evaluation of automated synthesis for chain and step-growth polymerizations: can robots replace the...

Evaluation of Automated Synthesis for Chain and Step-Growth Polymerizations: Can Robots Replace the Chemists?

RAMIRO ROJAS, NICOLE K. HARRIS, KAROLINA PIOTROWSKA, JOACHIM KOHN

The New Jersey Center for Biomaterials and Department of Chemistry and Chemical Biology, Rutgers,The State University of New Jersey, Piscataway, New Jersey 08854

Received 26 September 2008; accepted 8 October 2008DOI: 10.1002/pola.23119Published online in Wiley InterScience (www.interscience.wiley.com).

ABSTRACT: This article explores current challenges in the use of automated parallelsynthesizers in polymeric materials research. Four types of polymerizations wereinvestigated: carbodiimide-mediated polyesterification, diphenol phosgenation, freeradical, and reversible addition-fragmentation chain-transfer (RAFT). Synthetic chal-lenges of condensation polymerization, such as liquid and solid dispensing accuracy,dropwise addition, and toxic chemical handling, were successfully met using theautomated synthesizer. Both solid and liquid dosing of the diphenol and diacid weresuccessful for polyarylate synthesis. The high precision of liquid dispensing made itpossible to achieve stoichiometric balance using reagent stock solutions. For all reac-tions, molecular weights and their reproducibility were comparable to those obtainedwith manual synthesis. For RAFT polymerizations, solvent and mol ratio of chaintransfer reagent to initiator were successfully optimized on the automated synthe-sizer and a library of over 60 polymethacrylate copolymer compositions was gener-ated. Considerable savings in time relative to manual methods were achieved whengenerating polymer libraries (e.g., 4.5� faster for 96 polymethacrylates and 20�faster for 45 for polycarbonates). VVC 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym

Chem 47: 49–58, 2009

Keywords: automated parallel synthesis; combinatorial materials research; poly-arylates; polycarbonates; polycondensation; polymethacrylates; reversible additionfragmentation chain-transfer (RAFT)

INTRODUCTION

Modern polymer science takes advantage ofknown structure-property relationships and newsynthesis methods to assist in the creation of newmaterials. An emerging strategy in polymericmaterials research is the use of robotic platformsthat can accelerate the creation of structurallyrelated polymer libraries. Automated parallel syn-thesizers can accelerate the optimization ofsynthetic procedures through simultaneous explo-ration of reaction conditions.1 As a result, acceler-

ation of throughput is obtained, leading to theeffective exploration of polymer space. Ultimately,this can result in the identification of new anduseful material compositions for diverse applica-tions and even promote the discovery and devel-opment of new technologies.

Recent reviews advocate the use of combinato-

rial and high-throughput approaches in macromo-

lecular science, but they include only a few iso-lated cases that describe automated technologies

used instead of traditional polymerizations.2–5

Only a handful of publications describe the suc-

cess of translating manual polymer synthesis

methods to automated procedures.6–15 Studies bySchubert and coworkers, mostly describe chain-

Correspondence to: J. Kohn (E-mail: [email protected]).

Journal of Polymer Science: Part A: Polymer Chemistry, Vol. 47, 49–58 (2009)

VC 2008 Wiley Periodicals, Inc.

49

growth polymerizations,16 and a single casedescribing the step-growth synthesis of polyur-ethanes compares a single automated synthesis tomanual procedure without emphasis on the explo-ration of polymer space.8 Additional research isneeded to develop automated procedures for moretypes of industrial-relevant reactions and polymercompositions and to validate them relative tomanual syntheses. Challenges include toxic chem-ical handling, the accuracy of liquid and solid dis-pensing, and the reproducibility that can beachieved in both degree of polymerization andspecific copolymer composition.

In this article, we examine four types of polymer-ization using a commercially available robotic plat-form, focusing on the different challenges encoun-tered in each. First, the condensation of diphenoland diacid under mild conditions requires accuratedispensing to achieve the strict stoichiometric bal-ance necessary for high-molecular weight polyary-lates.17–19 Second, the condensation of triphosgenewith a diphenol20 involves both safety and dispens-ing challenges, such as ensuring adequate isolationof a toxic chemical, triphosgene, inside the auto-mated synthesizer and finding a suitable auto-mated process for dropwise addition to reactions inparallel. Lastly, two types of chain-growth polymer-izations require inert atmosphere and accurate liq-uid dispensing. For such free-radical reactions, weexpand on previous investigations13 by placing spe-cial emphasis on investigating reliability and repro-ducibility of generating target polymer composi-tions, relative to manual synthesis.

