Living Radical

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Perspective Cite This: Macromolecules XXXX, XXX, XXX−XXX

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Living in the Fast LaneHigh Throughput Controlled/Living Radical Polymerization Susan Oliver,†,‡ Lily Zhao,‡ Adam J. Gormley,∥ Robert Chapman,§ and Cyrille Boyer*,†,‡ Australian Centre for NanoMedicine (ACN), School of Chemical Engineering, ‡Centre for Advanced Macromolecular Design (CAMD), School of Chemical Engineering, and §Australian Centre for NanoMedicine (ACN), School of Chemistry, University of New South Wales, Sydney, Australia 2052 ∥ Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey 08854, United States

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†

ABSTRACT: Combinatorial and high throughput (HTP) methodologies have long been used by the pharmaceutical industry to accelerate the rate of drug discovery. HTP techniques can also be applied in polymer chemistry to more efficiently elucidate structure−property relationships, to increase the speed of new material development, and to rapidly optimize polymerization conditions. Controlled living/radical polymerization (CLRP) is widely employed in the preparation of potential materials for bioapplications being suitable for a large variety of polymeric materials with various architectures. The versatility of CLRP makes it an ideal candidate for combinatorial and HTP approaches to research, and recently, the development of oxygen tolerant CLRP techniques has greatly simplified the methodology. In this Perspective, we provide an overview of conventional CLRP, including automated parallel synthesizers, as well as oxygen tolerant CLRP applications for HTP polymer research.

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The first reported combinatorial approach applied to polymer development was in 1997.9 Brocchini et al. prepared a library of 112 biodegradable polyarylates by step-growth polymerization and assessed the effect of polymer structure on fibrinogen adsorption and the growth of fibroblasts. With the exception of polymers derived from oxygen-containing diacids in their backbone, which were uniformly good growth substrates, decreased proliferation of fibroblasts was correlated with increased surface hydrophobicity.10 A number of other researchers have used HTP techniques to prepare polymer libraries using step-growth polymerization,11−24 including the preparation of over 2000 structurally unique poly(β-amino esters) for potential applications in nonviral gene therapy,15 a gradient-based polymer library to rapidly investigate the relationship between polymer crystallinity and the proliferation of osteoblastic cells,18 and a temperature−composition library of blends of poly(DL-lactic-co-glycolic acid) and poly(3caprolactone) to regulate vascular cell adhesion and growth.17 A number of excellent reviews provide further details on the use of HTP and combinatorial methodologies with stepgrowth polymerization.4−6,25,26 HTP methodologies have also been applied to free radical polymerization,27,28 including emulsion polymerization,29 thereby increasing the diversity of materials that can be studied. The versatility of radical polymerization has been exploited to map out the effect of material properties, such as wettability, topography, elastic modulus, and surface chemistry,

INTRODUCTION Combinatorial and high throughput (HTP) methodologies have been used since the late 1980s by the pharmaceutical industry to accelerate the rate of drug discovery,1 dramatically expanding the breadth and scope of molecular structures that can be synthesized and screened for biological activity.2 Indeed, HTP synthesis and screening techniques have revolutionized the field of pharmaceutical development and led to the discovery of new drugs, such as sorafenib for the treatment of advanced renal cell carcinoma.3 HTP techniques are of particular interest when limited theory exists for predicting the performance and biological interactions of different structures, compositions, and surface properties of synthetic compounds in biological environments.4 In these circumstances significant progress can still be made in the investigation of material−biological interactions that are not currently well understood, including the development of synthetic biomaterials that can mimic properties of naturally occurring biomolecules. Polymeric materials have been widely researched for bioapplications, and the vast range of possible structures means they are wellsuited to combinatorial and HTP methodologies.5,6 As with small molecule pharmaceutical development, HTP techniques can be applied in polymer chemistry to more efficiently elucidate structure−property relationships and to increase the speed of new material development. In addition to bioapplications, they have been widely applied to materials development in solar energy and batteries, inorganic materials, catalysis, coatings, and nanomaterials.7 HTP techniques can also be used to rapidly optimize polymerization conditions.8 © XXXX American Chemical Society

Received: August 29, 2018 Revised: November 29, 2018

A

DOI: 10.1021/acs.macromol.8b01864 Macromolecules XXXX, XXX, XXX−XXX

Perspective

Macromolecules Table 1. HTP Conventional Controlled Living/Radical Polymerization CLRP technique

monomers

architecture

equipment

application

ASW 2000 Accelerator SLT106 ASW2000 SLT II

reaction optimization of star polymers effect of nitrone structure reaction optimization LCST investigation feasibility demonstration

NMP

styrene, BMI, DVB

star

Symyx

NMP NMP NMP NMP

styrene styrene/t-BA Amor, HPA, DMA Styrene, PrMI, BzMI, PFP-MI,TIPS-PMI

Chemspeed Chemspeed Chemspeed Chemspeed

RAFT

MMA

homo homo/blocks homo/statistical statistical/ sequence controlled homo

RAFT RAFT

MMA, BMA, BnMA, DMAEMA, MA, tBA, BnA, EHA DMAEMA, OEGMA

homo/block/ statistical homo/statistical

Chemspeed ASW2000/Chemspeed Accelerator SLT100/Chemspeed Autoplant A100 Chemspeed ASW2000/Chemspeed Accelerator SLT100 Chemspeed Accelerator SLT100

RAFT

MAA, MEOMA, MEO2MA, OEG(E)MA

homo/statistical

Chemspeed Accelerator SLT106

RAFT

homo/statistical


homo


cross-linked blocks homo

Symyx Core Module (customized)

RAFT

MMA, HPMA, HEMA, t-BA, BnA, MA, UMA, TFA-MA, TGEEMA, CHMA AA, NIPAM, HEA, HPA, DMA, n-BA, ODA, p-MS OEMA, GMA, HEMA, CEA, DMAEMA, MMA, MAA MMA/n-BA

RAFT

DMAEMA, DEGMA

RAFT RAFT

RAFT

library size

ref

384

48

9 21 25 9

58 59 60 61

24

62

kinetics, reaction optimization pH and thermoresponsive polymers pH and thermoresponsive polymers comparison with manual

128

63

11

64

60

65

63

66

16

67

1536

68

9

69

12

70

7 15

71 72

23

73

71

74

71

74

20 32

75 76

12 60

77 78

16

79

19

80

11

81

20

82

15

83

12

84 85, 86 87 88

automated synthesizer comparison


MA, VAc MMA/BMA

homo/quasiblock statistical quasi-block

RAFT

MMA/BMA

quasi-block

Chemspeed SwingSLT

RAFT

BMA, MMA, DEGMA, BzMA

quasi-block

Chemspeed SwingSLT

RAFT

BMA, MMA, DEGMA, BzMA

quasi-block

Chemspeed SwingSLT

RAFT RAFT

MAA, HPMA RBV-MA, HPMA

statistical statistical

Chemspeed SwingSLT Chemspeed SwingSLT

RAFT RAFT

NAM, IBA NIPAM, HEMA, DMAc, DEA, IPMA, Am

quasi-triblock statistical

Chemspeed ASW2000 Freeslate ScPPR

RAFT

NiPAAm, HPMAm

statistical

Chemspeed SwingSLT

RAFT

NIPAM, VAc

gradient

Chemspeed Accelerator SLT

RAFT

THP-HEMA, DMAEMA

statistical

Chemspeed SwingSLT

RAFT

MAA, BzMA, BMA

PISA

Chemspeed Autoplant A100

RAFT

MA, VAc

homo/statistical

Chemspeed SwingSLT

RAFT ATRP

PSS, VBTMA MMA

block homo

Carousel Chemspeed ASW2000

reaction optimization/ kinetics nanoparticles for intracellular delivery automated freeze/thaw degassing demonstration multi- and unilamellar vesicles kinetic study diblock feasibility demonstration diblock feasibility demonstration higher order block feasibility demonstration higher order block feasibility demonstration anti-HIV (pro)drugs anti-HIV/anti-HCV (pro) drugs hydrogel optimization of oral bioavailability thermoresponsive polymer development thermoresponsive polymers dual pH and ultrasound responsive NPs optimization of PISA formulations switchable chain transfer agent polyelectrolytes feasibility demonstration

