Chapter 4
Reversible Deactivation Radical Polymerization: Mechanisms and Synthetic Methodologies Downloaded from pubs.acs.org by UNIV OF MISSOURI COLUMBIA on 08/20/18. For personal use only.
Elements of RAFT Navigation RAFT 20 Years Later: RAFT-Synthesis of Uniform, Sequence-Defined (Co)polymers Joris J Haven,1,2,3 Matthew Hendrikx,1,4 Tanja Junkers,2,3 Pieter J Leenaers,1,4 Theodora Tsompanoglou,1,4 Cyrille Boyer,5 Jiangtao Xu,5 Almar Postma,1 and Graeme Moad1,* 1CSIRO
Manufacturing, Research Way, Clayton, VIC 3168, Australia of Chemistry, Monash University, Clayton, Vic 3800, Australia 3Insitute for Materials Research, Universiteit Hasselt, B-3590 Diepenbeck, Belgium 4Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, 5600 MB, Eindhoven, The Netherlands 5Centre for Advanced Macromolecular Design and Australian Centre for NanoMedicine, School of Chemical Engineering, University of NSW, NSW 2052, Australia *E-mail:
[email protected]. 2School
This paper focuses on one of the next directions in the evolution of reversible addition-fragmentation (RAFT) polymerization, namely, progress towards the synthesis of discrete or uniform, sequence-defined (co)polymers. Following a brief review of RAFT-single unit monomer insertion (RAFT-SUMI), we describe recent developments in the field. We point to difficulties in achieving consecutive RAFT-SUMI and report two strategies for overcoming the issue of initiator-derived by-products. We show that the selection of RAFT agent is critical in selective RAFT-SUMI of N,N-dimethylacrylamide (DMAm) into a trithiocarbonate in aqueous solution. Finally we recount on the use of photoRAFT- or PET-RAFT-SUMI in the high yield synthesis of discrete oligomers comprising two or more consecutive SUMI steps.
© 2018 American Chemical Society
Introduction RAFT polymerization with thiocarbonylthio compounds was first disclosed in a 1997 patent application (published 1998) (1). The year 2017, thus marks the 20th anniversary of this event. RAFT polymerization (2) is a reversible deactivation radical polymerization (RDRP) (3); a process that, with appropriate attention to reagents and reaction conditions, can possess most of the attributes normally associated with living polymerization (4, 5). These attributes include, low molar mass dispersity, high end group fidelity, a capacity for continued chain growth (in the presence of monomer and appropriate reaction conditions) and access to complex architectures. RDRP are often called living or controlled radical polymerizations. However, the use of these terms in this context is discouraged by IUPAC (3, 6). Our contribution to the previous volume in this series, RAFT Polymerization Then and Now (7), provided a review of 20 years of RAFT polymerization from a CSIRO perspective. That review commenced with a prehistory of thiocarbonylthio RAFT, with the discovery of what we later called macromonomer RAFT polymerization (8, 9) (now also known as sulfur-free RAFT (10)). We will not mark this occasion with another such review. Rather, we will focus on what we believe is one of the important next directions in the evolution of RAFT, and which, we believe, illustrates some of the more important features of controlling the RAFT process. The development of thiocarbonylthio RAFT polymerization from discovery in 1997 through 2012 is also detailed in a series of reviews published in the Australian Journal of Chemistry (11–14) and in subsequent reviews that cover RAFT agent synthesis (15), the fundamentals of RAFT polymerization (16, 17), RAFT end-group transformation (18), and the application of RAFT to optoelectronic polymers (19), RAFT crosslinking polymerization and polymer networks (20), RAFT polymerization of conjugated diene monomers (21) and stimuli responsive polymers (22).
Figure 1. Schematic depiction of the RAFT equilibria indicating the terminology used to describe the various species. 78
The mechanism of the RAFT process with thiocarbonylthio compounds as defined in the first papers on topic comprises the insertion of monomer units into an initial RAFT agent, which is a dormant chain of structure ZCS2-Pn-R. A schematic description of the RAFT equilibria is shown in Figure 1. The species labelled ‘intermediate’ should ideally be transient and play no direct role in the process.