An additional focus of our work is to obtain ageneral perspective on the advantages and chal-lenges of operating automated synthesizers.Potential advantages include rapid optimizationof reaction conditions, accelerated throughput,standardization of methods, and retention ofexpertise. Challenges include the substantialamount of time required for automation of man-ual protocols and the inherent limitations of theinstrument used. As far as we are aware, ours isthe first study that uses a comprehensive and sys-tematic methodology to compare manual andautomated procedures, particularly in the case ofpolycondensation reactions.

EXPERIMENTAL

Chemicals and Reagents

All chemicals were high purity, reagent-grade, orHPLC-grade and used as received except as

noted: (i) AIBN was recrystallized from MeOH,(ii) Monomers were purified through a column ofalumina to remove inhibitors, and (iii) Solvents,solutions, and monomers were degassed withnitrogen or argon before use in free radical orRAFT polymerizations.

Triethylene glycol ethyl ether methacrylate,cyclohexyl methacrylate, and undecyl methacry-late were purchased from Polysciences. The 2,2,2-trifluoroethyl methacrylate was purchased fromMatrix Scientific. Potassium carbonate and 2-hydroxypropyl methacrylate (HPMA) were pur-chased from Acros. Diisopropylcarbodiimide(DIPC) was purchased from Tanabe. Anhydrous,inhibitor-free tetrahydrofuran (THF), sebacicacid, succinic acid, methyl methacrylate (MMA),hydroxyethyl methacrylate (HEMA), and 2,20-Azobis(2-methylpropionitrile) (AIBN) were pur-chased from Aldrich. Toluene, 1,4-dioxane,dichloromethane (CH2Cl2), dimethylsulfoxide(DMSO), ethyl acetate (EtOAc), isopropanol (IPA),methanol (MeOH), methyl ethyl ketone (MEK),and 1-methyl-2-pyrrolidinone (NMP) were pur-chased from Fisher.

Desaminotyrosyl-tyrosine alkyl esters, 4-(dime-thylamino)pyridinium 4-toluenesulfonate (DPTS),and bis(thiobenzoyl) disulfide were synthesizedfollowing literature procedures.17,21,22 Synthesisof the RAFT agent, 2-Cyanoprop-2-yl dithioben-zoate (CTA) was slightly modified from the litera-ture procedure22: A mixture of AIBN (24.6 g, 0.15mol) and bis(thiobenzoyl) disulfide (30.6 g, 0.1mol) in EtOAc (800 mL) was heated in a roundbottom flask equipped with a magnetic stirrer,reflux condenser, and heating mantle. After 18 h,the solvent was evaporated under vacuum, andthe crude material was isolated with column chro-matography (silica gel 60, 240–400 mesh) withEtOAc:Hexanes (4:1) as the mobile phase. Afterevaporation of the solvents, the 2-cyanoprop-2-yldithiobenzoate was obtained as a red oil (yield60%). 1H NMR (300 MHz, CDCl3) d/ppm; 1.96 (s,6H, 2 � CH3); 7.38 (m, m-ArH, 2H); 7.55 (m, p-ArH, 1H); 7.90 (d, J ¼ 8.7 Hz, o-ArH, 2H).

Instrumentation

The automated parallel synthesizer was a Chem-speed Accelerator SLT100 equipped with four sol-vent reservoirs and four syringes (2 � 25, 10, and1-mL). The reactor blocks were equipped withsepta and reflux condensers and could be usedwith either simple or oil-jacketed reactors(13 mL). For the latter, temperatures could be

50 ROJAS ET AL.

Journal of Polymer Science: Part A: Polymer ChemistryDOI: 10.1002/pola

controlled from �20 to 150 �C (Huber UnistatTango control unit).

Proton NMR spectroscopy was performed on aVarian 300 or 400 MHz spectrometer to determinecopolymer compositions. Samples were dissolvedin either DMSO-d6 or CDCl3. Gel PermeationChromatography (GPC) was performed using a5 lm gel precolumn and two PL columns withpore size of 103–105 A (Polymer Labs) on a Waters510 HPLC equipped with a Waters 410 Differen-tial Refractometer. The mobile phase and flowrate was either THF at 1.0 mL min�1 or N,N-dimethylformamide (DMF) containing 0.1%trifluoroacetic acid (TFA) at 0.8 mL min�1. Molec-ular weights (number-average) and polydispersityindex (PDI) were determined relative to polysty-rene calibration standards.