ATRP ATRP

MMA MMA

homo homo

styrene/t-BA n-BA/MEA

homo homo/quasiblock di/triblock

reaction optimization automated purification investigation reaction optimization reaction optimization

108 64

ATRP Cu(0) mediated Cu(0) mediated

Chemspeed ASW2000 Chemspeed ASW2000/Solid phase extraction unit Symyx Chemspeed ASW2000

24 88

89 90

Chemspeed ASW2000

reaction optimization

92

91

RAFT

n-BA, DMAEA, EEA, proCEA

Chemspeed SwingSLT

Chemspeed SwingSLT Chemspeed SwingSLT

the structural control of living polymerizations. The first living polymerization was demonstrated with anionic polymerization in 1956 by Michael Szwarc, who showed that growing chains of polystyrene did not terminate and would continue to grow if

from over 450 polymer surfaces on the growth of human pluripotent stem cells.30 The aforementioned techniques allow the researcher to vary monomer structure and polymer composition but do not offer B


Perspective

Macromolecules

Figure 1. Photograph of Accelerator SLT100 and Chemspeed ASW2000 synthesis robots in gloveboxes (left). Overview of the automated synthesizer as it is shown in the programming software of the ASW2000 (right). Adapted with permission from ref 93. Copyright 2003 Wiley Periodicals, Inc.

more monomer was added to the system.31 Living polymerization techniques now include anionic, cationic, and ringopening polymerization (ROP) as well as controlled living/ radical polymerization. Non-radical-controlled living techniques that have been used in HTP include anionic polymerization,32−34 cationic polymerization,35,36 and ROP.36−39 For instance, Pettau et al.34 used a customized reactor setup for the combinatorial synthesis of a series of block copolymers using anionic polymerization. The setup comprised one main reactor and three secondary reactors and featured individual temperature control (down to −70 °C) on each reactor. An A- or ABblock was initially prepared in the main reactor, and this block was then piped to the secondary reactors, enabling four subsequent reactions to be undertaken in parallel. A library of 12 AB- and ABC-block copolymers with varying lengths and/ or chemical structures of the final block were synthesized using the setup. Controlled living/radical polymerization (CLRP), including atom-transfer radical polymerization (ATRP),40,41 reversible addition−fragmentation chain transfer (RAFT) polymerization,42 and nitroxide-mediated polymerization (NMP),43,44 is widely employed in the preparation of potential materials for bioapplications, being suitable for a large variety of polymeric materials with various architectures, and provides greater control over molecular weight and molecular weight distribution as well as greatly expanding the scope of functional monomers and compatible solvents.45−47 The versatility of CLRP makes it an ideal candidate for combinatorial and HTP approaches to research, and such research has been ongoing since 2001.48−51 The development of oxygen tolerant CLRP techniques52−57 has greatly simplified the methodology. In this Perspective, we will explore both conventional CLRP and oxygen tolerant CLRP applications for HTP polymer research.

Automated Synthesizers. HTP conventional CLRP is typically performed using automated parallel synthesizers.92−96 Chemspeed provides a number of options including the Accelerator SLT106,59 SLT II,61 ASW2000,85 SwingSLT,71 Autoplant A100,62 and Accelerator SLT100.64 Other options include the Symyx system48 and Freeslate ScPPR.78 Most systems include vortex mixers and automated liquid dispensing heads and can be configured to run different numbers of parallel reactions depending on the reaction volume.92−96 Figure 1 shows two examples of automated synthesizers: the Chemspeed ASW2000 and the Chemspeed Accelerator SLT100.49 The ASW2000 can run up to 80 parallel reactions in 13 mL glass reaction vessels or up to 20 reactions in 75 mL reaction vessels or a combination of both.49,93 High-viscosity vortex stirrers are available as an option to ensure adequate mixing within the reaction vessels, liquids can be dispensed via an xyz liquid-handling system, and reactors can be heated or cooled from −70 to 150 °C.93 The Accelerator SLT100 has similar features to the ASW2000 but has a larger workspace, allowing up to 192 reactions to be run in parallel (13 mL reaction vessels). It is also equipped with a robotic arm that weighs chemicals in the range of milligrams to grams into vials, flasks, and well plates and a four-needle liquid dosing head to facilitate the fully automatic exchange between liquid and solid dosing units.49,93 Schubert’s group compared the Accelerator SLT100 and the ASW2000 in the RAFT polymerization of methyl methacrylate (MMA).62 Reproducibility was demonstrated between reactions on the individual synthesizers as well as between the synthesizers. Reactions were also undertaken on a larger scale Chemspeed Autoplant A100, and in this case, molecular weights were slightly lower and dispersities were higher, which was attributed to insufficient heat transfer from the reactors to the reaction mixture. The Accelerator SLT100 has also been compared with manual synthesis for a range of homopolymers and statistical copolymers prepared from the RAFT polymerization of acrylates and methacrylates.66 A library of over 60 copolymers was generated, and for all reactions, molecular weights and reproducibility were comparable to those obtained with manual synthesis. Owing to the oxygen sensitivity of conventional CLRP, an inert atmosphere must be maintained throughout the polymer-

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HIGH THROUGHPUT (HTP) CONVENTIONAL CONTROLLED LIVING/RADICAL POLYMERIZATION (CLRP) The use of HTP experimentation with CLRP has substantially accelerated the synthesis, optimization, screening, understanding, and discovery of polymers with well-defined and complex structures. Table 1 details a number of studies that have been undertaken using HTP CLRP. C


Perspective

Macromolecules ization. To this end, the automated synthesizers are usually placed in a glovebox, and oxygen must be removed from reaction mixtures.49,94 Early work with automated synthesizers utilized inert gas sparging to remove oxygen from reaction mixtures,62,66,67 but a drawback of this technique is that the concentration of reagents can change if the chemicals or solvents are relatively volatile.69 Guerrero-Sanchez and coworkers demonstrated an automated and parallel freeze− evacuate−thaw degassing method to overcome these issues.69 The procedure was undertaken on a Chemspeed Swing-SLT and was fully automated. Initially, the reaction vessels were heated to 135 °C and subjected to 10 cycles of vacuum (2 min each) and filling with nitrogen (2 min each). Reactions mixtures were then automatically transferred to the vessels and subjected to three automated freeze−evacuate−thaw cycles involving cooling to −90 °C, while vortexing the reaction block (200 rpm, 2 min) and then applying a vacuum (∼5 mbar) to the reactor block while heating the reactors up to −10 °C (or up to the reaction mixture melting point) at 600 rpm for 2 min. After the three cycles, the reactors were sealed under a nitrogen atmosphere and then heated to the desired reaction temperature. The automated method was demonstrated for the RAFT polymerization of MMA, butyl methacrylate (BuMA), and N,N-dimethylacrylamide (DMA) and was found to be as effective as conventional manual laboratory techniques. Other automated equipment has been used in conjugation with automated parallel synthesizers. Zhang and co-workers connected a Chemspeed ASW2000 automated synthesizer with a solid phase extraction (SPE) unit to purify MMA polymers prepared by ATRP.88 The polymer solutions were automatically transferred to the columns, and the eluent was collected in an automated way in vials under the SPE columns. Sixty-four different purification conditions were investigated by varying column materials, column lengths, and eluent volumes, and the copper content of the purified polymer was determined by atomic absorption spectrometry. Optimum purification conditions were found to be a 1.5 cm long activated neutral or basic aluminum oxide column with 2 mL of tetrahydrofuran (THF) as the eluent. Nitroxide-Mediated Polymerization (NMP). NMP was historically the first form of CLRP and uses an organic alkoxyamine (nitroxide) as the chain transfer agent.97 A HTP approach was first applied to NMP in 2001 to optimize conditions for the preparation of star polymers from styrene and the cross-linker, 1,1-(methylenedi-4,1-phenylene)bismaleimide (BMI).48 Using a Symyx automated parallel synthesizer with 96 wells, they synthesized a total 384 different star polymers. Initially, a 96-member library was synthesized with varying ratios of styrene and BMI to polystyrene macroinitiator. Nine regions were identified in the library, and these can be seen in Figure 2. The best results in terms of molecular weight (MW) and peak profile were observed in regions “g” and “h” of the library, and further evaluation showed the optimal composition for well-defined, high-MW star formation was a ratio of polystyrene macroinitiator/BMI/ styrene of 1/3.5/8. Further libraries were subsequently developed using the lead reaction conditions from the first library, allowing optimization of other parameters, including MW of the macroinitiator (3.5−9.1 kDa was found to be optimal) and exploration of commercial grade divinylbenzene (DVB) as cross-linking agent. HTP techniques have since been used to optimize reaction conditions for the nitroxide-mediated polymerization of several