RAFT Single Unit Monomer Insertion Reversible addition-fragmentation-single unit monomer insertion (RAFT-SUMI), as the name suggests relates to the insertion of a single unit of monomer; a mechanism is shown in Figure 2. Radicals are generated (from an initiator), these can add to monomer to form a unimer radical, which can add further monomer (propagate) or react with RAFT agent to form a unimer RAFT agent or SUMI product by addition-fragmentation. For successful SUMI, the reactivities and concentrations must be such that the reaction of unimer radical with RAFT agent is very much faster than propagation to form an oligomer. Radical-initiated SUMI has a long history and has been widely applied in synthetic organic chemistry (23, 24) and in studying the reactions of initiator-derived radicals with monomers (by the radical trapping method (25)). Most RDRP methods were predated by corresponding SUMI processes, including ATRP (when it is often known as the Kharasch reaction (26), atom transfer radical addition or ATRA (27–29)), NMP (sometimes called unimer synthesis (30, 31)) and RAFT (vide infra). With appropriate selection of the monomer, initiator/deactivator (in the case of ATRP or NMP) or transfer agent (in the case of RAFT), and the reaction conditions selective SUMI can be effectively conducted. However, sequential SUMI leading to discrete sequence-defined oligomers is a bigger challenge (32–34). Schemes for sequential ATRA have been reported that are based on interspersing ATRA steps with other reactions (35–38) or template processes (39) but those reported to date lack both versatility and utility, so the challenge remains. Zard and coworkers (40) showed that single unit monomer insertion (SUMI) into xanthates was a valuable technique in organic synthesis a decade before the invention of thiocarbonylthio RAFT (1) (or MADIX) (41) as a method for RDRP. They developed a synthetic strategy based on SUMI of less activated monomers (LAMs, e.g., vinyl esters, vinyl amides, vinyl imides, allyl monomers) or slow-to-propagate monomers into xanthates. Various initiation methods, including direct photoinitiation and processes using added photoinitiators or thermal initiators, were explored. Many examples have been reported (42–44), including sequential SUMI of N-vinylphthalimide followed by an allyl monomer into a xanthate (45).
79
Figure 2. Schematic depiction of RAFT-SUMI indicating the terminology used to describe the various species.
In 2004, Chen and coworkers (46) demonstrated that selective RAFT-SUMI of more activated monomers (MAMs) was also possible with the selection of RAFT agent with an appropriately high transfer constant. They used SUMI to prepare new dithiobenzoate macro-RAFT agents as precursors to light harvesting polymers. This strategy was subsequently applied to a wide range of MAMs, which include styrenes (46–50), vinylthiophenes (e.g., Figure 3) (51) acrylamides (48, 49) and maleic anhydride (49) and either trithiocarbonate or dithiobenzoates RAFT agents (Figure 4). SUMI of monomers such as maleic anhydride (MAH) (52–55), Nalkylmaleimide derivatives (56, 57) or β-pinene (57) into macro-RAFT agents has also been used as a method of chain-end functionalization. These monomers do not readily undergo homopolymerization. This means that the monomer will give SUMI even when used in substantial excess with respect to the macro-RAFT agent (e.g. >1:20) (56) with a low risk of multiple monomer unit insertion (i.e., oligomerization). 80
Figure 3. Synthesis of poly(3-hexylthiophene macroRAFT agent by RAFT-SUMI. Regions 2.4–3.4 and 4.9–5.9 ppm of 1H NMR spectra showing signals for vinyl-P3HT (lower trace) and P3HT macro-RAFT agent (upper trace). Spectra are of reaction mixtures for time 0 and 20 h respectively. For signal assignments and further details see ref (51). Adapted with permission from ref (51). Copyright 2011 The Royal Society of Chemistry.