Step-Growth Case 1: Syntheses of PolyarlyatesVia Carbodiimide-Mediated Couplingof Desaminotyrosyl-Tyrosine Butyl Ester(DTB) and Sebacic Acid

Manual Synthesis Protocol

DTB (215.8 mg, 0.56 mmol), sebacic acid (113.2mg, 0.56 mmol), DPTS (70 mg, 0.24 mmol), DIPC(0.28 mL, 1.80 mmol), and CH2Cl2 (4.0 mL) werecharged into 8 � 7-mL glass vials with Teflon-lined caps and mixed on a shaker for 48 h at RT.The reactions were precipitated in IPA and driedunder vacuum for �24 h at 60 �C. The scale wasthe same as that used in the automated parallelsynthesizer.

Automated Parallel Synthesis Protocol

The oil-jacketed reactors were rendered inert byfive cycles of evacuation under vacuum at 120 �Cfor 10 min, backfilled with argon, and cooled toroom temperature (RT).

Solid Dispensing. Monomers (DTB and sebacicacid) and catalyst (DTPS) were dispensed as sol-ids using optimized dispensing parameters (finaldosing amount, initial dosing speed, mass flow, fil-ter coefficient, and oscillation periods) and ex-truder. The diphenol was dispensed first, and theamount was weighed as part of the automatedworkflow. Based on this information, the amountof diacid needed was calculated and programmedfor each individual reactor. DIPC was transferredas a solution in chloroform.

Liquid Dispensing. Monomer stock solutions,[0.4 M DTB in THF (1.4 mL, 215.8 mg, 0.56mmol) and 0.316 M sebacic acid in THF (1.77 mL,113.1 mg, 0.56 mmol)], were charged by syringetransfer to eight reactors using the 4-needle toolwith various syringe sizes. The transferred stocksolutions were evaporated to remove THF. Thereactors were cooled to 20 �C, and 0.136 M DPTSin CH2Cl2 (1.8 mL, 72 mg, 0.25 mmol), CH2Cl2(2.2 mL), and DIPC (0.28 mL, 1.80 mmol) weretransferred by syringe. The reactors were thenvortexed at 600 rpm for 48 h at RT. The polymerswere precipitated manually in IPA and were driedunder vacuum for �24 h at 60 �C.

Step Growth Case 2: Synthesis of PolycarbonatesVia Diphenol Phosgenation of Desaminotyrosyl-Tyrosine Ethyl Ester (DTE)

Caution: Triphosgene is a hazardous (toxic andcorrosive) chemical. A phosgene detector was in-stalled into the hood of the automated synthesizerso that the absence of phosgene could be verifiedat the end of the reaction before opening therobot’s hood to the laboratory. Additionally, twovials (8-mL) containing ammonium hydroxidesealed with septa and an empty vial (8-mL) totransfer the ammonia were placed in the instru-ment in case any residual phosgene (from the tri-phosgene breakdown) needed to be quenched, asfurther discussed in Results and Discussion.


DTE (2.5 mL, 0.6 g DTE, 1.68 mmol, 0.67 M) inpyridine/CH2Cl2 (3.45 equivalents of pyridine/DTE) was transferred via syringe into two 50-mLround bottom flasks, each equipped with magneticstir bar and septa with Teflon tubing connected toa 2-syringe infusion pump. Triphosgene solution(19 wt %, 1 mL, 0.2 g, 0.67 mmol) was delivereddropwise (50 lL min�1) to the two reactions usingthe syringe pump. The reactions were stirred anadditional 45 min before quenching with 5-mLTHF:H2O.


A 25-mL stock solution of 0.67 M DTE in pyri-dine/CH2Cl2 was prepared using 6.0-g DTE (16.78mmol) and 4.7-mL (57.6 mmol) pyridine. The DTEstock solution (2.5 mL, 0.6 g DTE, 1.68 mmol) wastransferred to four of the simple (non-jacketed)reactors equipped with septa. The reactions were

CHAIN AND STEP-GROWTH POLYMERIZATIONS 51

Journal of Polymer Science: Part A: Polymer ChemistryDOI 10.1002/pola

vortexed at 600 rpm at RT. A stock solution of tri-phosgene in toluene (20 wt %, 1 mL, 0.2 g, 0.67mmol) was dispensed to each reaction (i.e., 10 ali-quots of 100 lL dispensed at 1 mL min�1) usingthe 1 mL syringe equipped with a ceramic-coatedneedle. After the addition was complete, the reac-tions were vortexed for 45 min at RT, quenchedwith a 1:1 mixture of THF/H2O, and then vor-texed for 30 additional minutes. The reactionswere precipitated manually in IPA and driedunder vacuum for �24 h at 60 �C. [Note: Precipi-tation also removes low molecular weight polymerfractions.]