Figure 2. Schematic representation of the nine different regions present in library 1. Reproduced with permission from ref 48.

other homopolymers58,59 as well as both statistical60 and block copolymers.59 For instance, a library of homopolymers from both styrene and tert-butyl acrylate were prepared in a Chemspeed Accelerator SLT106, and this knowledge was subsequently used to prepare block copolymers from the two monomers.59 HTP NMP has also been applied to the synthesis of complex sequence controlled polymers. Polymers with controlled monomer sequences are highly prevalent in the natural world and include nucleic acids and proteins.98 Sequence-controlled polymers can be prepared using CLRP, but traditional methods of preparation can be experimentally demanding, requiring numerous successive monomer additions and sample withdrawals thereby limiting the total number of monomer additions.99 Using a Chemspeed SLT II, Lutz’ group61 demonstrated how the upper limit of monomer additions could be markedly increased using HTP synthesis methods. NMP polymerization using the alkoxyamine BlocBuilder MA (2-(N-tert-butyl-N-[1-(diethoxyphosphoryl)-2,2-dimethylpropyl]aminooxy)-2-methylpropionic acid) at 120 °C in an anisole solution was used to precisely insert N-substituted maleimides (MIs) onto styrene-based backbones by injection of the monomer at defined time points. Initially, a comparison of manual methods with the automated synthesizer utilizing two MIs was undertaken to ensure that no substantial kinetic differences were observed between the two techniques. Once this was confirmed, the automated protocol was used to determine how many MIs could be efficiently inserted into polystyrene backbones of varying chain lengths. Using Nbenzylmaleimide (BzMI) as the model MI, it was found that four, seven, and eight discrete BzMI additions could be achieved without significant overlapping on polystyrene chains with 20, 50, and 100 degrees of polymerization (DP), respectively. Finally, the automated protocol was used to prepare polymers with complex sequence patterns from four model MIs: BzMI, N-(n-propyl)maleimide (PrMI), pentafluorophenyl 4-maleimidobenzoate (PFP-MI), and triisopropylsilyl-protected N-propargyl maleimide (TIPS-PMI). Figure 3 shows the semilogarithmic plot of monomer conversion versus time for three examples with eight or nine additions of two, three, or four MIs, demonstrating that HTP polymerization can be used for highly complex monomer sequence patterns. Reversible Addition−Fragmentation Chain Transfer (RAFT) Polymerization. RAFT polymerization, which employs a thiocarbonylthio compound as a chain transfer D


Perspective

Macromolecules

Figure 3. Automated preparation of complex monomer sequence patterns: (a) microstructure containing alternated BzMI (red) and PFP-MI (purple) regions; (b) microstructure containing scrambled BzMI (red), PrMI (blue), and PFP-MI (purple) regions; and (c) microstructure containing periodic PFP-MI (purple), PrMI (blue), BzMI (red), and TIPS-PMI (green) regions. The graphs show the semilogarithmic plot of monomer conversion versus time for each experiment. Experimental conditions in all cases: 120 °C, anisole, [styrene]0/[BlocBuilder]0 = 100:1. Reproduced with permission from ref 61. Copyright 2012 WILEY-VCH Verlag GmbH & Co. KGaA.

decreasing trend in LCST was observed as the number of ethylene glycol units attached to each repeating unit decreased. Furthermore, there was a substantial decrease in LCST when the methoxy end group was replaced with an ethoxy group as a result of its higher hydrophobicity. Statistical copolymers were subsequently prepared with MAA and OEGMA475 or OEGMA1100. Interestingly, although neither MAA nor OEGMA1100 homopolymers exhibited LCST behavior, copolymers of these two monomers at certain ratios of MAA to OEGMA1100 (namely 90:10, 80:20, 70:30, and 60:40) were found to be both thermoresponsive and pH-responsive. The ability to uncover these unexpected properties is a clear advantage of using HTP methodologies. HTP methodologies have also been used to investigate the preparation of thermoresponsive one-pot spontaneous gradient copolymers from N-isopropylacrylamide (NIPAM) and vinyl acetate (VAc).80 The amphiphilic copolymers displayed temperature-dependent changes in aggregation behavior that were similar to those of the corresponding block copolymers, but with some interesting differencesthey formed dynamic aggregates that responded rapidly to changes in solubility whereas the block copolymers formed kinetically frozen aggregates. A particular advantage of CLRPs is the livingness of the propagating chain allowing the formation of block copolymers and other higher order structures. However, the preparation of block copolymers by conventional means is typically timeconsuming requiring two (or more) separate polymerizations and multiple purification steps.106 There is also the issue that CLRPs produce some unavoidable dead chains, which necessitates ending polymerizations before full conversion to minimize this, thereby leading to poor reproducibility. One-pot synthesis via sequential monomer addition is one potential method to overcome these limitations, and this method was explored and optimized using a HTP Chemspeed Swing-SLT automated parallel synthesizer by Guerrero-Sanchez and coworkers.72 A library of 15 quasi-diblock copolymers was synthesized from n-butyl methacrylate (BMA) and MMA.

agent, is arguably the most versatile CLRP technique owing to its tolerance of the widest range of monomers under a variety of experimental conditions.46,47,100 It is also the most widely explored conventional CLRP methodology using combinatorial and HTP experimentation. HTP RAFT techniques have been used to develop (quasi-)block copolymers,70,72−74,77 for drug delivery applications,75,76,81 and for kinetic studies71 and reaction optimization.63,83 For instance, a Chemspeed SwingSLT automated parallel synthesizer was used to assess the effect of a Lewis acid, scandium triflate, on the activity of an acid/base “switchable” chain transfer agent in the RAFT copolymerization of methyl acrylate (MA), a more activated monomer, and vinyl acetate (VAc), a less activated monomer.83 Fifteen different polymers were prepared with varying reaction conditions, and it was found that the introduction of the Lewis acid at either 0.5 or 1 mol equiv with respect to the RAFT agent substantially improved control, leading to significantly reduced dispersities (∼1.1−1.3). Stimuli-responsive polymers have applications in a wide variety of fields.101−105 A number of studies have investigated the preparation of stimuli-responsive polymers via RAFT polymerization with HTP methodologies, including pH and thermoresponsive polymers64,65,70,80 and dual pH and ultrasound responsive nanoparticles.81 For example, Schubert’s group65 was able to use HTP RAFT polymerization to develop a library of 60 homopolymers with varying molecular weights in order to investigate their thermoresponsive behavior. Homopolymers with varying degrees of polymerization were prepared from MAA, monoethylene glycol methyl ether methacrylate (MEOMA), oligo(ethylene glycol) methyl ether methacrylate (OEGMA1100 and OEGMA475), oligo(ethylene glycol) ethyl ether methacrylate (OEGEMA246), and diethylene glycol methyl ether methacrylate (MEO2MA), allowing a wide range of parameters to be investigated in a relatively short time. The lower critical solution temperature (LCST) is the temperature at above which a polymer will phase separate from solution. Only a slight effect on LCST behavior was observed as the degree of polymerization was varied, but a strong E