Figure 4. Scope of RAFT-SUMI for insertion of a monomer into 2-cyanoprop-2-yl dithiobenzoate. 81
Prior to these studies, McLeary, Klumperman and colleagues (55, 58–63) had observed that complete conversion of an initial RAFT agent to a species incorporating only a single monomer unit (i.e., SUMI) preceded polymerization in many well-behaved RAFT polymerizations (including those of styrene (St) (58, 61), methyl acrylate (MA) (60, 63), N-vinylpyrrolidone (62) and vinyl acetate (VAc) (62)). This behavior was called selective initialization. However, similar selectivity in formation of a two unit adduct was not observed. We made similar observations for styrene polymerization and found that the phenomenon was strongly dependent on the RAFT agent and the specific polymerization conditions used (64). For example, with 4.3 M St and 0.5 M RAFT agent, selective initialization is observed with 2-cyanoprop-2-yl and cumyl dithiobenzoates, but not with benzyl dithiobenzoate (poorer homolytic leaving group) or 2-cyanoprop-2-yl dodecyl trithiocarbonate (lower transfer constant RAFT agent) (64). Selective initialization may be observed with 2-cyanoprop-2-yl dodecyl trithiocarbonate but only when higher RAFT agent to styrene ratios are used (48). Selective SUMI requires a RAFT agent with Ctr such that, on average, there is >k-add, by low relative monomer concentrations (e.g., stoichiometric with RAFT agent) and an initiator-derived radical that is identical to the RAFT agent ‘R’ group (48, 49). SUMI is an important technique for converting macromonomers into macroRAFT agents that can be later elaborated by RAFT polymerization (51). In cases where high yield SUMI is not possible, the application of separation techniques, such as preparative recycling size exclusion chromatography (65–68), or flash column chromatography (69) can enable separation of discrete oligomers from the reaction-derived oligomer mixtures. Thus, Vandenbergh et al. (67) performed four consecutive SUMI of acrylate monomers into a trithiocarbonate RAFT agent. Excess (10-fold) monomer was used in the experiments and the degree of oligomerization was controlled by limiting the monomer conversion through short (10 min) reaction times. Automated recycle size exclusion chromatography (SEC) was developed to provide a pure SUMI product after each step.
Thermally-Initiated Sequential RAFT SUMI Zard and co-workers (45) reported consecutive SUMI of NVPI followed by an allyl monomer into a xanthate. We have demonstrated high yields in consecutive SUMI for St followed by maleic anhydride (MAH) (49). Success in this case can be partly attributed to MAH being essentially inert towards the AIBN-derived 2-cyanoprop-2-yl radicals (Figure 5). A key factor contributing to success in both of these examples is the use of a non-homopolymerizable monomer (70) (i.e., kp~0) in the second SUMI step.
82
Figure 5. Scope of RAFT-SUMI for sequential insertion of styrene and a second monomer into 2-cyanoprop-2-yl dithiobenzoate. Attempted SUMI of MAH or maleimide monomers into RAFT agents with R=tertiary cyanoalkyl and AIBN initiation was unsuccessful. The RAFT agent remained largely untouched. However, SUMI of maleimide monomers into the dithiobenzoate with R=tertiary ester 1 with azobis(methyl isobutyrate) (AIBMe) initiation proceeded in very high yield to provide 2 (Figure 6, 60% isolated yield after chromatography).
Figure 6. RAFT-SUMI for insertion of NPMI into (2-methoxycarbonyl)prop-2-yl dithiobenzoate (1) to provide the insertion product 2. However, 2 was unreactive towards RAFT-SUMI of various monomers [methyl acrylate, N,N-dimethylacrylamide (DMAm), styrene (St)] and the RAFT agent being recovered unchanged. PET-RAFT-SUMI (vide infra) of monosubstituted MAMs into maleimide terminal macroRAFT agents was also unsuccessful. The explanation for low reactivity of these RAFT agents in SUMI experiments is still being investigated. We found that the RAFT agent 2 is effective in controlling, e.g., styrene polymerization (Table 1), though some irregularity for short reaction times is apparent, where the higher than expected molar masses may indicate slow utilization of RAFT agent. 83
SUMI of non-homopolymerizable monomers also provides a method of chainend functionalization for RAFT synthesized polymers. MAH (52–55), maleimides (56, 57), β-pinene (57), and ABOC (for a primary amino end-group) (71) have been used in this context.
Table 1. Molar Mass Conversion Data for Styrene Polymerizations (110 °C, Thermal Initiation, No Added Initiator) with RAFT Agent 2
a
Time (h)
Conversion
Mn
Mn(calc)a
Dispersity
1
9.0
2300
3253
1.07 (bimodal)
2
11.4
3600
4003
1.07 (trimodal)
4.5
17.2
6300
5815
1.06
17
55.0
18600
17626
1.08
Mn(calc) = [Styrene]t/[RAFT agent]0+MW(RAFT agent).