Chain-Growth Cases: Syntheses ofPolymethacrylates Via Free Radical Solution (FRS)and Reversible Addition-FragmentationTransfer (RAFT) Polymerizationof Isobutyl Methacrylate


Purified isobutyl methacrylate (3 g), toluene,AIBN stock solution ([iBuMA]0/[AIBN]0 ¼ 400)for FRS or AIBN stock solution ([CTA]0/[AIBN]0¼ 4) for RAFT, RAFT chain transfer reagent stocksolution ([iBuMA]0/[CTA]0 ¼ 1000), and a mag-netic stir bar were charged in a 50-mL round-bot-tomed flask before sealing with a septa. The reac-tions were degassed by bubbling nitrogen throughthe solutions. The reactions were then stirred for6 h (or 20 h for RAFT) at 70 �C, cooled to RT, pre-cipitated in MeOH, and dried under vacuum for�24 h at 60 �C. Ten reactions were run inparallel.


The 13-mL oil-jacketed reactors equipped withsepta and reflux condensers were inertized beforereagent addition as described above. The reactorswere cooled to RT and the degassed reagents(purified monomers, stock solution of either AIBN([iBuMA]0/[AIBN]0 ¼ 400) (conventional free radi-cal) or a co-solution of AIBN with 2-cyanoprop-2-yl dithiobenzoate (RAFT chain transfer reagent)([CTA]0/[AIBN]0 ¼ 4), and ([iBuMA]0/[CTA]0 ¼1000)) and solvent were charged by syringe trans-fer using the 4-needle tool while being purgedwith argon. Volumes �1 mL were transferredusing the 1 mL syringe to maximize the accuracy.The reactions were vortexed at 600 rpm at 70 �Cfor 6 h (FRS) or 20 h (RAFT) under argon. Thereactions were cooled to 20 �C and precipitated

manually. The polymers were dried under vac-uum for �24 h at 60 �C.

RESULTS AND DISCUSSION

Stoichiometric Balance: Investigation of SolidVersus Liquid Dispensing

Automated synthesis of condensation polymerswith high molecular weight is only feasible whenautomated reagent dispensing is accurate to �2%.In other words, the mol ratio of the monomersmust be �0.98 to achieve a degree of polymeriza-tion (DP) in excess of 99. A reaction based on100-mg diphenol and 60-mg diacid requires accu-racy within 2 and 1 mg, respectively. Scaling upto 0.5-g diphenol increases the acceptable vari-ability five-fold, but it also increases the chancesof clogging the extruders during solid dispensing.

To achieve accurate and reproducible solid dos-ing, we focused on both materials preparation(e.g., grinding and sieving the reagents into a uni-form powder, vacuum drying, and storing in adehumidifier) and on adjustable parameters ofthe parallel synthesizer (e.g., type of extruder andthe rate of oscillation toward the end of the dis-pensing). However, for desaminotyrosyl-tyosinebenzyl ester (DTB), despite these efforts toimprove fine dosing, the standard deviations wereoutside of the acceptable range to maintain stoi-chiometric balance within 2%. The typical resultobtained for 20 replicates was 223 � 10.9 mg,which is �5%, whereas 2% is needed. In contrast,the synthesizer could successfully dispense diac-ids with the requisite precision (see Table 1).

One possible ‘‘work-around’’ is to make thediphenol the first reagent dispensed and use theautomatically generated recordings of the exactamount delivered to the vial to re-calculate theamount of second reagent needed for exact stoi-chiometric balance. This work-around requiresthat the workflow be temporarily stopped so thatthe necessary amounts of second reagent can becalculated for each individual reactor, followed byrestarting the automated workflow. The averagemolecular weight of poly(DTB sebacate), whichwas synthesized in this way in three repetitionsby automated synthesis, was 174 � 46 kg mol�1

(Table 2), when compared with 118 � 44 kg mol�1

for manual synthesis. The degree of polymeriza-tion was 200 for the manual method and 288 forthe automated. Without this work around, the av-erage molecular weight achieved in three repeti-tive syntheses of poly(DTB sebacate) was beyond

52 ROJAS ET AL.


the lower limits of our standard curve, indicativeof oligomer formation of less than 20 repeatingunits. It is important to emphasize that thiswork-around only works when one of the tworeagents that need to be in stoichiometric equiva-lence presents facile solid dispensing (in this case,the diacid, as evidenced by the data for accuracyand repeatability of extruder in Table 1).