Perspective

Macromolecules Figure 4 shows the reaction scheme and setup. First, several BMA macro-RAFT agents with at least 80% monomer

conversion were synthesized. These were then equally divided into different reaction vessels, different amounts of MMA were added, and the polymerization continued. All polymers prepared had low dispersities, and the amount of BMA incorporated into the second block was 75% activity in the DNA delivery assay. Owing to the number of variables involved, a smaller study of 5−10 of these nanoparticles would almost certainly have failed to locate these highly active formulations. Beyond this, the screening approach also enabled several structure−function relationships to be identified, which could be used to guide the design of future formulations. These included the importance of the balance between nonreactive and reactive blocks, a stoichiometric balance between epoxides and amines, a thin water-soluble hydrophilic shell, using tertiary amines with 1−2 reactive sites and using amines with buffering capacity. The best performing nanoparticles from the in vitro screening were modified via covalent cholesterol attachment and screened for in vivo

Figure 6. Schematic setup of the automated synthesizer and combinations of metal salts, initiators, and ligands used in this study. The symbols used in the figure are as follows: dMbpy, M; dHbpy, H; dNbpy, N; dTbpy, T; CuBr, CB; CuCl, CC; CuSCN, CS; FeBr2, FB; FeCl2, FC; CuBr + ligand + TsCl (ligand = 4,5-dMbpy, 1; 5,5-dMbpy, 2; 4Mbpy, 3; and 6Mbpy, 4), and CuCl + ligand + TsCl (ligand = 4,5′-dMbpy, 5; 5,5′-dMbpy, 6; 4Mbpy, 7; and 6Mbpy, 8). Reproduced with permission from ref 87. Copyright 2004 Wiley Periodicals, Inc. G


H

a

homo/diblock/star/ PISA statistical/block homo/block

Boc-AEAm, PEAm, HEAm

DMA, OEGA, OEGMA, HEA, HEAm, MBA, DAAm

DMAEMA, MMA, EMA, IPMA, CHMA, HEMA, DEGMA, OEGMA, PPGMA

BA, MA, tBA, EA, OEOA, MMA homo

statistical/quasi-block

DMA, DEA, DAAm, MA, BnA

BA, DEGMA, OEOMA, DMAEMA, DEAEMA, MMA, styrene

statistical/star (postfunctionalized) homo

DMA, NHS acrylate

NIPAm, MMA, MA, EA, tBA

homo/statistical/ block/star block (postfunctionalized) homo/statistical/block

block/PISA

mPEG, HPMA

NAM, DEA, DMA, NEAm, HEAm, MPAm, MA, EA, AA, GA, HPA, CEA, CyEA, SDA, DEAEA, SA, TFA, DEGDA, TEGDA AEAm, DMA, AMPL

homo block/PISA

architecture

DMA, NAM, HE(M)A, OEGMA, HPMA HPMA, OEGMA

monomers

Enz = enzyme assisted; rosa = “rapid one-pot sequential aqueous”; PET = photoinduced energy transfer.

ARGETATRP

PETRAFT PETRAFT PETRAFT photoRAFT photoRAFT ATRP

RAFT/ Biginelli RAFT

rosa-RAFT

Enz-RAFT Enz-photoPISA Enz-RAFT

CLRP technique

Table 2. HTP Oxygen Tolerant Controlled Living/Radical Polymerizationa

Symyx core module (customized)

Gilson Pipetmax 268 liquid handling robot, well plate, blue LED modified 4DNA synthesizer

well plate, 530 nm LED

530 nm LED



96-well plate

PCR tubes, homothermal shaker

PCR tube strips, thermocycler

well plate

well plate, water bath well plate, 405 nm LED

equipment

structure activity relationship with antimicrobial action DNA−polymer hybrids demonstration reaction optimization

structure activity relationship with antimicrobial action ultralow volumes

feasibility demonstration feasibility demonstration, encapsulation of HRP and BSA feasibility demonstration, nanoobjects reaction optimization for star polymers radical scavengers, metal chelating agents, imaging agents feasibility demonstration for film forming polymers structure activity relationship with ConA binding reaction monitoring via fluorescence

application

ref

288

9

108

62

134

133

132

131

130

129

56 32

128

127

126

125

124

122 123

82

25

60

92

109 27

library size

Macromolecules Perspective


Perspective

Macromolecules

(Enz-RAFT) by Chapman and co-workers.114 GOx is an inexpensive and readily available enzyme, which consumes molecular oxygen dissolved in solution, generating hydrogen peroxide through the oxidation of glucose into D-glucono-δlactone. The mechanism of the removal of oxygen using GOx is decoupled from the polymerization process, which means that low concentrations of initiator can be used, enabling good control and high end-group fidelity in the final polymer. Chapman and co-workers122 demonstrated the applicability of degassing by GOx to HTP RAFT polymerization by undertaking the reactions in 96 and 384 multiwell plates. A range of monomers could be polymerized by Enz-RAFT in 300 μL (96-well plates) or 40 μL volumes (384-well plates) at 45 °C (see Figure 7). In 30% (v/v) t-butanol/PBS, the Enz-RAFT

CuBr, CuCl, CuSCN, FeBr2, and FeCl2 as metal salts; and 2,2′bipyridine and its derivatives with dimethyl, dihexyl, dinonyl, or ditridecanyl groups on 4,4′-positions, dimethyl groups on 4,5′- or 5,5′-positions, and one methyl group on the 4- or 6position as ligands. Under the studied conditions, Cu(I)catalyzed polymerizations were found to be more effective than Fe(II)-catalyzed ones, and the best performing ligand with this system was a bipyridine-type ligand with a critical length of the substituted alkyl group (i.e., 4,4′-dihexyl-2,2′-bipyridine). Both EBIB and TsCl were found to be effective initiators for this system. Automated parallel synthesizers have also been used to optimize the ATRP of styrene and tert-butyl acrylate (t-BA) with researchers finding that less than one-third of the experimental time was required compared with manual techniques.89 Copper(0)-mediated polymerizations are considered particularly attractive CRLPs owing to their ability to be performed at ambient temperatures.109 Hoogenboom’s group demonstrated that an automated parallel synthesizer could be used to rapidly optimize the reaction conditions of the Cu(0)mediated polymerization of n-butyl acrylate (BA) and 2methoxyethyl acrylate (MEA) homopolymers and these reaction conditions were subsequently used for the one-pot synthesis of (quasi-)diblock copolymers by sequential monomer addition.90 The group later extended this work to prepare one-pot amphiphilic (quasi-)diblock copolymers and ABAtriblock copolymers from hydrophobic BA in the first or middle block and hydrophilic 2-(dimethylamino)ethyl acrylate (DMAEA), 1-ethoxyethyl acrylate (EEA), or 1-ethoxyethyl-2carboxyethyl acrylate (proCEA) in the second or outer blocks in a Chemspeed ASW2000 automated synthesizer.91 A large number of reaction conditions were able to be screened; under optimal conditions, conversion of BA was almost complete, and pure triblock copolymers with good control over molecular weight and dispersities around 1.1 were prepared.