SUMI of N-isopropylacrylamide (NIPAm) into the macroRAFT agent formed by SUMI of St into a dithiobenzoate was selective but very slow. However, yields of the desired SUMI product are substantially lowered by the concurrent formation of products from initiator-derived chains (48, 49). This finding has prompted us to investigate RAFT-SUMI of acrylamides in aqueous media and PET-RAFT-SUMI.
RAFT-SUMI of Acrylamides in Aqueous Media
Trithiocarbonates 3 with R=2-carboxyeth-2-yl and Z′S=primary alkylthio (specifically, 4-7) have been shown to be very effective agents for mediating the polymerization of monosubstituted MAMs such as acrylate, acrylamides and styrene providing low dispersities and good molar mass control. The most common RAFT agents of this class are 4 (30 references in ScifinderTM in Jan 2018), 5 (190 references), 6 (24 references) and 7 (144 references). The last three RAFT agents are commercially available. 84
Tertiary cyanoalkyl trithiocarbonates 8 with Z’S=primary alkylthio (e.g., 812) are very effective agents for mediating the polymerization of both mono- and 1,1-disubstituted MAMs. They (8) have substantially higher transfer constants than 3. Amongst the most common RAFT agents of this class (8) are those with R=4-carboxy-2-cyanobut-2-yl, which include 9 (typically in aqueous media, 191 references in SciFinderTM) and 11 (typically in organic media, 340 references). These RAFT agents, along with 10 (5 references), are commercially available.
Some initial experiments on attempted RAFT SUMI in an organic solvent (CD3CN) with trithiocarbonates 5 or 12 are shown in Figure 7. Trithiocarbonate 12 had been successfully used in earlier work (48). With trithiocarbonate 5 (Figure 7a), the reaction rate is very much faster than with 12 and selective SUMI is not observed. Products from SUMI and multiple unit insertion are formed simultaneously even at very low monomer conversion. The final product is an oligomer Xn 1.4. With 5 propagation is rate determining. With trithiocarbonate 12 selective SUMI is seen and oligomeric products from multiple unit insertion are not detected. However, the reaction rate is very much slower. After 1500 min, when the conversion plateaus due to the initiator (AIBN) being largely depleted, only 60% of the initial RAFT agent has been converted to SUMI. Under these condition the rate determining step is the 2-cyanoprop-2-yl radical adding to monomer (48). Note also that relatively high initiator concentrations were used in these experiments. 85
Figure 7. Evolution of species observed by in situ NMR during attempted RAFT SUMI of NIPAm into acid functional trithiocarbonates (a) 5 or (b) 12 in CD3CN at 70 °C. [NIPAm]:[RAFT]:[AIBN]=1:1:0.2. The amount of residual RAFT agent in (b) was estimated as [RAFT est]=1.0-[SUMI]. The amounts of AIBN and TMSN are assumed to be the same as in (a).
The diacid trithiocarbonate 6 was first reported in 2005 when it was shown to be an effective RAFT agent in bulk polymerization of butyl acrylate (BA) (72). 6 was also successfully used to mediate bulk styrene polymerization.73 The RAFT agent is water soluble and suitable for controlling aqueous copolymerization of water soluble styrenic monomers (74). It has also been successfully used to mediate RAFT inverse miniemulsion of acrylamide (Am) (75), acrylic acid (AA) (76) and AA-Am copolymers at various pH in the range 3-10 (77). Partial loss of control was observed for pH >7, which was attributed to the (hydrolytic) 86
instability of the RAFT agent (76). Most recently 6 was used in the synthesis of low dispersity acrylamide multi-block copolymers using a looped flow process (78). With this background, we initially chose 6 as a candidate for performing SUMI of acrylamide monomers (DMAm and NIPAm) in aqueous media. To ensure full solubility in aqueous DMAm at the concentration desired, the RAFT agent 6 was neutralized by addition of two equivalents of Na2CO3. Surprisingly, in an attempted SUMI experiment, we found that the RAFT agent was essentially unreactive and could be observed still largely unchanged by 1H NMR at the end of the experiment, during which period a higher molar mass poly(DMAm) was formed. Under similar conditions, we found that 5- was consumed but provided an oligomeric product consistent with the transfer constant being lower than required for successful SUMI. This result is consistent with the observation made for attempted SUMI in organic media (vide infra). Out of the series of trithiocarbonates, 6=, 5- and 9-, selective SUMI was only observed for 9-, which has a tertiary R group and, consequently, a higher transfer constant in DMAm polymerization (Figure 8).
