Continuous Flow Aminolysis of RAFT Polymers Using Multistep

Article pubs.acs.org/Macromolecules

Continuous Flow Aminolysis of RAFT Polymers Using Multistep Processing and Inline Analysis Christian H. Hornung,* Karin von Kan̈ el, Ivan Martinez-Botella, Maria Espiritu, Xuan Nguyen, Almar Postma, Simon Saubern, John Chiefari, and San H. Thang CSIRO Manufacturing Flagship, Bag 33, Clayton South, Victoria 3169, Australia S Supporting Information *

ABSTRACT: The reversible addition−fragmentation chain transfer (RAFT) method enables the synthesis of polymers with well-defined architecture and narrow molar mass distribution. Simple postpolymerization reactions using amines and Michael acceptors make it possible to conjugate RAFT polymers to a variety of active small molecules and macromolecules. Herein we demonstrate an efficient continuous flow process for aminolysis of RAFT polymers and subsequent Michael addition reactions, using continuous flow reactors, resulting in either thiolor thioether-terminated polymer chains. After initial reaction optimization we managed to achieve the following: (1) establishment of an integrated flow process, which is capable of producing free thiol containing polymer without the formation of disulfide byproduct; this was achieved by means of an inline, amine scavenging process post-aminolysis using a polymer supported column; (2) the application of UV spectroscopy for inline monitoring of the continuous flow aminolysis reaction; (3) establishment of a simple two-step flow process for the polymerization and subsequent end-group removal by aminolysis; this was achieved by using two continuous reactor units in series in which the residual monomer from the polymerization acted as the Michael acceptor to cap the thiol after aminolysis.

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INTRODUCTION Reversible addition−fragmentation chain transfer (RAFT) polymerization is a reversible deactivation radical polymerization (RDRP) process that has shown great tolerance to reaction conditions, compatibility with most monomers, and capability to provide polymers with defined structures, narrow molecular weight distributions, and defined end-groups.1−5 Removal or transformation of the thiocarbonylthio end-group of RAFT polymers is often desirable for several reasons. The presence of the thiocarbonylthio group gives rise to color, in some cases it produces odor, it is intrinsically reactive, and it has the capacity to quench fluorescence;6,7 and further, even though some early studies indicated low to no cytotoxicity of RAFT-synthesized polymers,8−12 the removal of the thiocarbonylthio end-group may still be warranted for some biological applications. One of the advantages of the RAFT process is that it allows for the easy access to thiol end-functional polymers which have seen an increase in use for bioconjugation.13−15 The transformation of the thiocarbonylthio end-group of RAFT polymers to a thiol can be approached through a variety of methods, and these have been captured in several reviews,16,17 including reactions with nucleophiles (amine,18−20 hydroxide,21 thiols,22 azide23) and borohydrides21,24−27 to provide a thiol end-group. Other methods are also available to transform the RAFT end-group; these include radical-induced reduction (to provide a hydrocarbon end-group),28,29 radical exchange,30−32 treatment with oxidizing agents,33−35 UV irradiation,36,37 and thermolysis.38−47 Published 2014 by the American Chemical Society

An issue with thiol end-groups is that they form disulfides, particularly under oxidative conditions in the presence of base. Once formed, they can be reduced to thiol groups via reduction with zinc in acetic acid42 or tris(2-carboxyethyl)phosphine (TCEP).48,49 The formation of disulfides can also be avoided by the use of reducing agents (sodium dithionite, sodium bisulfite, or phosphines)42,43,48,49 during the aminolysis reaction. Alternatively, the formed thiol can be immediately capped via a Michael addition with a Michael acceptor such as an acrylate or methacrylate in a one-pot reaction.50,51 Interestingly, the use of hydrazine as a nucleophile has been successfully applied in air without the use of a reducing agent or thiol capture, giving minimal disulfide formation.52 In the past few years, continuous flow chemical processing53−62 has found a widespread uptake in organic chemistry research laboratories, especially where translation from lab discovery to production was of focus. As part of this development, the synthesis of polymers was also investigated using this technology, and the benefits of continuous flow microreactors for polymerizations have been published by several research groups.63−65 One of the first examples of solution phase radical polymerization in a specialized continuous microreactor system was conducted by Iwasaki and Yoshida.66 More recently, Received: August 7, 2014 Revised: October 5, 2014 Published: November 24, 2014 8203