Figure 7. Representation of enzyme-deoxygenated RAFT polymerization (Enz-RAFT) performed in 40 μL water/solvent mixtures in 384-well plates, showing the structure of the RAFT agent and monomers investigated. Reproduced with permission from ref 122. Copyright 2016 WILEY-VCH Verlag GmbH & Co. KGaA.

polymerizations at 300 μL volumes proceeded at a similar rate to large-scale polymerizations degassed by traditional means, although the well-plate reaction exhibited a slightly shorter inhibition time, suggesting RAFT equilibrium was reached rapidly. At the lower reaction volume of 40 μL, a lower polymerization rate was observed, but the molecular weight evolution was unchanged. Furthermore, all systems displayed kinetics consistent with controlled living polymerization and low dispersities (Đ < 1.1). The preparation of triblock copolymers by sequential monomer addition without purification of the intermediate blocks was also demonstrated. Tan and co-workers123 combined GOx enzyme degassing with photoinitiated RAFT-mediated polymerization-induced self-assembly (PISA), allowing the rapid preparation of polymer nano-objects with a number of different morphologies. Different degrees of polymerization were targeted for the chain extension of 2-hydroxypropyl methacrylate (HPMA) on the presynthesized macro-CTA poly(poly(ethylene glycol) methyl ether methacrylate)−chain transfer agent (PPEGMA8CTA), and the reactions were prepared in 96-well plates exposed to visible light (405 nm) using the photoinitiator sodium phenyl-2,4,6-trimethylbenzoylphosphinate (SPTP). Polymeric nanoparticles with relatively low dispersities (Đ < 1.25) and well-defined morphologies, including spheres, worms, and vesicles, were generated within tens of minutes. A library of 27 polymer nano-objects with varying monomer concentrations and DPs was prepared, leading to the construction of a phase diagram (Figure 8) in considerably shorter time than with low throughput polymerizations. Horseradish peroxidase (HRP) and bovine serum albumin

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HIGH THROUGHPUT (HTP) OXYGEN TOLERANT CONTROLLED LIVING/RADICAL POLYMERIZATION (CLRP) While combinatorial and HTP methodologies applied to conventional CLRP have been and continue to be extremely advantageous in reaction optimization and the development of polymer libraries for screening of structure−activity relationships, the need to perform reactions without the presence of oxygen limits their use to laboratories with robotic synthesizers enclosed in gloveboxes and inert gas sources. The need to initially remove oxygen from reaction mixtures via either inert gas sparging62,66,67 or freeze−evacuate−thaw degassing69 also precludes the use of low volumes. A number of strategies have now been developed that allow CLRP to proceed in the presence of oxygen,55 including enzyme degassing,110−114 polymerizing through oxygen,115 PET-RAFT,53,116 PhotoRAFT,117−120 and A(R)GET ATRP.121 Table 2 provides details of studies that have used oxygen tolerant HTP methodologies. Many of these can be performed on multiwell plates in the open atmosphere, which enables the replacement of glovebox bound automated synthesizers with less expensive automated pipetting systems and multichannel pipets. Enzyme Deoxygenation. The use of enzymes to remove oxygen from solutions is a well-established technique used by biochemists135 and was first applied to free radical polymerizations in 1991.136 The enzyme glucose oxidase (GOx) was first employed to remove oxygen in RAFT polymerizations I


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Figure 8. (a) Digital photograph of PPEGMA8−PHPMAn diblock copolymers prepared via enzyme-assisted photo-PISA of HPMA by varying the monomer concentration and DP of PHPMA. (b) Detailed phase diagram constructed for the preparation of PPEGMA8−PHPMAn diblock copolymer nano-objects via enzyme-assisted photo-PISA of HPMA by varying the monomer concentration and DP of PHPMA. Phase regions consist of spheres (S), worms (W), vesicles (V), and mixed morphologies. Reproduced with permission from ref 123.

(BSA) were successfully loaded into the self-assembled vesicles, and their activity was unaffected by the encapsulation. More recently, Tan and co-workers124 prepared AB diblock polymer nano-objects with various morphologies at room temperature without the need for a photoinitiator. By use of the GOx-HRP cascade, hydrogen peroxide was generated by oxidation of glucose, and free radicals were subsequently generated via the oxidation of acetylacetone by the formed hydrogen peroxide, thereby initiating the polymerization. High monomer conversion (>97%) could be achieved even at low volumes (200 μL) in a 96-well plate, demonstrating that this technique could be employed for HTP polymer synthesis. GOx has also recently been used for enzyme deoxygenation to enable ATRP to be undertaken in open reaction vessels,56 paving the way for HTP techniques to be employed in well plates for ATRP. “Polymerizing Through” Oxygen. The “polymerizing through” approach relies on an excess of initiating radical species to consume molecular oxygen to enable the CLRP to acquire some degree of oxygen tolerance.55 RAFT polymerization has been shown to be compatible with “polymerizing through” techniques under optimized conditions, owing to its reliance on the generation of sufficient initiating radicals to commence polymerization. The application of the “polymerizing through” approach to RAFT polymerization means that only a small proportion of initiating radicals are deactivated by molecular oxygen, leaving the livingness of the polymerization uncompromised. The “polymerizing through” approach was used by Gody and co-workers115 to prepare a heptablock homopolymer with a well-defined architecture by conducting iterative RAFT polymerizations of 4-acryloylmorpholine (NAM) in the presence of air in only 21 min (3 min per block). Cooper-White’s group125 demonstrated that the “polymerizing through” oxygen approach could also be adapted to HTP polymerization for the preparation of star polymers via rapid one-pot sequential aqueous RAFT (rosa-RAFT). A schematic representation of the preparation method is shown in Figure 9. First, acrylamide or acrylate monomers were polymerized in

Figure 9. (a) Schematic representation of combinatorial HTP polymer library preparation of homopolymer, star, and miktoarm star polymer via parallelized rosa-RAFT polymerization, (b) performed in air and in 50 μL reaction volumes in PCR tube strips, and (c) utilizing a thermocycler to control each reaction step (3 min at 100 °C). With this methodology, hundreds of well-controlled (star) polymers can be synthesized simultaneously from a variety of acrylamide or acrylate monomers, which provides a novel means to rapidly and systematically assess a multitude of reaction parameters (i.e., [monomer]:[CTA] or [macro-CTA]:[cross-linker] ratio) or even form miktoarm star polymer from mixtures of macro-CTAs. Reproduced with permission from ref 125. Copyright 2017 John Wiley and Sons.

PCR tube strips at a temperature of 100 °C for 3 min to produce polymeric macro-CTAs, achieving high monomer J


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Figure 10. HTP analyses of polymers. (a) Polymer solutions in a 96-well plate (100 μL, 5 mg mL−1 in acetonitrile/H2O (1/1)) prior to analyses, with acetonitrile/H2O (1/1) as the control. A1−6 represent the polymer precursors and B1−5 the different benzaldehydes used. (b) Samples after adding the DPPH radical. (c) Samples after adding Cu(II). (d) Samples after adding the ARS dye. Reproduced with permission from ref 126. Copyright 2017 Royal Society of Chemistry.

PC* to regenerate the initial PC, repeating the catalytic cycle. Compared with conventional RAFT polymerization, PETRAFT polymerization is extremely oxygen tolerant, owing to the strong reductive properties of the employed PCs.140 Some PCs that have been reported in the literature to date include tris[2-phenylpyridinato-C2,N]iridium(III) ( fac-[Ir(ppy)3]),53 tris(2,2′-bipyridyl)dichlororuthenium(II) hexahydrate (Ru(bpy)3Cl2),54 5,10,15,20-tetraphenyl-21H,23H-porphine zinc (ZnTPP),141 and various organic dyes.116 PET-RAFT is highly oxygen tolerant and can be readily adapted to HTP methodologies. In a recent example from Boyer and Chapman, PET-RAFT was used to prepare a library of well-defined linear, 3-arm, and 4-arm star acrylamide polymers, which were postfunctionalized with mannose to probe structure−activity relationships for polymer−protein interactions, namely the lectin Concanavalin A (ConA).128 This was achieved by copolymerization of N,N-dimethylacrylamide (DMA) and N-hydroxysuccinimide (NHS) acrylate to DPs of 20−960 using ZnTPP in low volume well plates (96 and 384) open to the atmosphere at room temperature. At monomer concentrations of 1 M, high conversion (>90%) and low dispersity were achieved after 5 h polymerization. Following postfunctionalization with mannose, the polymer samples were screened by incubation with a ConA−horseradish peroxidase conjugate and revealed that the lectin binding efficiencies of the polymers did indeed change with polymer structure. Polymer−protein binding efficacy was strongest for the 3-arm star polymers; the binding affinity increased with size (DP) relative to polymer molarity, but relative to total mannose concentration smaller polymers had stronger affinity. Changes in the fluorescence emission of ZnTTP were exploited by Boyer’s group129 for HTP online monitoring of PET-RAFT polymerizations conducted in 384-well plates. The group found that the fluorescent emission bands of ZnTPP shifted significantly (up to 20 nm) during PET-RAFT polymerization, and a strong linear correlation was observed between this emission and monomer conversion. The selfreporting fluorescence monitoring technique was found to be independent of the RAFT agent, reaction volume, and target DP and not influenced by oxygen. Polymerization could therefore be monitored using a fluorescent plate reader allowing both HTP polymerization and monitoring of up to 384 separate reactions.