Figure 8. Scope of RAFT-SUMI for sequential insertion of NIPAm into acid functional trithiocarbonates. An explanation for this behavior is that the transfer constant of the RAFT agent increases in the series 6=kp(n) for each step. It also helps if the product macroRAFT agent formed by SUMI is less active as a photoiniferter than the initial RAFT agent. Since no thermal initiator is used, initiator-derived byproducts (initiatorderived chains, cage products) and a slow rate of reaction caused by poor initiator efficiency – vide infra) are not an issue Products from termination will be formed in amounts consistent with the radical concentrations. With an appropriately (low) rate of photo-initiation this can be controlled. For the second monomer, N-substituted maleimides (N-phenylmaleimide (PMI), N-benzylmaleimide (BMI) and N-ethylmaleimide (EMI)) were selected due to their high reactivity towards propagating radicals with a terminal styrene unit. The maleimides undergo homopolymerization very slowly (85, 86). The PET-RAFT-SUMI experiment was performed with fac-tris[2-phenylpyridinato-C2,N]iridium(III) (fac-[Ir(ppy)3]) as the photoredox catalyst under blue light irradiation. As in the thermally initiated experiments described above, this allowed a 1:1 molar ratio of monomer to RAFT agent to be utilized. Essentially complete conversion was achieved within 48 h. As the third monomer VAc was inserted into the CDTPA-St-PMI using zinc tetraphenylporphyrin (ZnTPP) as photocatalyst under red light irradiation (λmax = 630 nm, 0.4 mW/cm2) with DMSO as solvent [[VAc]:[CDTPA-St-PMI]:[ZnTPP] of 20:1:0.01]. The selection of ZnTPP over fac-[Ir(ppy)3] as photocatalyst was driven by preliminary results that indicated the C-S bond of VAc macroRAFT agents undergo (re)activation by fac-[Ir(ppy)3], which could lead to multiple monomer insertion. RAFT polymerization of VAc using trithiocarbonate RAFT agents with thermal initiation is known to be strongly inhibited, which has been attributed to slow fragmentation of the intermediate radical (87, 88). Thermally initiated RAFT and PET-RAFT of VAc has used xanthate (89, 90) or dithiocarbamate RAFT agents (91–95). In the case of SUMI, processes that disfavour propagation following SUMI are desirable. Experiments were also performed with the non-propagating monomer limonene as third monomer.. 92
The analyses that attest to the success of our sequential PET-RAFT-SUMI experiments are shown in Figure 12 (GPC traces) and Figure 13 (ESI mass spectra).
Figure 12. GPC traces for the products from sequential PET-RAFT-SUMI into CDTPA (11). Traces shown are for CDTPA-St, CDTPA-St-NPMI, CDTPA-St-NPMI-VAc and CDTPA-St-NPMI-Lim. Reproduced with permission from ref (84). Copyright 2017 Wiley-VCH.
Figure 13. ESI-MS spectra for the products from sequential PET-RAFT-SUMI into CDTPA (11). Those shown are for initial SUMI product CDTPA-St (D), dimer CDTPA-St-NPMI (C), and trimers CDTPA-St-NPMI-VAc (B) and CDTPA-St-PMI-Lim (A). Reproduced with permission from ref (84). Copyright 2017 Wiley-VCH. 93
Figure 14. Strategy for producing discrete oligomers by successive SUMI, aminolysis, thiol-Michael addition and esterification steps.
