation. However, use of the conventional process imposes severe limitations on the degree of control that can be asserted over features such as molecular weight distribution, copolymer compositions and macromolecular architecture.
Conventional radical polymerization is a chain reaction (Scheme 1.1). Chains are initiated by radicals, formed from an initiator, adding to monomer. These chains propagate by sequential addition of monomer units. Chain termination occurs when the propagating radicals self-react by combination or disproportionation. Continuous initiation and termination provides a steady-state radical concentration of only ~10-7 M and the lifetimes of individual chains are typically ~5–10 seconds within a reaction span that may be many hours. In the absence of chain transfer, the lengths of the chains formed during the early stages of polymerization are high. The breadth of the molecular weight distribution is governed by statistical factors. The dispersity (Ð), the ratio of weight to number average molecular weights (Mw/Mn), is ideally 2.0 if termination is by disproportionation or chain transfer, or 1.5 if termination is by combination.
In marked contrast, in a living polymerization, all chains are initiated at the beginning of the process, grow at a similar rate and all survive the polymerization (Scheme 1.2). By definition, there is no termination or irreversible chain transfer. If initiation is rapid with respect to propagation, the molar mass distributions should be very narrow, approaching a Poisson distribution. In a living polymerization, chains can be extended indefinitely with the provision of monomer and conditions to support polymerization. In a conventional radical polymerization, the propensity of radicals to undergo self-termination means that all chains cannot be simultaneously active.
The first examples of what we now recognize as stable radical-mediated polymerization (SRMP) mediated by dithiocarbamyl radicals were reported by Otsu in 1956–1957. Further examples of what may be considered SRMP mediated by diarylmethyl radicals were described by Braun and colleagues in the period 1970–1990. Braun termed these processes "resuscitatable" radical polymerizations.
However, the concept of living radical polymerization (now known as RDRP) was only introduced by Otsu and coworkers in 1982. They recognized that radical polymerizations might display living attributes in the presence of reagents that are capable of reversibly deactivating active chains (propagating radicals, Pn•) such that the majority of living chains are maintained in a dormant form (Pn-X). A further requirement is reaction conditions that support an equilibrium between active and dormant chains that is rapid with respect to propagation. The terms "initer" (for initiator-terminator) and "iniferter" (for initiater-transfer agent-terminator) were introduced to describe the reagents used. A similar terminology ["inifer" (for initiater-transfer agent)] had already been used by Kennedy in describing cationic polymerizations with reversible deactivation.
1.3 Initiation Mechanisms in Radical Polymerization by Radical Trapping
Even though there are clear differences in the mechanism of radical (Scheme 1.1) and other processes for chain polymerization, for example, anionic polymerization (Scheme 1.2), polymers formed are usually represented by the same structure (Figure 1.3). This structure defines only the dominant repeat unit and ignores connectivity, end-groups and side reactions during propagation.
This idealized structure has deficiencies when it comes to rationalizing certain polymer properties. For example, poly(methyl methacrylate) (PMMA) synthesized by anionic polymerization can be more stable than the (apparently) same polymer made by radical polymerization. The stability of PMMA made by radical polymerization depends on the initiator used and other details of its preparation. Similar observations have been made for other polymers, including poly(vinyl chloride) (PVC) and polystyrene (PSt). These observations led to a recognition that chain polymers contain structural irregularities, which include the structures formed by chain initiation and termination (Scheme 1.1).
At CSIRO, these issues prompted the application and development of methods for probing the detailed chemistry of initiation of radical polymerization. Amongst these was the radical-trapping method making use of nitroxides [the IUPAC recommended term for nitroxide is aminoxyl]. A now well-known feature of the chemistry of nitroxides (e.g. 1.1–1.8) is that they combine with carbon-centred radicals to give alkoxyamines at close to diffusion controlled rates. This property led to the use of nitroxides in the so-called inhibitor method for the determination of initiator efficiency and was the basis of the radical-trapping method.
The radical trapping method using nitroxides had been developed at CSIRO in the late 1970s in response to a need to be able to quantitatively characterize radical reactions. The use of spin-trapping using nitroso-compounds and nitrones had already been explored by several research groups in this context and had been used to study the initiation of polymerization. However, that method was not generally regarded as quantitative due to the complication of various side reactions. One side reaction is the formation of stable alkoxyamines by the further reaction of the nitroxides formed to scavenge carbon-centred radicals. There was other literature to indicate that the nitroxides were able to selectively scavenge carbon-centred radicals and limited kinetic data to indicate that the rate of reaction was extremely rapid (kc 107–109 M-1 s-1). Nitroxides were also known to be effective inhibitors of radical polymerization. Thus a stable nitroxide, in particular 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO, 1.1) (Figure 1.4), was explored as a radical trap initially to study initiation pathways in methyl acrylate (MA) polymerization. This and subsequent studies confirmed that nitroxides selectively scavenge carbon-centred radicals to yield stable alkoxyamines (under the conditions used and when isolated) while oxygen-centred radicals either did not react or reacted reversibly with the nitroxide.