Next, we explored the alternative approach ofusing liquid stock solutions. Experimental varia-bles that had to be optimized were (i) syringe sizeand delivery rate and (ii) solvent choice. Liquiddispensing was performed with a high degree ofaccuracy and precision when the solvent lines

were primed and an appropriately nonvolatile sol-vent was chosen (i.e., it was necessary to useTHF, toluene, or DMF instead of the highly vola-tile CH2Cl2) (Table 1). The precision was furtherimproved from �30 lL to �4 lL by dispensingwith a 1 mL syringe instead of a 25 mL one.

Solvent Optimization

For carbodiimide-mediated polycondensations,the CH2Cl2 is the preferred solvent, but cannot beused with the available liquid dispensers due toits high volatility and because it is a poor solventfor the monomers used in this study. However, as

Table 2. Comparison of Automated and Manual Synthesis of Step and Chain Polymerization

PolymerType of

PolymerizationAutomatedDispensing

Mwa (kg mol�1)

nbAutomated Manual

Poly(DTB sebacate)by condensation

Step Solid 174 � 46 118 � 44 3,8Liquid 95 � 38 – 8

Poly(DTE carbonate)by phosgenation

Step Liquid, dropwise(25 mL)

374 � 218 297 � 92 4

Liquid, dropwise(1 mL)

218 � 86 – 4

Liquid, 25 lL 137 �134 – 4Liquid, 50 lL 84 � 8 – 4Liquid, 100 lL 194 � 40 – 4

Poly(isobutyl methacrylate)by free radical polymerization

Chain Liquid 125 � 13 127 � 18 10

Poly(isobutyl methacrylate)by RAFT polymerization

Chain Liquid 49 � 4 110 � 5 (46 � 0)c 10

aMeasured by SEC, values relative to polystyrene standards.bNumber of repetitions.cHigher MW when degassing was final step.

Table 1. Determination of Liquid and Solid Dispensing Accuracy on the Chemspeed SLT100

Solid TransferSolidType Extruder

ProgrammedValue (mg)

ExperimentalAverage (mg)

StandardDeviationa

DTB Powder Type 4, cone 215.80 222.89 10.90Sebacic acid Beads Modified type 2 113.20 113.19 0.40Adipic acid Fine powder Modified type 2 81.84 81.95 0.36

Liquid TransferReservoirSolvent

SyringeSize

ProgrammedValue (mL)

ExperimentalAverage (mL)

StandardDeviationa

THF reactor to vial CH2Cl2 1 mL 0.500 0.463 0.008Toluene reactor to vial Toluene 1 mL 0.500 0.496 0.002THF vial to vial THF 1 mL 0.500 0.496 0.001Toluene reactor to vial Toluene 25 mL 3.930 3.900 0.010

aBased on n ¼ 10–20.



the reaction progresses with the fraction of themonomer molecules in solution the solubility isnot longer an issue as the polymer is soluble inCH2Cl2. On the other hand, all of the polar,aprotic solvents that work well with the liquiddispensing system and were good solvents for themonomers, interfered with the carbodiimide-mediated polycondensation reaction and producedonly low molecular weight products. Previously, itwas reported that addition of 3% pyridine to thereaction mixture, reduced the molecular weight ofthe product by one-half.18 These results are con-sistent with reports that polar solvents decreasethe reaction rate of carbodiimide with acids byimproving solvation of the acid.23

Thus, we had to address the significant chal-lenge of selecting a solvent system that would dis-solve the monomers, be suitable for liquid dis-pensing, and be suitable for the polymerization.Because none of the solvents that exhibited goodmonomer solubility were suitable to obtain highmolecular weight polymers (see Table 3), it wasnecessary to use different solvents for dispensingof the monomers and for performing the polycon-densation reactions. Of the solvents listed in Ta-ble 3, THF was identified as the preferred dis-pensing solvent. Once the reagents weredispensed, THF was removed by evaporation, andCH2Cl2 was added into the reactors as the poly-merization solvent.