dx.doi.org/10.1021/ma501628f | Macromolecules 2014, 47, 8203−8213

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continuous flow processing has been used for the synthesis and modification of RAFT polymers,67−72 including work undertaken by our own group.73−76 As part of our research activities in the RAFT polymer area, we recently investigated the removal of the thiocarbonylthio end-group of these polymers using either a radical-induced process, thermolysis, or aminolysis at moderate temperatures in a tubular continuous flow reactor.46,77,78 Herein we describe an alternative flow process for the transformation of RAFT end-groups into thiols via aminolysis, limiting polymer− polymer coupling through disulfide formation by either (1) excess amine capture or (2) end-capping the free thiol through Michael addition. A continuous flow approach, such as the one described herein, can provide a solution for reproducibly synthesizing gram or kilogram quantities of aminolyzed and capped polymers with well-defined architectures, which is otherwise difficult to achieve using standard batch processes. In one set of examples, we present a very simple, yet efficient sequential process to synthesize a low dispersity, unreactive, and RAFT end-group free polymer, without the use of expensive reagents or the need for manual handling of intermediates. Furthermore, the addition of UV−vis monitoring allowed us to implement simple online quality control of the continuous aminolysis process. Continuous processing in the herein described tubular and fixed bed column flow reactor modules is the enabling technology, which allows for the synthesis and modification of RAFT polymers to be carried out in an efficient and integrated manner, suitable for scale-up to production scale.

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Reaction conversions were calculated from 1H NMR spectra. 1,3,5Trioxane was used as an internal standard for calculating the conversion of polymerization. UV spectroscopy was used to measure the disappearance of the strongly UV-active RAFT end-group; hence, we used offline UV spectroscopy to verify the NMR results and inline UV spectroscopy to monitor the continuous flow aminolysis directly at the reactor outlet. Number-average molecular weight of the polymers (Mn) and their dispersity (Đ) were measured using size exclusion chromatography (SEC). Molecular weight distributions of the oligomers were measured by matrix-assisted laser desorption ionization (MALDI). For more details on analysis see the Supporting Information. Batch Synthesis of RAFT Oligomers and Polymers. The following procedure is typical for the preparation of oligomers. A reactant solution of DMA monomer (2776 mg), AIBN initiator (46.0 mg), and RAFT agent 2 (782 mg) in MeCN (1.1 mL) was premixed and deoxygenated using nitrogen purging. The reaction was conducted in a laboratory microwave reactor (Biotage Initiator) at 65 °C with a reaction time of 30 h. An intensely red, viscous oligomer solution was obtained, from which conversion was determined by NMR; the solvent was evaporated under reduced pressure to yield a red polymer foam. This foam was purified by multiple precipitations from chloroform into heptane (three times) followed by multiple precipitations from chloroform into a 4:1 diethyl ether/heptane mixture (three times), resulting in a pink powder. For synthesis of RAFT polymers in batch, a similar experimental protocol was used with lower amounts of RAFT agent and initiator, a shorter reaction time, and with the difference that the precipitation procedure was significantly simpler and less laborious for polymers than it was for oligomers, primarily due to differences in solubility. All but one polymer were synthesized in batch as described above; for a procedure of the RAFT polymerization using a Vaportec R-series reactor in continuous flow please refer to earlier work.73 Detailed reaction conditions and reagent compositions for each polymer prepared can be found in Table 2 (vide inf ra). Aminolysis and Capping in a Batch Microwave Reactor. The following procedure is typical of trapping a thiol-terminated polymer or oligomer using a Michael acceptor. A 5 mL microwave vial fitted with a magnetic stirrer bar was charged with pNIPAM (201.8 mg, 0.033 mmol), MA (59.0 mg, 0.685 mmol, 20 equiv), and MeCN (3 mL). The yellow solution was deoxygenated in the sealed microwave vial by nitrogen purging for 20 min. Subsequently, HA (34.5 mg, 0.341 mmol, 10 equiv) was added to the solution, which turned light yellow. The solution was purged with nitrogen for a further 5−10 min, before it was heated in a Biotage initiator microwave at 80 °C for 2 h. On cooling, a colorless solution was collected; the solvent was evaporated under reduced pressure to yield a colorless polymer film, which was purified by precipitation in diethyl ether, resulting in a white polymer powder. Detailed reaction conditions and reagent compositions can be found in Tables 1 and 3 (vide inf ra). Aminolysis on a Polymer Supported Column in Continuous Flow. A Vaportec R-series reactor was fitted with a fixed bed glass column (Omnifit, o.d.: 11.3 mm; i.d.: 6.6 mm; maximum operating pressure: 900 psi) filled with DETA (250 mg) mixed with sand (250 mg, 50−70 mesh). A 100 psi backpressure regulator was positioned inline after the reactor column in order to prevent solvent from boiling off. Solvents and reagent solutions were deoxygenated by nitrogen purging. The reactor was flushed with deoxygenated MeCN, before loading the reagent solution containing pNIPAM (100 mg, 0.015 mmol) in MeCN (1 mL). The reagent solution was pumped through the reactor at a flow rate of 0.1 mL/min while heating the reactor bed to 80 °C. The product stream was collected as a colorless solution; the solvent was evaporated under reduced pressure to yield a colorless polymer film, which was purified by precipitation in diethyl ether, resulting in a white polymer powder. Detailed reaction conditions and reagent compositions can be found in Table 3 (vide inf ra). Aminolysis and Capping in a Tubular Continuous Flow Reactor. The following procedure is typical. A Vaportec R-series reactor was fitted with 4 × 10 mL reactor coils in series. The two reagent solutions were mixed in a T-piece upstream of the reactor and then fed into the reactor coils, which were heated to 80 °C. Solvent and