Largely over the period 1979–2000, the radical trapping technique was successfully used to define the initiation pathways for the reactions of mainly oxygen-centred (t-butoxy, cumyloxy, other t-alkoxy, isopropoxy, ethoxy, benzoyloxy, isopropoxycarbonyloxy, hydroxy,), more reactive carbon-centred radicals (methyl, t-butyl, phenyl) and cyanoisopropyl radicals with a range of monomers. The nitroxides used in these studies included 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO, 1.1) and its derivatives (1.6, 1.7), and the isoindoline nitroxide, 1,1,3,3-tetramethylisoindolin-2-oxyl (1.8). The nitroxides 1.6–1.8 (Figure 1.4) possess a UV chromophore facilitating chromatographic detection.
A number of observations were made when applying the radical-trapping method with nitroxides that led to the development of NMP (note that most of the references cited below postdate the invention of on NMP — the original observations were not published or were published later).
• Certain alkoxyamines appeared unstable during isolation or subsequent handling. This was sometimes indicated by color development or the appearance of the characteristic absorbance of the corresponding nitroxide.
• Certain alkoxyamines were observed to equilibrate to a mixture of isomers on heating or on standing for prolonged periods. For example, the isolated "styrene dimer" alkoxyamines shown in Scheme 1.3 undergo cis–trans isomerization to form the same mixture of isomers on heating. The allylic alkoxyamines shown in Scheme 1.4 isomerize with a 1,3-shift of the nitroxide functionality. In both examples, the findings can be understood if the alkoxyamines undergo reversible homolytic dissociation as shown.
• In some trapping experiments, the formation of small amounts of oligomers was observed. This was attributed to the rate of trapping of the initiating radical being slow with respect to propagation. The yield of propagation products was consistent with the known kinetics of propagation and trapping, and this remains the likely explanation. NMP was unlikely under the conditions used for the trapping experiments because of the nitroxide used (1.1 or 1.8), the significant excess of nitroxide (~10% at complete initiator consumption), and the low reaction temperatures used (60 °C). Nonetheless, the observations led us to consider other possibilities.
These and similar observations suggested that the alkoxyamines formed were thermally labile, perhaps undergoing reversible dissociation as shown in Scheme 1.5. This in turn suggested the possibility of a method for controlled-growth radical polymerization based on alkoxyamine chemistry with the potential to open the door to structures that were not readily approached by conventional radical polymerization.
1.4 First Examples of Nitroxide-mediated Polymerization
The concept of NMP as a method for living radical polymerization was first disclosed in a Plenary lecture by Ezio Rizzardo at the 14th Australian Polymer Symposium, which was held in Ballarat in February 1984 only a few days after the first patent application had been lodged.
The alkoxyamines based on the nitroxides used in the trapping work (1.1 and 1.6–1.8) were not very effective in NMP and required the use of relatively high reaction temperatures for homolysis, particularly, with acrylates and styrene. It was reasoned that the rate of homolysis should be lowered by steric congestion. Therefore, the first successful NMP experiment (Scheme 1.6) made use of the tetraethylisoindoline nitroxide 1.2, an analog of the tetramethylisoindoline nitroxide 1.8 that had been used in the trapping experiments. The patent generically covered the use of nitroxides of general structure 1.9 in NMP with specific examples being 1.1–1.3 (Figure 1.1) and 1.10–1.13 (Figure 1.5).
1.4.1 Homopolymer Synthesis
The first successful NMP experiment carried out in 1982, detailed as Example 23 of the original patent application, is summarized in Scheme 1.6. It was found that heating the alkoxyamine 1.19 with MA in benzene (50% v/v) solution at 80 &@176;C provided complete conversion of the alkoxyamine to the single-unit monomer insertion product 1.20). When the same alkoxyamine 1.19 was heated at 80 1C in bulk MA, ~7 units of MA were inserted to give the heptamer 1.21. In both cases, no further reaction (oligomerization) was observed when the mixtures were heated at 80 °C for longer times.
These observations are explained as follows. At 80 °C, the alkoxyamine 1.19 dissociates and MA units add; the number is dictated by the relative concentrations of MA and nitroxide. Combination of the propagating species with nitroxide gives alkoxyamine 1.20 or 1.21. These insertion products 1.20 and 1.21 are stable at 80 °C, so no NMP was observed.
NMP required higher reaction temperatures, sufficient to allow reversible dissociation of the alkoxyamine products. When the heptamer 1.21 was heated at 100 °C, slow NMP was observed such that a 14-mer was obtained after 1.5 h. Faster NMP took place at 120 °C providing a 70-mer after 1.5 h. NMP of styrene (Scheme 1.7) was also successful at 100 °C. A 4.5-mer macro-alkoxyamine was obtained after 1 h and a 12-mer after 2 h at 100 1C. The mechanism proposed for NMP is shown in Scheme 1.8.
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