These extra steps would have been very incon-venient in manual synthesis, but in the context ofan automated workflow, the solvent exchange stepsdid not cause any additional work for the operator.The polymers obtained by manual synthesis andautomated synthesis using THF stock solutions ineight repetitions resulted in similar weight-aver-age molecular weights and standard deviations:

118 � 44 kg mol�1 for manual (using solid dispens-ing and CH2Cl2 as reaction medium) and 95 � 38kg mol�1 for automated synthesis (THF for dis-pensing and CH2Cl2 for reaction) (Table 2).

In summary, the use of accurately prepared re-agent stock solutions made it possible to achievethe stoichiometric balance required to obtain highmolecular weight polymers via automated synthe-sis. Additional steps for the evaporation of the dis-pensing solvent were needed, but were readilyincorporated into the automated workflow.

Dropwise Addition of Reagent and Use ofHazardous Materials During DiphenolPhosgenation Towards Polycarbonate Synthesis

Triphosgene is a versatile phosgene substituteuseful in a myriad of chemical transformations,such as chlorination, chloroformylation, carbony-lation, and dehydration. Often, manual proce-dures using triphosgene solutions call for slowand dropwise addition to the reaction mixture;thus, the development of an automated protocolmimicking the ‘‘drop-wise’’ addition of a triphos-gene solution would be beneficial in a wide rangeof synthetic procedures, not only polycarbonatessynthesis.24

The first step towards automating this processwas to determine if triphosgene could be safelyused in the automated synthesizer. For the liquidtransfer, a ceramic-coated needle was required tohandle the corrosive triphosgene stock solution.Teflon tubing was used during all procedures. Theuse of ammonia (dispensed from vials of ammo-nium hydroxide, as outlined in the Experimentalsection) worked well to quench phosgene in theair space of the hood. Unused triphosgene solu-tion was quenched with equal volumes of 10%triethylamine in ethanol.

The major challenge with automating the phos-genation reaction was defining dispensing param-eters that could mimic the dropwise addition oftriphosgene solution over 30 min to 1 h in themanual protocol and allow for multiple reactionsto be run in parallel. Specifically, the synthesis ofpoly(DTE carbonate) was investigated as a modelreaction. First, we tried to mimic dropwise addi-tion directly by reducing the dispensing rate to0.05 mL min�1. Both 25 mL and 1 mL syringeswere evaluated, and the triphosgene solution wasdispensed dropwise in four cycles of 250 lL eachto four reactors. The resulting polymers hadweight-average molecular weights of 374 �218 kg mol�1 and 218 � 86 kg mol�1 for the 25

Table 3. Solvent Effect on Polymerizationof Poly(DTB sebacate)

SolventPolarityIndex r ¼ NA/NB

Mwa

(kg mol�1)

DMSO 7.2 1.00 6NMP 6.7 1.00 10DMF 6.4 0.99 12EtOAc 4.4 0.98 51THF 4.0 0.99 12CH2Cl2 3.1 1.00 111

aMeasured by THF SEC, values relative to polystyrenestandards.

54 ROJAS ET AL.


and 1 mL syringes, respectively, which compareswith 292 � 92 kg mol for the manual syntheses(Table 2). Although the average molecular weightwas greater than 200 kg mol�1 for both the auto-mated and manual phosgenations, the variabilitywas very high when the 25 mL syringe was usedfor the triphosgene addition.

The obvious approach was to investigate theeffect of increasing the size of the aliquot of tri-phosgene solution dispensed. Specifically, wewanted to determine if the same results could beobtained when triphosgene solution was deliveredat a faster dispensing rate and in larger aliquotsof 25, 50, or 100 lL. Additions with aliquots of 25or 50 lL at 1 mL min�1 failed to provide eitherhigh molecular weight polymer or reproducibleresults (137 � 134 kg mol�1 and 84 � 8 kg mol�1,respectively). We expect this is due to quenchingof the triphosgene solution by moisture inside thehood of the automated synthesizer.

By using a larger aliquot of 100 lL, we couldminimize the exposure of the solution in the nee-dle and in the stock solution vial to the atmos-phere of the automated synthesizer and acceler-ate the rate of addition. Specifically, 10 cycles of100 lL of triphosgene solution were dispensed at1.0 mL min�1 to four reactions and yielded poly-mers with weight-average molecular weights of194 � 40 kg mol�1. Although there was a slightdecrease in molecular weight moving from drop-wise addition to dispensing 100 lL aliquots of tri-phosgene solution, the addition can be completedin a time frame (i.e., 30 min) amenable to parallelreactions. Based on these results, we expect thatwith two needles working in parallel, we will beable to run eight reactions in parallel. Becausethe total reaction time is only 1 h, 48 reactionscould be performed overnight. Comparatively,manual synthesis of 48 polycarbonates could atbest be performed in 2 to 3 weeks by running fourreactions a day, or 20 reactions per week; thus,the automated synthesis of polycarbonates is apreferred approach to accelerate output andexplore polymer space.