EXPERIMENTAL SECTION

Materials and Analysis. All solvents and reagents were used without further purification unless stated otherwise. The following initiators were used for the polymerizations: azobis(isobutyronitrile) (AIBN, supplied by Acros), 1,1′-azobis(cyanocyclohexane) (supplied by DuPont as Vazo 88), and 2,2′-azobis(2-methylbutyronitrile) (supplied by DuPont as Vazo 67). RAFT agents 1 and 3 were synthesized in our group,79,80 and RAFT agent 2 was purchased from Sigma-Aldrich (see Figure 1). The monomer N-(2-hydroxypropyl) methacrylamide

Figure 1. RAFT agents used for the synthesis of polymers and oligomers. (HPMA) was obtained from Polysciences Inc.; the monomers N-isopropylacrylamide (NIPAM), N,N-dimethylacrylamide (DMA), methyl methacrylate (MMA), poly(ethylene glycol) methyl ether acrylate (PEGA, average Mn = 480 g/mol), tert-butyl acrylate (tBA), and methyl acrylate (MA) were obtained from Sigma-Aldrich. With the exception of NIPAM and HPMA all monomers were pretreated using polymer resin (for removal of hydroquinone and monomethyl ether hydroquinone, Sigma-Aldrich, Cat. No: 31,133-2) in order to remove the polymerization inhibitor. The reagents hexylamine (HA), phenylmaleimide (PMI), and the polymer supported reagents Quadrapure benzylamine (particle size: 400−1100 μm; loading: 20 mg/g) (PS-BZA), p-toluenesulfonyl hydrazide resin (100−200 mesh, loading: 2−3 mmol/g) (PS-HYD), and Amberlite IR-120 (particle size: 300−1180 μm, 14−52 mesh) were obtained from Sigma-Aldrich; the polymer supported amine StratoSpheres PL diethylenetriamine resin (particle size: 150−300 μm; loading: 8.0 mmol/g) (PS-DETA) was obtained from Polymer Laboratories Ltd. The solvents acetonitrile (MeCN), diethyl ether, and heptane were obtained from Merck KGaA. 8204


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reagent solutions were deoxygenated by nitrogen purging. The reactor was flushed with deoxygenated MeCN, before loading the reagent solutions. The first solution contained pNIPAM (266.5 mg, 0.044 mmol) and MeCN (2 mL); the second contained MA (229.5 mg, 2.667 mmol, 20 equiv), HA (268.6 mg, 2.654 mmol, 20 equiv), and MeCN (5.4 mL). Both solutions were pumped at 0.333 mL/min, which resulted in a combined flow rate of 0.666 mL/min and a reaction time of 60 min. The line delivering the amine solution was turned on and switched off before the line delivering the polymer solution, making sure that there was always an excess of amine. The product stream was collected as a colorless solution; the solvent was evaporated under reduced pressure to yield a colorless polymer film which was purified by precipitation in diethyl ether, resulting in a white polymer powder. Detailed reaction conditions and reagent compositions can be found in Table 3 (vide inf ra). In some experiments (entry 3.9), a packed bed using polymer supported sulfonic acid (Amberlite IR-120) was situated inline after the reactor coils in order to scavenge excess amine left over from the reaction. Polymerization, Aminolysis, and Capping in a Two-Stage Continuous Flow Reactor. The following procedure is typical for a two-stage process combining polymerization and aminolysis (see also Two-Stage Continuous Flow Process section): A Vaportec R-series flow reactor system was fitted with a set of two steel reactor coils (i.d.: 1 mm), operated in series. A 100 psi backpressure regulator was positioned inline after the second reactor coil in order to prevent solvent from boiling. The polymerization was performed in the first coil (10 mL) heated to 80 °C and the aminolysis in the second coil (10 mL) heated to 60 °C. The monomer solution was fed into the first reactor coil, and the amine solution was fed in via a T-piece between the first and second coil. The flow rate was set to 0.111 mL/min, each resulting in a reaction time of 90 min for the polymerization and 45 min for the aminolysis. Before the start of the reaction, deoxygenated MeCN was used to flush the reactor. Solvent and reagent solutions were deoxygenated by nitrogen

purging. The monomer stock solution consisted of NIPAM monomer (566 mg), AIBN initiator (2.5 mg), and RAFT agent 1 (30.3 mg) in MeCN (2.4 mL), and as an amine stock solution HA (1 M in MeCN) was used. A colorless polymer solution was obtained after the reaction. Following solvent removal and redissolving in dichloromethane, the product was precipitated in diethyl ether, resulting in a white polymer powder after filtration. After work-up, the conversion was determined by NMR. Detailed reaction conditions and reagent compositions can be found in Table 4 (vide inf ra).