An issue in conducting sequential SUMI of monosubstituted monomers is that the macroRAFT agents formed by SUMI do not have a sufficiently high transfer constant to allow their use in a subsequent selective SUMI experiment. It is necessary to alter of the activity of the macroRAFT agent formed by SUMI. In developing an approach to iterative SUMI, we were inspired by the work of Porel et al. (96–98) who demonstrated a synthesis of discrete oligomers based on successive thiol-ene reactions. Our approach then uses successive aminolysis, thiol-ene and esterification steps to transform the secondary trithiocarbonate end produced by photo-SUMI into a more active tertiary cyanoalkyl trithiocarbonate (Figure 14). The process may be seen to lack elegance and yields are ultimately limited by the efficiency of the isolation steps. Nonetheless, we have demonstrated a new protocol for incorporating the rich functionality of available vinyl monomers into polymers whose sequence is precisely defined at the monomer level. Thus far we have taken the process through three SUMI steps. In the course of this study we demonstrated catalyst-free photo-RAFT-SUMI (green light) in to a range of monosubstituted monomers (acrylates, acrylamides and styrenes) into trithiocarbonate 11 (Table 3). Attempted photo-RAFT-SUMI MMA into 11 under similar conditions was unsuccessful and provided an oligomeric product, which is attributed to the low transfer constant of 11 in MMA polymerization. 94
Table 3. Catalyst-Free Photoinitiated (Green Light) Single Unit Monomer Insertion into Trithiocarbonate (11)a Monomer
Time (h)
[monomer]/[RAFT]
NMR Yield (%)b
Isolated Yield (%)c
MA
24
12
>94
72
HEA
24
15
>95
66
DMAm
24
15
>95
72
NIPAm
24
15
>95
68
TlaAm
22
10
>95
60
PFSt
24
15
>95
80
a Reactions were carried out in DMSO and were degassed by nitrogen sparging. MA – methyl acrylate, HEA – hydroxyethyl acrylate, DMAm – N,N-dimethylacrylamide, NIPAm – N-isopropylacrylamide, TlaAm - thiolactone acrylamide [N-(2-oxotetrahydrothiophen3-yl)acrylamide], PFSt – pentafluorostyrene. b crude yield based on RAFT agent consumed; c isolated yield after purification by silica column chromatography.
The proposed mechanism of photoRAFT-SUMI is shown in Figure 15. Photolysis of the RAFT agent causes reversible dissociation of the C-S bond (iniferter process). The radical (Rˑ) formed can add monomer (or RAFT agent, which is a degenerate process). The radical formed by addition of monomer (R-Mˑ) can combine with a thiocarbonylthio radical to form the SUMI product, It can react with RAFT agent by addition-fragmentation, also to form the SUMI product. It may also add further monomer, which is slow. The relative concentrations of the reacting species dictate that RAFT should be the dominant process.
Figure 15. Mechanism of photoRAFT-SUMI with a trithiocarbonate RAFT agent. 95
In more recent work, we have examined visible light-initiated SUMI of DMAm into trithiocarbonate 10 in aqueous solution (99). This established that selective photoSUMI could be achieved using relatively high monomer concentrations (1 M) and with stoichiometric RAFT agent and monomer. We found that that the specificity for SUMI, over formation of higher oligomers (or byproducts), was strongly dependent on the irradiation wavelength. In particular, red light provided for selective excitation of the initial RAFT agent (10) in the presence of DMAm. This was not possible with blue or green light, which when used gave a conversion plateau at ~60-70% monomer conversion. Red light provided the cleanest reaction product and a linear kinetic profile to high (>80%) conversion, albeit with a much slower rate of reaction.
Conclusions This paper has shown progress in the development of RAFT-SUMI as a pathway discrete oligomers. Thermally initiated RAFT-SUMI represents an important, potentially high yield, route to macroRAFT agents but has obvious limitations as a route to discrete oligomers. Circumstances which allow very low initiator concentrations, such as those that pertain in aqueous polymerization of acrylamides, offer some promise. A big opportunity lies with PET-RAFT-SUMI, which allows one important source of byproducts to be avoided, and we anticipate further developments will quickly follow.
Experimental The procedures and instrumentation used for thermal SUMI not detailed below are described in our previous papers (48, 49). PET-RAFT-SUMI is described elsewhere (84, 100).