Reproducibility of Automated Free Radicaland RAFT Polymerizations Through Synthesisof Poly(isobutyl methacrylate)

Automated synthesis of polymethacrylates byRAFT polymerization, using 2-cyanoprop-2-yldithiobenzoate as the chain transfer reagent, haspreviously been reported.13 We developed similarprotocols without purging the automated synthe-

sizer hood with argon, as first trials indicatedthat we could omit this step from the publishedmethod and still get reproducible high-molecularweights. Specifically, the purified monomers,stock solutions, and solvent were degassed andtransferred by syringe to the reactors, which hadbeen thrice evacuated and refilled with argon.The manual synthesis was executed by degassingthe reaction after reagents were charged and theflask was sealed with a septum.

For conventional free radical polymerization,the reproducibility for the manual and automatedsynthesis of poly(isobutyl methacrylate) wasexcellent (Table 2). In the case of RAFT polymer-ization, the polymer molecular weights obtainedby automated synthesis were lower than thoseprepared by manual synthesis. Oxygen has beenshown to retard radical polymerizations.25 There-fore, for direct comparison of the automated pro-cedure, manual synthesis of the RAFT procedurewas performed using syringe transfer of degassedreagents to a flask while purging with nitrogen.The molecular weights of the polymers obtainedby manual synthesis without the final degassingstep were comparable to the products of the auto-mated protocol, suggesting that the oxygen incor-porated during the syringe transfer was sufficientto affect the polymerization. Thus while ourresults show that purging of the automated syn-thesizer is not needed for conventional free radi-cal reactions, stringent exclusion of oxygen maybe needed to optimize RAFT polymerizations, forexample by purging with argon while transferringthe reagents.

Reaction Optimization: A Case Studyof a Polymethacrylate Library Synthesis

Solvent effects on initiator efficiency, monomerreactivity ratio, and polymerization rate havebeen reported.22,26 Usually, these experimentstake considerable amount of time, as reactionsare executed one at a time. We wanted to provethe advantages of automated parallel synthesisfor the reaction optimization of different polyme-thacrylates in a single experiment. In particular,we evaluated the effect of solvent on the synthesisof several homopolymers and copolymers (Table 4).Comparison of copolymerization reactions of ben-zyl and hydroxypropyl methacrylate (MA) withMMA revealed that lower molecular weightpolymers with high polydispersities were ob-tained when toluene or DMF was used as thesolvent, but well-defined high-molecular weight



polymers could be obtained using MEK. Also,polymerization of methacrylic acid in dioxanewas significantly faster than in DMF, even whenthe mol ratio of CTA to AIBN was reduced tofour. In the case of undecyl methacrylate, bulkpolymerization provided the highest molecularweight product. Additionally, control of the poly-merization depends on the chain transfer effi-ciency of the RAFT chain transfer reagent.27 Themolecular weight of a benzyl MA-MMA copoly-mer and poly(tetrahydrofuryl methacrylate)were successfully increased when the mol ratio ofCTA to AIBN was reduced from 10 to 4. Forpoly(t-butyl methacrylate), the combination ofthe low mol ratio of CTA to AIBN and the use oftoluene as the reaction solvent resulted in a poly-mer with a broad PDI. By changing the reactionsolvent to either EtOAc or MEK and increasingthe CTA to AIBN mol ratio to 10, the polymeriza-tion of t-butyl methacrylate resulted in a productwith a lower PDI. In short, parallel synthesisallows for rapid optimization of reaction condi-tions by analyzing several parameters at once.

Reproducibility of RAFT Polymerization on theAutomated Synthesizer: Synthesis of a LargeMethacrylate Copolymer Library

Evaluation of monomer feed versus actual compo-sition parameters of 63 polymethacrylate copoly-mers synthesized twice by RAFT methods (two

different experiments) on the automated synthe-sizer revealed that the target copolymer composi-tions could be achieved with excellent accuracyand repeatability. In summary, 10 reactions out ofthe 63 did not produce an isolable solid (indicativeof low-molecular weight oligomer), but of theremaining 53 copolymers, 52 exhibited a composi-tion within 2 mol % of the theoretically expectedcomposition, as determined by 1H NMR spectros-copy (Results not shown). The high precision inthe copolymer compositions that were successfullysynthesized is a direct reflection of the perform-ance of the automated liquid dispensing. Theinability to synthesize a few of the compositionswas governed by the monomer reactivity ratio, asthe reaction conditions were the same for allpolymerizations.