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RESULTS AND DISCUSSION Aminolysis of RAFT Oligomers. At first we wanted to establish conditions for aminolysis of oligomers, which could be used as a model study that is easy to evaluate by NMR and MALDI. For this we used a system containing the monomer DMA, the RAFT agent 2, and the initiator AIBN. The synthesis of the oligomer progressed very slowly, when compared to a polymer using the same monomer, RAFT agent, and initiator; and the precipitation following synthesis is also significantly more complicated. The reason for this is the high ratio of RAFT agent to monomer (monomer:RAFT:initiator = 100:10:1). After 30 h at 65 °C, only 42% conversion of monomer was achieved, and at that point, the reaction had started to progress very slowly, if at all. The pink oligomer product obtained after precipitation had an average of 5.2 repeat units and an average molecular weight, Mn, of 794 g/mol. It was then used as the starting material for a series of aminolysis reactions at 80 °C (see Scheme 1). In a one-pot procedure, the thiocarbonylthio end-group was first reacted with hexylamine to form a thiol, which was then reacted with a Michael acceptor, to form a thio ether. The Michael addition step is base catalyzed, and in this one-pot procedure the

Scheme 1. Aminolysis Followed by Capping via Michael Addition of a Dithiobenzoate End-Group Containing DMA Oligomer

Table 1. Experimental Conditions and Results for the Aminolysis and Michael Addition of RAFT Oligomers Using Different Capping Agents entry 0 (SM) 1.1 1.2 1.3 1.4

capping agent

T [°C]

t [min]

aminolysis conversionb [%]

average no. of repeat unitsc

Mnc [g/mol]

MA tBA PEGA PMI

80 80 80 80

120 120 120 120

98 ∼100 99 84

5.2 ± 0.2 5.3 ± 1.0 4.9 ± 0.9 c c

794 ± 15 769 ± 94 773 ± 89

a

a

Entry 0 contains data from the oligomer starting material (SM), which was used in the aminolysis experiments in entries 1.1 to 1.4. bThe Michael addition resulted in complete conversion in all cases, based on the available thiol groups formed by the aminolysis. cThe average number of repeat units in the oligomer chain was determined by 1H NMR, and Mn was derived from that value; the error values were derived from the NMR calculations and are based on standard deviation; for entry 0 the error was ±3%a series of sharp phenyl signals from the RAFT end-group were used as reference; for entries 1.1 and 1.2 the error was ±18%the methyl- and tert-butyl-signals from the capping agent were used as reference; for entries 1.3 and 1.4 the 1H NMR spectra did not allow for determination of Mn using the above-described method. 8205


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Figure 2. 1H NMR spectra before and after aminolysis; the signals associated with the RAFT end-group (phenyl group and CH− group, situated within the polymer backbone adjacent to the dithio benzoate) are highlighted in red; the signals associated with the capping agents (MA, tBA, PEGA, and PMI) are highlighted in blue.

possible to monitor the changes at the RAFT-group containing end of the chain by 1H NMR, which is very difficult or impossible in the case of high molecular weight polymers. Past experience has shown that a practical limit for quantitatively determining changes at the end-group of polymers by using 1H NMR lies between 50 and 100 repeat units, and this is highly dependent on the type of monomer and the end-group and if these signals overlap. The information gathered from this set of oligomer experiments laid down the basis for further investigations with polymers with an Mn between 6000 and 20 000 g/mol. Aminolysis of RAFT Polymers. The next step was to optimize the conditions for aminolysis of longer chain polymers. Following on from the protocols described above, a set of seven different polymers were synthesized using the RAFT agents 1−3 (see Figure 1), the monomers NIPAM, HPMA, DMA, and MMA, and the initiators AIBN, Vazo 67, and Vazo 88. The reaction conditions and characterization results for these polymerizations are listed in Table 2. In one set of experiments, these polymers were reacted under aminolysis conditions to transform the thiocarbonylthio group into a free thiol (see scheme in Figure 4). In another set of experiments, the resulting thiol was reacted further using a capping agent to form a thio ether (entries 3.12−3.23), in a similar fashion as with the oligomers in Table 1. Table 3 presents results from a set of experiments on the aminolysis of the polymers A to G, listed in Table 2, and Figure 5 shows SEC traces of a selection of these polymers before and after reaction. The experiments were carried out in one of three different reaction environments: in continuous flow in a tubular