Materials The RAFT agents 6 and 10 were obtained from Boron Molecular. The RAFT agents and 5 were obtained from Sigma-Aldrich. Monomers (BA, DMAm, NVP, VAc) were obtained from Sigma-Aldrich and were treated with inhibitor remover (Aldrich) and flash-distilled prior to use as appropriate. NIPAm (Sigma-Aldrich) was purified by recrystallization from hexane/Et2O 4:1. MAH (Sigma-Aldrich) was used as received. The initiator (E)-2,2′-(Diazene-1,2-diylbis(propane2,2-diyl))bis(4,5-dihydro-1H-imidazol-3-ium) chloride (Wako VA-044) was obtained from Novachem and used as received. 1,1′-Azobis(isobutyronitrile) AIBN was obtained from DuPont (VAZO64) and was recrystallized from methanol/chloroform. 4,4′’-Azobis(4-cyanopentanoic acid) was obtained from Sigma-Aldrich. Non-aqueous solvents of high purity were obtained from commercial sources (Acros or Sigma-Aldrich) and used without purification. 96
Thermally-Initiated Sequential RAFT SUMI 2-(2,5-Dioxo-1-phenyl-4-((phenylcarbonothioyl)thio)pyrrolidin-3-yl)-2methylpropanoate (2) Ethyl 2-methyl-2-(phenylthiocarbonylthio)propionate (1) (600 mg, 2.24 × 10-3 mol), N-phenylmaleimide (387 mg, 0.00224 mol), 2,2′-azobis(2methylpropionitrile) (AIBN) (73.42 mg, 0.000447 mol) and acetonitrile (11.4 mL) were combined in an ampoule. The ampoule was degassed by three freeze-pump-thaw cycles, sealed under reduced pressure (9.0 × 10-3 mbar) and subsequently heated at 75 ºC for 21 hours. After cooling the ampoule was opened and the resulting dark red solution concentrated in vacuo. The reaction mixture was further purified using column chromatography (silica gel, eluent gradient 100% pentane -> 100% methylene chloride) to give 634 mg of a crystalline red solid ethyl 2-(2,5-dioxo-1-phenyl-4-((phenylcarbonothioyl)thio)pyrrolidin-3-yl)2-methylpropanoate (2) (yield: 64%). 1H-NMR (400 MHz, CDCl3, δ): 7.92 (dd, J1 = 8.4 Hz, J2 = 1.3 Hz, 2H); 7.59 (tt, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H); 7.34-7.53 (m, 7H); 5.11 (s (br), 1H); 4.21 (m, 2H), 3.46 (d, J = 6.6 Hz, 1H); 1.58 (s, 3H); 1.41 (s, 3H); 1.28 (t, J = 7.1 Hz, 3H). 13C-NMR (100 MHz, CDCl3, δ): 175.54; 174.94; 143.81; 133.50; 132.15; 129.30; 128.93; 128.73; 127.34; 126.61; 61.71; 52.43; 49.61; 45.46; 25.30; 23.83; 14.27. ESI-MS: [M-H+] calc: 442.1141, found: 442.1140.
RAFT Polymerization of Styrene Mediated by Dithiobenzoate 2 A stock solution containing of styrene (4.55 g) and dithiobenzoate 2 (64.3 mg) was prepared in a 10 mL Erlenmeyer flask. Aliquots of this solution (1 mL) were transferred to 4 ampoules and each was degassed by three freeze-pump-thaw cycles, sealed under reduced pressure (9.0 × 10-3 mbar) and heated at 110 ºC for 1, 2, 4.5 and 17 hours respectively. The resulting polymers were diluted with DCM and 3 times precipitated into methanol to obtain a pink polystyrene. The molar mass and dispersity for various monomer conversions are shown in Table 1. RAFT-SUMI of Acrylamides in Aqueous Media 4-Cyano-4-(((ethylthio)carbonothioyl)thio)Pentanoic Acid (9) A 1 L round bottom flask was charged with NaH (13.35 g, 0.334 mol; 60% in oil) and 630 mL Et2O. The suspension was cooled (ice-bath) and stirred vigorously while ethanethiol (20 g, 24 mL, 0.321 mol) was added dropwise. A colour change from grey to yellow was observed. The mixture was stirred for a further 10 min. The crude sodium S-ethyl trithiocarbonate (41.83 g) was collected by filtration, then resuspended in Et2O (500 mL). Iodine (19.95 g) was added to the suspension with vigorous stirring. A colour change from yellow to brown was observed. The solution was washed with Na2S2O3 (5% in water, 3 × 160 mL), Brine (1 × 100 mL) and dried over Na2SO4. The solvent was removed in vacuo and the crude bis-ethyl 97
trithiocarbonate (5 g) was dissolved in ethyl acetate (100 mL) and 4,4’-azobis(4cyanopentanoic acid) (7.68 g, 27.4 mmol) was added with additional ethyl acetate (30 mL). The reaction mixture was degassed by sparging with N2 for 20 min then heated under reflux for 18 h. The mixture was cooled and the solvent removed in vacuo. The product was purified by chromatography on silica gel with 70 : 30 pentane : ethyl acetate + 5% acetic acid as eluent. The solvents were evaporated to leave an orange oil. The product was further purified by recrystallization from carbon tetrachloride (4.51 g, 93.8%). 1H-NMR: δ (ppm) = 3.32 (q, S-CH2-CH3), 3.66 (t, -CH2-CH2-COOH), 2.53-2.37 (m, -CH2-CH2-COOH), 1.86 (s, -CH3), 1.34 (t, -CH2-CH3).