conversion (97.5%) A di(ethylene glycol) diacrylate (DEGDA) cross-linker, along with 2,2′-azobis(2-(2-imidazolin-2-yl)propane) dihydrochloride (VA-044), was then directly added to the aqueous solution containing the macro-CTA, followed by another 3 min RAFT polymerization step at 100 °C, resulting in the generation of core-cross-linked star polymers. This HTP approach enabled rapid assessment of the effect of cross-linker molecular weight, macro-CTA mixing, and cross-linker to macro-CTA ratio on the final star polymer parameters. As discussed in the conventional CLRP section, HTP techniques can also be used for the postfunctionalization of polymers.68,137 The Biginelli reaction,138,139 which efficiently generates dihydropyrimidin-2H-ones (DHPMs) from three common reactants (β-ketoesters, aldehydes, (thio)ureas, or their derivatives), was used by Tao’s group126 for the HTP postfunctionalization of polymers prepared using the “polymerizing through” oxygen technique. A two-stage process was used whereby three monomersa synthesized β-ketoester monomer, 2-(acetoacetoxy)ethyl acrylamide (AEAm, monomer a), the commercial dimethyl acrylamide (DMAm, monomer b), and 4-acryloylmorpholine (AMPL, monomer c)were first used to prepare a series of six triblock copolymers (ABC, ACB, BAC, BCA, CAB, and CBA, A1− 6). In the second stage these six copolymers were combined with five benzaldehyde compounds (B1−5) and two ureas to form a library of 60 polymers. HTP techniques were also used to rapidly analyze the polymers and detect their distinctive properties, including radical scavenging, metal chelating, 1,2diol receptivity, and CT imaging, by utilizing 96-well plates (Figure 10). Photoinduced Electron Transfer−Reversible Addition−Fragmentation Chain Transfer (PET-RAFT) Polymerization. PET-RAFT polymerization was developed by Boyer’s group53 and is a robust and versatile technique, demonstrating compatibility with a variety of monomers and solvents to generate well-defined polymers with narrow dispersities. Using low-energy visible light, PET-RAFT involves a redox process, whereby the RAFT agent is reduced to generate the radical R• and the oxidized form of the photoredox catalyst (PC). The radical R• may then initiate the monomer to form a propagating radical enabling the normal RAFT process to proceed or become deactivated by K


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polymerization.130 The antimicrobial activity of the prepared polymers was determined by measuring the minimum inhibitory concentration (MIC) for one Gram-positive and four Gram-negative bacterial strains (Figure 12), and hemolysis was performed to measure mammalian cell compatibility. Antimicrobial and hemolytic activities were found to be dependent on the distribution of monomers within blocks, and bacteria genus specificity could be tuned via polymer block order and to a lesser extent via combined modulation of polymer chain length. Photo-RAFT Polymerization. In addition to PET-RAFT, a number of other photoinitiated RAFT polymerization methodologies are able to be undertaken in the presence of air.117−119 An interesting approach was discovered by Qiao’s group,120 who reported that, in the presence a sacrificial tertiary amine, a trithiocarbonate RAFT agent was able to effectively remove oxygen from polymerization systems. This technique was recently exploited by Gibson’s group132 for the HTP development of a library of 108 potentially antimicrobial copolymers using a Gilson Pipetmax 268 liquid handling robot in conjunction with 96-well plates (Figure 13). A series of cationic statistical copolymers were formed from DMAEMA and eight different comonomers with either hydrophobic or hydrophilic substituents at four concentrations (5, 10, 15, and 20 mol %) with three repeats. The liquid handling robot facilitated transfer to screening where all copolymers were assessed for antimicrobial and hemotoxicity. A number of “hits” were identified, and in particular, a copolymer with

Figure 11. Representation showing the ZnTPP polymerization mechanism and RAFT agents used in the library design. Reproduced with permission from ref 128. Copyright 2018 John Wiley and Sons.

HTP techniques are particularly valuable when structure− activity relationships are not well understood. Such was the case with the effect on antimicrobial activity of polymer block order in synthetic polymers designed to mimic the action of antimicrobial peptides.130 A library of 32 copolymers with the same overall composition (three monomers chosen to mimic the cationic, hydrophobic, and hydrophilic functionalities of the amino acids lysine, phenylalanine, and serine, respectively) but different architectures (block length and monomer placement) was prepared using HTP one-pot PET-RAFT

Figure 12. Heat map of MICs for all polymers synthesized in this study where the selection of polymer structures from each family is shown. The bacterial strains are Pseudomonas aeruginosa PAO1 and ATCC 27853 strains, Escherichia coli K12 strain, Acinetobacter baumannii ATCC 19606 strain, and Staphylococcus aureus ATCC 29213 strain. Reproduced with permission from ref 130. Copyright 2018 John Wiley and Sons. L


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Figure 13. Schematic showing the HTP RAFT synthesis of amine-containing antimicrobial polymers in well plates. Reproduced with permission from ref 132. Copyright 2018 John Wiley and Sons.

optimized for eight different monomers followed by the systematic synthesis of a library of 96 polymers with DPs from 15 to 375 using the optimized conditions. Bis(2-hydroxyethyl) disulfide bis(2-bromo-2-methylpropionate) was used as the initiator allowing cleavage of the polymers, upon exposure to dithiothreitol, to two thiol-terminated chains, which could potentially be used for conjugation to biomolecules, such as drugs, proteins, and siRNA.

propylene glycol side chains showed significantly enhanced antimicrobial activity. Inspired by the work of Oster in the 1950s,142 Yeow et al.131 developed an oxygen tolerant aqueous photopolymerization technique which used organic dyes, such as eosin Y and the vitamin B2 derivative, riboflavin-5′-phosphate, in the presence of ascorbic acid as a reducing agent to initiate controlled RAFT polymerization of a range of monomers (acrylamide, acrylate, and methacrylate families). They subsequently demonstrated that this technique could be applied to HTP polymerization by preparing a number of polymers with different architectures at ultralow volumes (20−50 μL) in a 96-well plate, including block copolymers, star polymers, and in situ self-assembled nanoparticles using a polymerization-induced self-assembly (PISA) approach. Furthermore, parallel polymerizations were performed in a 96-well plate to systematically study the effect of cross-linker concentration on the synthesis of star polymers via the arm-first methodology. Activators Regenerated by Electron Transfer (ARGET) ATRP. Conventional ATRP is extremely sensitive to oxygen as it can lead to rapid oxidation of some catalyst complexes and their subsequent deactivation.55 In ARGET ATRP, the inclusion of a reducing agent allows the catalyst to be regenerated, thereby eliminating the need to deoxygenate prior to polymerization.121 Using a customized Symyx core module equipped with four different liquid dispensing elements, Anderson’s group134 employed a HTP methodology to optimize the catalyst and reducing agent concentration for the synthesis of thiol-functionalized polymers. The HTP methodology allowed reaction conditions to be rapidly

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OUTLOOK: OPPORTUNITIES AND CHALLENGES FOR HIGH THROUGHPUT CLRP The above examples highlight the value of high throughput (HTP) techniques in the optimization of reaction conditions, in the simplification of experimentally laborious syntheses, and in the design of materials where the underlying mechanisms that govern their performance are not well understood. HTP techniques have long been applied to the development of small molecule therapeutics and to mapping out the effect of monomer chemistry and polymer composition on properties such as cell proliferation and differentiation, but their application to the design of controlled/living radical polymers is comparatively limited. The recent development of oxygen tolerant CLRP methodologies has opened up the field of HTP polymer synthesis to chemists, biochemists, and biologists who do not have access to robotic synthesizers enclosed in gloveboxes and inert gas sources, and as we have shown, a number of oxygen tolerant CLRP techniques have now been demonstrated in HTP formats. The methodology that should be used in any given application will depend upon a whole range of factors including (i) the monomer/polymer solubility, M