excess amine left over from the aminolysis acts as the catalyst. Table 1 contains the reaction conditions and analysis data of these experiments. The conversion of the aminolysis reactions followed by Michael addition was high for all samples and close to completion for samples 1.1 to 1.3 (see Table 1). In the case of entry 1.3 the product was a DMA-PEG diblock, consisting of an average of ∼5 DMA repeat units linked via a thio ether two an average of 10−11 ethylene glycol units. Figure 2 shows 1H NMR spectra of the oligomer before and after reaction (all entries in Table 1); the characteristic signals for the disappearing RAFT end-group are highlighted in red, and the signals of the respective capping agent product are highlighted in blue. As a side product of the aminolysis reaction, N-hexylbenzothioamide was formed, which could be isolated by column chromatography from the supernatant obtained after precipitation; the structure was confirmed by literature,81 and a 1H NMR spectrum can be found in the Supporting Information (Figure S1). Figure 3 shows a MALDI spectrum of one of the samples, namely entry 1.2, which was capped with tBA. Here the distribution of different chain length oligomers can be observed, ranging from 2 to 8 repeat units, all of which contained the thioether-linked tert-butyl ester end-group. The observed masses correspond well with the theoretical molecular weights of these oligomers (theoretical values calculated for [M + Na]+). The herein described aminolysis experiments using small molecular weight oligomers gave us a more detailed understanding of the underlying processes. Because of the small number of DMA repeat units, it was 8206


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Figure 3. MALDI spectrum of DMA oligomer capped with tBA (entry 1.2).

Table 2. RAFT Polymers and Their Synthesis Conditions (These Polymers Were Used in the Aminolysis Experiments Below) polymer

monomer

RAFT agent

cmona [mol/L]

molar ratio M/R/Ib

T [°C]c

t [min]

conv [%]

Mn [g/mol]

Đ

A B C Dd E F G

NIPAM HPMA DMA DMA MMA NIPAM DMA

1 1 1 2 2 3 3

2.5 2.5 4.0 3.0 3.0 2.8 3.5

100/1.5/0.30 100/1.5/0.30 100/1.0/0.10 100/1.2/0.30 100/1.6/0.35 100/2.0/0.35 100/0.5/0.10

80 80 80 100 80 80 85

120 150 60 360 600 180 60

93 78 99 85 85 97 98

6700 7800 8900 9100 7300 10100 19300

1.06 1.13 1.11 1.22 1.06 1.07 1.19

a All polymers were synthesized using MeCN as solvent. bMolar ratio of monomer to RAFT-agent to initiator (M/R/I). cPolymers A to C were synthesized using AIBN as initiator, polymer D was synthesized using Vazo 88, and polymers E to G were synthesized using Vazo 67. dPolymer D is the only example that was synthesized in the tubular continuous flow reactor; all others were synthesized in a batch microwave reactor.

reactor (TFR), in continuous flow on a fixed bed column using polymer supported reagents (PSC), and in batch on a microwave reactor (BMW) (see Figure 4). A set of different amines were used in these reactors: hexylamine (HA) for homogeneous liquid phase reactions in the TFR and the BMW and the three polymer supported reagents, Quadrapure benzylamine (PS-BZA), diethylenetriamine resin (PS-DETA), and p-toluenesulfonyl hydrazide resin (PS-HYD) in the PSC (see Figure 4). For entries 3.12 to 3.23 one of the following capping agents was usedPMI, DMA, MA, and tBAand for entry 3.9 an Amberlite IR-120 acidic scavenger column was set up inline after the TFR in order to remove excess amine after reaction. The reactions were carried out at 60 or 80 °C, and the reaction times in the BMW and TFR were set to 30, 60, or 120 min. Because it is not possible to accurately determine the residence time of the polymer solution on the PSC, for this set of experiments only the flow rate is reported. Several observations were made during the course of these experiments. First, it was found that the amine source has a great influence on conversion and rate of reaction, with the liquid HA being much more reactive than any of the three polymer supported reagents. Among the latter, PS-DETA gave the best results. Comparable results between HA and PS-DETA were only achieved at the cost of using a much larger excess of amine

reagent and higher temperatures (compare entries 3.1, 3.4, 3.5, and 3.6). The lower activity of the polymer supported amines is believed to be due to one or a combination of the following issues: (1) Other than the liquid HA, the amine group of the supported reagents is attached to a solid surface, and the resulting heterogeneous process, including diffusion and adsorption and desorption steps, is assumed to be significantly slower than the homogeneous reaction with HA. (2) The steric hindrance of the relatively large polymer chains makes the heterogeneous process even less efficient. (3) The short contact time of the polymer solution on the relatively densely packed column is not long enough to progress the reaction to high conversions. [This contact time was limited by the flow rate of our pumps. The pumps used in our experimental configuration have a lower limit of 0.1 mL/min; hence, we could not investigate longer contact times as the ones reported herein.] Further optimization of the heterogeneous process using supported amine reagents could improve the performance of this system. When using HA, the conversion was generally close to 100%, and there was no significant difference in performance between the BMW and the TFR (e.g., compare entries 3.7, 3.8, 3.18, and 3.19). In all high conversion reactions, the resulting product was colorless and for most samples the values for Mn and Đ only changed marginally compared to before reaction. However, there was a difference 8207


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Figure 4. Aminolysis of RAFT polymers using different reactors and amine sources.