Attempted SUMI of NIPAm into 2-(((Butylthio)carbonothioyl)thio)Propanoic Acid (5) in CD3CN at 70 °C NIPAm (0.1132 g, 1.0004 mmol), 5 (0.2380 g, 0.9984 mmol) and CD3CN (1 mL) were combined in a 10 mL sample vial and AIBN (0.0328 mg, 0.1997 mmol) was added. 0.75 mL of this solution was transferred into a valved NMR tube [the NMR tube was a Wilmad 528-PP-7 NMR tube with a J Young valve fitted, manufactured by GPE Scientific Limited (UK)] and the solution was degassed by freeze-pump-thaw (4 cycles) with the use of dry ice. After the fourth cycle, the NMR tube remained under vacuum and was placed in the NMR probe at ambient temperature (25 °C). The lock was established at 25 °C, The NMR tube was then removed from the probe and the probe is heated to 70 °C. After achieving the desired temperature the NMR tube was loaded into the NMR spectrometer and that time was taken as time zero. After 24 hrs the reaction was quenched by removing the NMR tube from the spectrometer and exposing the mixture to air. Based on integration of the post-reaction NMR spectra the Xn of oligo(NIPAm) was estimated to be ~1.4. The kinetic data obtained in the experiment are reported in Figure 7a.
Automated Sequential Insertion of DMAm RAFT Agent 9 in D2O at 60 °C Using a Chemspeed® Robotic Platform The various stock solutions were prepared and degassed by N2 sparging for ~15 minutes. The RAFT agent stock solution (A, 10 mL) contained the RAFT agent 9 (0.35 g, 1.33 mmol, 0.133 M) and 3-(trimethylsilyl)propionic-2,2,3,3-d4 acid sodium salt (1H NMR reference, 5 mg) in D2O/CD3CN (40%). The first monomer stock solution B (5 mL) contained DMAm (1.15 mL, 11.10 mmol, 2.22 M) in D2O. The second monomer stock solution C (5 mL) contained DMAm (0.23 mL, 2.2 mmol, 0.44 M) in D2O. The initiator stock solution (D, 5 mL) contained VA-044 (65 mg, 0.2 mmol, 0.04 M) in D2O. The stock solutions were placed in the Chemspeed® SLTII sample holder and the chamber was purged with N2 to obtain an inert atmosphere. A first reactor was charged with stock solution A (3 mL), B (0.9 mL) and C (0.1 mL), which was heated to 70 °C and vortexed for 2 h before withdrawing 0.1 mL for analysis. At this stage, stock solution C (0.9 mL) and D 98
(0.1 mL) were added. After 2h of vortexing an aliquot (0.1 mL) was withdrawn for analysis. All analysis samples were immediately dispensed into cool D2O (0.9 mL) to quench further reaction. This process was repeated for all subsequent blocks. GPC data relevant to this experiment is shown in Figure 10.
Acknowledgments Research on thermally initiated SUMI was conducted by MH, PJL and TT while they were present at CSIRO under the industrial traineeship component of their Masters degrees at Eindhoven University of Technology. Research by JJH was carried out as part of his PhD program at Hasselt University while on an exchange visit to CSIRO, which was in part funded under a CSIRO Newton-Turner Award provided to GM. We are grateful to Roger Mulder and Jo Cosgriff for assistance with NMR spectroscopy and to Ben Muir and Shaun Howard for assistance in designing and conducting the high throughput (Chemspeed®) experiments. PET-RAFT-SUMI experiments were largely conducted by JX, Changkui Fu and Sivaprakash Shanmugam (84) or Changkui Fu and Zixuan Huang (100) at CAMD UNSW under the supervision of CB as part of an informal collaboration also involving Craig Hawker (University of California Santa Barbara) and GM.
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