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Macromolecules (ii) the monomer family and reactivity, (iii) the purity requirements in the application of interest and its compatibility with solvents and additives used in the synthetic process, (iv) the availability of light sources, gloveboxes, and robotics, (v) the complexity of the polymers required, (vi) the importance of working in low volume, and (vii) the size of the library to be studied. While most studies using these techniques have involved small libraries focused on either optimization of reaction conditions or a demonstration of the synthetic methodology, we expect that the coming years will see the application of these techniques to a more rational design of controlled/living radical polymers where structure−activity relationships are currently unknown, as is often the case in biological settings. We see three key lessons can be learned from the experience of other fields with HTP methodologies: Experimental Design. It is attractive to think that high throughput techniques can be used to screen an entire area of chemical space for a property of interest, generating a small number of hits that can be taken forward for lead optimization. Unfortunately, the diversity of chemical space, even in very well-defined situations, is usually too vast to do this in practice.143 This has become well known in the field of small molecule drug discovery, where the number of synthetically tractable compounds is thought to be practically unlimited. In the words of Bleicher et al., “the days in which compounds were generated just for filling up the companies inventories, without taking any design or filtering criteria into account, have passed”.144 The total number of potential molecules for drug screening is estimated to exceed 1064 candidates, far too many to assess in any screen, and as a result libraries constructed without any design criteria have tended to yield very low hit rates.143 Coupled with this are the statistical problems that occur whenever sampling large libraries, where screen false positives and false negatives will inevitably interfere with the decision-making process. These challenges increase with library size, and simply improving the sensitivity and specificity of the screening protocol will not eliminate them. Robust statistical methods with appropriate use of control experiments and replicates are therefore critical even in the initial screening stages.145 These problems will be as true in high throughput polymer experimentation as they are in small molecule studies. Finding target molecules will require more than simply scanning a diverse chemical space, but also careful experimental design. These may include the use of gradient arrays, in which three or more variables in a material are modified to produce a continuous compositional spread,143,146 split-plot designs,147 or more targeted design methods.143 High Throughput Characterization. High throughput material synthesis experiments require integration of analytical processes to establish a structure−function correlation.7,143 There is limited value in preparing large libraries of polymers if the material cannot be adequately characterized in an equally high throughput fashion. Fortunately, there are many polymer characterization techniques that are amendable to high throughput analysis (Figure 14). Conversion. Monomer-to-polymer conversion is typically measured by either NMR spectroscopy or gas chromatography, but neither technique is well suited for high throughput analysis. Recently, PET-RAFT was shown to have the unique ability to provide online reporting of conversion by following changes in fluorescence emission,129 allowing for high throughput characterization of conversion using a standard

Figure 14. Schematic of an integrated analysis in high throughput polymer synthesis.

plate reader with fluorescence. A similar method has also been described by employing RAFT agents that display aggregation induced emission.148 These tools and others will provide reliable and high throughput information about the polymerization reaction. SEC/GPC. Characterization of polymer size and dispersity by size-exclusion chromatography (SEC) and related gel permeation chromatography (GPC) is also possible in high throughput when short SEC/GPC columns designed for higher flow rates are employed.149 High-speed GPC columns can enable sample run times as short as 3 min per sample albeit with some loss of resolution. This capability has been used for online reporting of conversion using conventional GPC and autosampling from microtiter plates.150,151 In order to take full advantage of this capability, software that can automatically record, process, and analyze high throughput GPC data will be required. Light Scattering. Accurate determination of molar mass, radius of gyration, hydrodynamic radius, and aggregation is typically characterized using static and dynamic light scattering (SLS and DLS). Multiangle light scattering (MALS) detectors are frequently appended to SEC/GPC instruments and can therefore be used in combination with high throughput GPC. In situations where microwell plate analysis is preferred, plate readers that can measure SLS and DLS are also available. The DynaPro Plate Reader (Wyatt Technology), for example, has the ability to measure the size and stability of polymers in standard microwell plates including 96-, 384-, or 1536-well formats. This tool has been primarily applied to protein engineering where stable formulation is desired but can also be applied to wide applications in polymer science. Other High Throughput Characterization Techniques. There are many other methods that can be employed to characterize polymer systems depending on the intended use. For example, many polymer systems are designed to interface with biology to either stabilize proteins or deliver drugs. These experiments can easily be performed in high throughput using standard well plate assays. Förster resonance energy transfer (FRET) experiments can also be performed using plate readers to measure polymer assembly, binding, and association and are therefore useful in high throughput applications.152 Mechanical N


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Macromolecules testing,153,154 differential scanning calorimetry (DSC),155 and thermogravimetric analysis (TGA)156 have all been used in a high throughput setting, but the nature of these techniques makes these tools difficult to fully automate. Integration with Computational Techniques. The rapid advances of computational methods have had a significant impact upon high throughput screening across a range of fields including drug discovery,144,157 solar materials, carbon capture and gas storage, catalysis, and energy storage.158 Such methods can improve the hit rate of a high throughput screen by guiding the experimental design and/or reducing the number of experimental candidates by prescreening virtual structures through a theoretical framework. This has been standard practice in the field of drug discovery for some time, where docking studies can be used to select the most promising small molecules for experimental screening or where similarity searches can be used to match compounds of known activity with derivatives that could be promising for screening.157 Systematic storage and analysis of experimental data in large database repositories can also aid in the design of high throughput experiments.158−160 The materials project is one such open database, which enables the use high throughput computing to rapidly prototype materials for in silicio prior to synthesis in an experimental setting.161 At present, the database contains over 80 000 inorganic crystal structures and over 500 000 nanoporous materials along with thousands of other molecules, band structures, and other data. Within the polymer landscape at present there is no comparable database, although several studies have made use of computational techniques to design polymer structures.162 The growth in high throughput polymerization opens up new opportunities for the development of such databases and the application of machine learning algorithms to the design of polymeric materials. In summary, high throughput experimentation in controlled/living radical polymerization has been a useful tool in enabling the design of some new materials and optimization of reaction conditions, but the intolerance of these reactions to oxygen has somewhat limited the adoption of HTP techniques by the field. Recent advances in oxygen tolerant techniques are changing this, but most studies to date have focused on platform development. We believe there is now an opportunity to apply these platforms to design new polymeric materials where structure−activity relationships are poorly understood and in the optimization of reactions. In doing so, we would do well to learn the lessons from the application of HTP methods in other fields, in both the opportunities and challenges of such an endeavors, particularly in the way experiments are designed and characterized as well as the way we leverage the power of computational chemistry.

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Biographies

Dr. Susan Oliver joined the Boyer laboratory after many years in industry, primarily in the pharmaceutical area. Her research focuses on developing functional polymeric materials and nanoparticles from both natural and synthetic products for antimicrobial, anticancer, and advanced materials applications. She also leads a team of researchers working in collaboration with an industry partner to develop nontoxic polymeric materials for use in advanced fire-retardant materials.