Table 3. Experimental Conditions and Results for the Aminolysis of RAFT Polymers entry

polymer

process/ reactor

amine/equivalents

capping agent/scavenger

T [°C]

t [min]/ flow rate [mL/min]a

convb [%]

Mn [g/mol]

Đ

3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.18 3.19 3.20 3.21 3.22 3.23

A pNIPAM A pNIPAM A pNIPAM A pNIPAM B pHPMA B pHPMA C pDMA C pDMA C pDMA D pDMA D pDMA D pDMA D pDMA D pDMA D pDMA E pMMA F pNIPAM F pNIPAM G pDMA G pDMA G pDMA G pDMA

batch−BMW flow−PSC flow−PSC flow−PSC batch−BMW flow−PSC batch−BMW flow−TFR flow−TFR flow−PSC flow−PSC batch−BMW batch−BMW batch−BMW batch−BMW batch−BMW batch−BMW flow−TFR batch−BMW flow−TFR flow−TFR flow−TFR

HA 20 equiv PS-BZA 60 equiv PS-DETA 60 equiv PS-DETA 180 equiv HA 20 equiv PS-DETA 180 equiv HA 5 equiv HA 8 equiv HA 8 equiv PS-DETA 120 equiv PS-HYD 120 equiv HA 10 equiv HA 10 equiv HA 10 equiv HA 10 equiv HA 10 equiv HA 10 equiv HA 20 equiv HA 15 equiv HA 10 equiv HA 10 equiv HA 20 equiv

none none none none none none none none scavenger: Amberlite none none capping agent: PMI 10 equiv capping agent: DMA 10 equiv capping agent: MA 20 equiv capping agent: tBA 20 equiv capping agent: tBA 20 equiv capping agent: MA 20 equiv capping agent: MA 20 equiv capping agent: MA 30 equiv capping agent: MA 20 equiv capping agent: MA 20 equiv capping agent: MA 20 equiv

60 80 80 80 60 80 60 60 60 80 80 80 80 80 80 80 80 80 80 80 80 80

30 min 0.1 mL/min 0.1 mL/min 0.1 mL/min 30 min 0.1 mL/min 30 min 30 min/0.33 mL/min 30 min/0.33 mL/min 0.05 mL/min 0.05 mL/min 60 min 120 min 120 min 120 min 120 min 120 min 60 min/0.67 mL/min 120 min 60 min/0.67 mL/min 120 min/0.33 mL/min 60 min/0.67 mL/min

∼100/− 17/− 45/− 80/− 75/− 71/− ∼100/− ∼100/− ∼100/− 70/− 19/− ∼100/78 ∼100/0 ∼100/93 84/∼100 60/∼100 ∼100/∼100 ∼100c/∼100 ∼100/∼100 97c/40 99c/65 ∼100c/54

6700 6400 7200 6700 8200 7700 9300 11100 7400 11000 9000 8900 11400 9600 10200 7300 6200 6800 12000 14300 13200 13400

1.15 1.16 1.16 1.15 1.18 1.14 1.15 1.18 1.12 1.24 1.20 1.21 1.27 1.19 1.17 1.15 1.09 1.09 1.12 1.19 1.17 1.20

a For BMW a reaction time is reported, for TFR the flow rate through the reactor and a mean residence time is reported, and for PSC accurate reaction/residence times could not be calculated; hence only the flow rate is reported. bConversion of aminolysis/Michael addition (for reactions where a capping agent was used), the second set of values are based on the available thiol groups formed by the aminolysis. cIn addition to the NMR measurements, the conversion of these experiments was also measured online, using a UV detector which was placed in line with the continuous flow reactor.

additional inline acidification step. This integrated flow process is capable of producing free thiol containing polymer without the formation of disulfide byproduct, which is an inherent problem for such aminolysis reactions.16,82 The oxidative formation of disulfide bonds between thiol-terminated polymer chains can proceed with atmospheric oxygen and in the presence of a base catalyst such as HA. Figure 5a shows SEC traces of

between samples that were only reacted with amine (entries 3.1 to 3.11) and those where also a capping agent was added (entries 3.12 to 3.23) (vide inf ra). By incorporating either a scavenging or a capping step as well as online monitoring into our continuous flow process, we could further intensify the aminolysis reaction of RAFT polymers. Figure 6 portraits a continuous flow aminolysis setup with an 8208


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Figure 5. SEC traces from polymer samples before (dashed lines, see Table 2) and after aminolysis (solid lines, see Table 3); some of these traces were corrected using Mn values obtained by UV spectroscopy and 1H NMR.

Figure 6. Continuous flow setup for the aminolysis of RAFT polymers using a fixed bed column filled with polymer supported acidic scavenger (Amberlite IR-120).

SEC traces, shown in the diagram in Figure 5b, which compares the results from the polymer before and after aminolysis in the TFR, once with and once without the scavenger column. Without the Amberlist scavenger, large amounts of disulfide have formed, while the experiment with the scavenger column did not show any evidence of disulfide. A second approach to suppress disulfide formation is the already discussed Michael addition (see Aminolysis of RAFT Oligomers section). A series of different Michael acceptors have been investigated as capping agents, including acrylates, PMI, and DMA. MA, tBA, and PMI resulted in efficient capping of the

pNIPAM before and after aminolysis without capping agent or scavenger (entries 3.1 and 3.4). The large shoulder around 13 000 g/mol can be attributed to the disulfide byproduct, which has roughly twice the Mn of the polymer before reaction. Using the TFR setup shown in Figure 6, complete suppression of this side reaction was achieved by inline neutralization of the polymer solution directly after aminolysis using a fixed bed column filled with polymer supported acid (Amberlite IR-120) (entry 3.9). The acid column conveniently removed the excess amine before the solution was exposed to air, and disulfide formation could take place. The success of this approach is clearly visible in the 8209


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Scheme 2. Aminolysis of Polyacrylamides Synthesized with a Bisfunctional RAFT Agent

Figure 7. Continuous flow setup for the aminolysis of RAFT polymers using inline UV spectrometry for conversion monitoring; photos and UV spectra show pNIPAM (entry 3.19), before and after reaction.

agent), while the corresponding thiol- and thioether-terminated polymers are colorless/white. We investigated this color change as a means of monitoring reaction progress, using offline and inline spectroscopy. The maximum absorbance of polymers F and G made with RAFT agent 3 lies around 309 nm; hence, we used an HPLC type UV spectrometer (Waters 490E programmable multiwavelength detector) inline after the tubular flow reactor to monitor reaction conversion during the continuous process (see Figure 7 and also Figure S2). Because of the sensitivity of the UV detector, the quantitative inline analysis was more accurate than 1H NMR. For entries 3.19, 3.21, 3.22, and 3.23, the reaction conversion was measured successfully using this method, though all results were additionally confirmed by 1H NMR. Two-Stage Continuous Flow Process: RAFT Polymerization and Aminolysis. In addition to the single stage flow process, we investigated a sequential approach consisting of polymerization and aminolysis in one synthesis line. Here we conducted the polymerization in a first tubular steel reactor at 80−85 °C and the aminolysis in a second reactor (either TFR or PSC)

thiol, while DMA (entry 3.13) did not react, which we believe is due to the lower reactivity of acrylamides in Michael reactions. Figure 5c shows the SEC traces of one example: pMMA capped with tBA. The traces before and after aminolysis look very similar, and there is no high molecular weight shoulder which would otherwise indicate disulfide formation. We also investigated the aminolysis of polymers made with the bisfunctional RAFT agent 3 (see Table 2, polymers F and G). Upon aminolysis and capping by Michael addition, these polymer chains break down into two smaller fragments of roughly half the length (entries 3.18 to 3.23), as shown in Scheme 2. Figure 5d shows the SEC traces of pNIPAM, which was synthesized with this RAFT agent and then reacted either in the BMW or the TFR. As it was capped with MA, there is no evidence of disulfide formation, and the peak molecular weights have roughly halved (from 11 800 to 6700 g/mol) after aminolysis. The aminolysis reaction of thiocarbonylthio end-group containing polymers is accompanied by a very distinctive color change. The presence of the thiocarbonylthio group usually leads to intense yellow or red/pink polymers (depending on RAFT 8210


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Figure 8. Two-stage continuous flow process: RAFT polymerization followed by aminolysis and Michael addition to form thioether-terminated polymers.