Lily Zhao is an undergraduate Bachelor of Chemical Engineering/ Bachelor of Commerce student at the University of New South Wales (UNSW), Sydney. Her interests include polymer research and creating sustainable resources for the future. In 2016, she was involved in a research project with the Centre for Advanced Macromolecular Design (CAMD) in the preparation of well-defined polymeric nanosized drug carriers of various morphologies using a sustainable, light-activated polymerization method. Lily also completed her Honours thesis with the same research group in 2018 on the high throughout synthesis of complex polymers with antimicrobial properties. Lily has also been heavily involved as an executive of the

AUTHOR INFORMATION

UNSW Chemical Engineering Undergraduate Society during her time

Corresponding Author

*E-mail [email protected].

at university and was awarded the New Colombo Plan Scholarship

Notes

earlier in 2018 to further her interests in using her skills as an engineer

The authors declare no competing financial interest.

to promote sustainability in less developed countries. O


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Prof. Cyrille Boyer received his Ph.D. from the University of Montpellier II. Cyrille moved to UNSW in the Centre for Advanced Macromolecular Design at the end of 2006. Cyrille is the codirector of Australian Centre for Nanomedicine and a member of the Centre for Advanced Macromolecular Design. He was awarded the SCOPUS Young Researcher of the Year Award in 2012, one of the six 2015 Prime Minister’s Science Prizes (Malcolm McIntosh Prize for Physical Scientist of the Year), and the 2016 LeFevre Memorial Prize and was nominated as one of the inaugural Knowledge Nation 100 selected by the Knowledge Society, guided by Australia’s Chief Scientist, Professor Ian Chubb, and senior commentators from The Australian newspaper. Cyrille’s research has also been recognized by several international awards, including 2016 ACS Biomacromolecules/ Macromolecules Award, 2016 Journal of Polymer Science Innovation Award, 2018 Polymer International-IUPAC Award, 2018 Polymer Chemistry Lectureship, and 2018 Awards of Excellence in Chemical Engineering awarded by IChemE. Cyrille has co-authored over 230 articles. Cyrille’s research interests mainly cover the use of photoredox catalysts to perform living radical polymerization and polymer postmodification for bioapplications and antimicrobial polymers.

Adam Gormley is an Assistant Professor of Biomedical Engineering at Rutgers University and an expert in nanobiomaterials. Prior to Rutgers, Adam was a Marie Skłodowska-Curie Research Fellow at the Karolinska Institutet (2016) and a Whitaker International Scholar at Imperial College London (2012−2015) in the laboratory of Professor Molly Stevens. He obtained his PhD in Bioengineering from the University of Utah in the laboratory of Professor Hamid Ghandehari (2012) and a BS in Mechanical Engineering from Lehigh University (2006). In January 2017, Adam started the Gormley Lab which seeks to develop bioactive nanobiomaterials for therapeutic and regenerative medicine applications.

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LIST OF ABBREVIATIONS AA, acrylic acid; AEAm, 2-(acetoacetoxy)ethyl acrylamide; Am, acrylamide; Amor, acryloylmorpholine; AMPL, 4acryloylmorpholine; ATRP, atom transfer radical polymerization; BA, butyl acrylate; BEB, (1-bromoethyl)benzene; BMA, n-butyl methacrylate; BMI, 1,1′-(methylenedi-4,1phenylene)bismaleimide; BnA, benzyl acrylate; BnMA, benzyl methacrylate; Boc-AEAm, tert-butyl (2-acrylamidoethyl)carbamate; BSA, bovine serum albumin; BzMI, N-benzylmaleimide; CEA, 2-carboxyethyl acrylate; CHMA, cyclohexyl methacrylate; CLRP, controlled living/radical polymerization; ConA, Concanavalin A; CTA, chain transfer agent; CyEA, 2cyanoethyl acrylate; DAAm, diacetone acrylamide; DEA, N,Ndiethylacrylamide; DEAEA, 2-(diethylamino)ethyl acrylate; DEAEMA, 2-(diethylamino)ethyl methacrylate; DEGDA, di(ethylene glycol)diacrylate; DEGMA, di(ethylene glycol) methyl ether methacrylate; DHPM, dihydropyrimidin-2Hone; DMA, N,N-dimethyl acrylamide; DMAEA, 2(dimethylamino)eth yl acrylate; DMA EMA, N, N(dimethylamino)ethyl methacrylate; DP, degree of polymerization; DSC, differential scanning calorimetry; DVB, divinylbenzene; EA, ethyl acrylate; EEA, 1-ethoxyethyl acrylate; EBIB, ethyl 2-bromoisobutyrate; EHA, 2-ethylhexyl acrylate; EMA, ethyl methacrylate; fac-[Ir(ppy)3], tris[2-phenylpyridinatoC2,N]iridium(III); GA, glycidyl acrylate; GMA, glycidyl methacrylate; GOx, glucose oxidase; HCV, hepatitis C virus; HEA, hydroxyethyl acrylate; HEAm, N-hydroxy-

Robert Chapman is a lecturer and ARC DECRA fellow in the School of Chemistry at the University of NSW (UNSW). He completed a B.Eng (Insdustrial Chemistry, Hons I) at UNSW in 2007 and a PhD in Chemistry at the University of Sydney in 2013, before working for three years as a research associate in the Stevens group at Imperial College London. In 2016, he returned to UNSW as a Vice Chancellor’s postdoctoral research fellow. Robert has expertise in polymer and peptide chemistry, self-assembly, and nanoparticle-based biosensing. His research focuses on the use of oxygen tolerant polymerizations and high throughput techniques for the design of macromolecular therapeutics. P


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ethylacrylamide; HEMA, 2-hydroxyethyl methacrylate; HEMA, hydroxyethyl methacrylate; HIV, human immunodeficiency virus; HPA, hydroxypropyl acrylate; HPMA, hydroxypropyl methacrylate; HRP, horseradish peroxidase; HTP, high throughput; IBA, isobornyl acrylate; IPMA, isopropyl methacrylate; LCST, lower critical solution temperature; MA, methyl acrylate; MAA, methacrylic acid; MBA, N,N′methylenebisacrylamide; MBP, methyl 2-bromopropionate; MEA, 2-methoxyethyl acrylate; MEO2MA, diethylene glycol methyl ether methacrylate; MEOMA, monoethylene glycol methyl ether methacrylate; MI, maleimide; MIC, minimum inhibitory concentration; MMA, methyl methacrylate; MPAm, N-(3-methoxypropyl)acrylamide; NAM, N-acryloylmorpholine; n-BA, N-butyl acrylate; NEAm, N-ethylacrylamide; NHS, N-hydroxysuccinimide; NIPAM, N-isopropyl acrylamide; NMP, nitroxide-mediated polymerization; ODA, octadecyl acrylate; OEGA, oligo(ethylene glycol) methyl ether acrylate; OEMA, oligo(ethylene oxide) methacrylate; OEGEMA, oligo(ethyleneglycol) ethyl ether methacrylate; OEGMA, oligo(ethyleneglycol) methyl ether methacrylate; PC, photoredox catalyst; PEAm, 2-phenylethyl acrylamide; PFP-MI, pentafluorophenyl 4-maleimidobenzoate; PISA, polymerization-induced self-assembly; p-MS, p-methylstyrene; PPGMA, poly(propylene glycol) methacrylate; PrMI, N-(npropyl)maleimide; proCEA, ethoxyethyl-protected 2-carboxyethyl acrylate; RAFT, reversible addition−fragmentation chain transfer; RBV-MA, ribavirin methacrylate; Rosa, rapid one-pot sequential aqueous; Ru(bpy)3Cl2, tris(2,2′-bipyridyl)dichlororuthenium(II) hexahydrate; SA, sodium acrylate; SETLRP, single electron transfer living radical polymerization; SPA, 2-sulfopropyl acrylate; SPE, solid phase extraction; SPTP, sodium phenyl-2,4,6-trimethylbenzoylphosphinate; t-BA, tertbutyl acrylate; TEGDA, tetra(ethylene glycol) diacrylate; TFAMA, 2,2,2-trifluoroethyl methacrylate; TFA, tetrafurfuryl acrylate; TGEEMA, triethylene glycol ethyl ether methacrylate; THF, tetrahydrofuran; THP-HEMA, 2-((tetrahydro-2Hpyran-2-yl)oxy)ethyl methacrylate; TIPS-PMI, triisopropylsilyl-protected N-propargyl maleimide; TsCl, p-toluenesulfonyl chloride; UMA, undecyl methacrylate; VA-044, 2,2′-azobis(2(2-imidazolin-2-yl)propane) dihydrochloride; VAc, vinyl acetate; ZnTPP, 5,10,15,20-tetraphenyl-21H,23H-porphine zinc.

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