Table 4. Experimental Conditions and Results for the Two-Step Process: RAFT Polymerization and Aminolysis, with or without End-Capping entry

monomer

RAFT agent

amine

Ta [°C]

tb [min]

flow ratec [mL/min]

convd [%]

Mn [g/mol]

Đ

4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8

NIPAM NIPAM HPMA HPMA DMA DMA DMA MA

1 1 1 1 1 1 3 3

HA PS-DETA HA PS-DETA HA PS-DETA HAe HAe

80/60 80/80 80/60 80/80 80/60 80/80 85/80 85/80

90/45 90/− 150/75 150/− 60/30 60/− 85/60 85/60

0.11/0.22 0.11/0.11 0.07/0.13 0.07/0.07 0.17/0.33 0.17/0.17 0.24/0.34 0.24/0.34

82/∼100/− 89/32/− 72/∼100/− 70/52/− 90/∼100/− 93/63/− 99/∼100/∼100e 91/∼100/∼100e

6400 6100 6800 6400 5300 5200 10700 9200

1.08 1.10 1.14 1.13 1.10 1.16 1.11 1.10

a Reaction temperature of polymerization/aminolysis. bReaction time of polymerization/aminolysis, for reactions with solid supported reagents an accurate reaction time could not be calculated. cFlow rate through polymerization/aminolysis reactor unit. dConversion of polymerization/ aminolysis/Michael addition, the last was calculated for entries where a capping agent was used and is based on the available thiol groups formed by the aminolysis. eMA was used as a capping agent.

Figure 9. SEC traces of polymers prepared using the two-stage continuous flow procedure: (a) entry 4.7−pDMA, capped with additional MA; (b) entry 4.8−pMA, capped with residual MA left over from polymerization.

situated in-line directly after the polymerization at 60−80 °C. This configuration enabled the synthesis of RAFT end-group free polymer product in a single operation without isolation and manual handling of intermediates. Figure 8 shows a schematic flow diagram of the two-step process, Table 4 shows the reaction conditions and polymer characterization results, and Figure 9 shows SEC traces of two examples.

The conversion column in Table 4 has values for the polymerization, the aminolysis, and the Michael addition (only for entries 4.7 and 4.8). All three conversions were calculated from 1H NMR, by either integration of the residual monomer peaks, the characteristic peaks associated with the RAFT endgroup or the peaks associated with MA, which appear after capping. For some samples it was difficult to follow all three 8211


Macromolecules conversions at once; hence, offline UV spectroscopy (for aminolysis) and SEC (for monitoring disulfide formation) were used to verify the 1H NMR results. With the exception of HPMA, the polymerization progressed to high conversions between 80 and 100%, and with the exception of the reactions conducted in a PSC, the aminolysis progressed to full conversion. The two examples where also the capping agent MA was present (entries 4.7 and 4.8) resulted in full conversion to the thioetherterminated product. The average molecular weight of the samples in Table 4 was between 5200 and 10 700 g/mol, and all polymers observed a low dispersity of around 1.1. While entry 4.7 required additional MA to be fed into the system together with the amine, this was not necessary for entry 4.8; here the residual MA monomer left over from the polymerization step was used to from the Michael adduct after the thiocarbonyl thio endgroup was transformed to a thiol in the aminolysis reactor. The SEC traces of these two samples showed no evidence of disulfide formation. The pMA example presents a very simple, yet efficient sequential process to synthesize a low dispersity, unreactive and RAFT end-group free polymer, without the use of expensive reagents or the need for manual handling of intermediates.

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REFERENCES

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CONCLUSIONS In summary, we have presented a simple and convenient way to remove the RAFT end-group of a series of (meth)acrylate and (meth)acrylamide polymers in a continuous fashion. The polymers were subjected to aminolysis conditions using either a liquid or solid-supported amine source and were then isolated either as a free thiol or as a thioether after a subsequent Michael addition. The aminolysis reactions in our tubular continuous flow reactors generally resulted in full conversion at temperatures between 60 and 80 °C. As part of these investigations we achieved the following: (1) establishment of an integrated flow process, which is capable of producing free thiol containing polymer without the formation of disulfide byproduct; this was achieved by means of an inline, amine scavenging process in a polymer supported column which was situated after the aminolysis reactor; (2) the application of UV spectroscopy for inline monitoring of the continuous flow aminolysis reaction; (3) establishment of a simple and convenient two-step flow process for the polymerization and subsequent end-group removal by aminolysis; this was achieved by using two continuous reactor units in series in which the residual monomer from the polymerization acted as the Michael acceptor to end-cap the thiol after aminolysis. The continuous multistage processes described above present a strategic advantage of our tubular reactor system over conventional batch processing, as the need to isolate and/or handle intermediates is removed. ASSOCIATED CONTENT

S Supporting Information *

Analysis procedure; Figures S1 and S2. This material is available free of charge via the Internet at http://pubs.acs.org.

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ACKNOWLEDGMENTS

The authors thank Carl Braybrook for assistance and guidance with the MALDI experiments, Roger Mulder for advice on the NMR results, and Graeme Moad and Ezio Rizzardo for many helpful discussions.

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AUTHOR INFORMATION

Corresponding Author

*Tel +61 3 9545 2222; e-mail [email protected] (C.H.H.). Notes

The authors declare no competing financial interest. 8212


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Continuous Flow Aminolysis of RAFT Polymers Using Multistep

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