Acceleration of Output: ManualVersus Automated

As with manual synthesis, preparation for a largenumber of repetitive experiments requires signifi-cantly more time for planning and preparationthan running a single experiment. Reaction opti-mization is critical when a large set of polymershas to be synthesized, irrespective of the use ofmanual or automated synthesis. However, whenusing an automated parallel synthesizer, there isan extra step: The translation of a manual syn-thetic procedure into an automated ‘‘workflow’’ of

Table 4. Solvent Effect on Polymethacrylate Polymerizations

Solvent Monomer Polymerized [CTA]0/[AIBN]0 Mna (kg mol�1) PDI

Dioxane Methacrylic acid 10 221 1.5DMF Methacrylic acid 10 48 1.5DMF Methacrylic acid 4 98 1.6DMF Tetrahydrofurfuryl MA 4 137 1.6DMF HPMA-MMA (75-25) 10 54 1.8DMF Tetrahydrofurfuryl MA 10 44 1.8EtOAc t-Butyl MA 10 32 1.5MEK Benzyl MA-MMA (25-75) 10 97 1.4MEK HPMA-MMA (75-25) 10 154 1.4MEK Benzyl MA-MMA (50-50) 4 144 1.5MEK t-Butyl MA 10 49 1.6MEK Undecyl MA 4 85 1.6None Undecyl MA 4 185 1.8Toluene Undecyl MA 4 19 1.8Toluene Benzyl MA-MMA (25-75) 10 22 1.9Toluene t-Butyl MA 4 31 2.0Toluene Benzyl MA-MMA (50-50) 10 43 2.1

aMeasured by SEC, values relative to polystyrene standards.

56 ROJAS ET AL.


the sequence of tasks to be performed, such as heat-ing, cooling, stirring, precipitating, filtering, etc.

This time needed to translate manual synthesisto automated is usually long (from 2 h to 2 daysfor the polymerization systems we studied), and itmay also include making time for performing oneor more dry runs with inactive ‘‘placebo’’ reagentsbefore expensive or scarce reagents are used. Thecritical question, therefore, is when a ‘‘crossover’’is achieved and the time to generate the workflowis more than compensated by savings in time,throughput, quality, etc.

As a specific example, we compared the timerequired for manual and automated synthesis of10 and 45 methacrylate polymers. For 10 repli-cates of the RAFT polymerization of isobutylmethacrylate, the total time required from startto finish for automated synthesis was severalhours longer than for manual synthesis. Further-more, the total operator time (e.g., the time a per-son was engaged in performing the synthesisexclusive of waiting or idle time) was 30 minlonger for automated synthesis than manualsynthesis.

As one would expect, the use of an automatedsynthesizer became significantly more efficientthan manual synthesis when 45 reactions had tobe performed. The set up for 45 reaction vesselson the automated synthesizer took only 10 minmore than setting up 10 reactions. The expansionof the number of polymethacrylate synthesesfrom 10 to 45 required almost no extra time ofeffort on the automated synthesizer, whereas therepetitive manual synthesis of 45 polymethacry-lates required 4.5 times more operator time thanthe synthesis of 10 polymethacrylates.

In the case of manual polycarbonate synthesis,the dropwise addition of the triphosgene reactionrequired significant operator time. When synthe-sizing polycarbonates manually, even an experi-enced operator could not conduct more than sixindividual manual syntheses per day. Here theautomated synthesizer was able to reduce thetime required to synthesize 45 different polycar-bonates from over 2 weeks to a single overnightprocedure.

One clear advantage of the automated protocolis the ability for two different individuals toobtain the exact same results over a shorter pe-riod of time. Even with the most explicitly docu-mented manual synthesis, subtle differences inan individual’s technique affect the outcome of acomplex synthetic procedure. In the case of anautomated workflow, exactly the same results will

be obtained each time the workflow is executed,as long as the reagent solutions are identical.

CONCLUSIONS

Successful solutions to synthetic challenges inautomated synthesis, such as stoichiometric bal-ance, dropwise addition, and handling of toxicchemicals, have been described in this article. Inparticular, procedures for the automated synthe-sis of condensation polymers (tyrosine-based poly-arylates and polycarbonates) have been describedfor the first time. These results establish the fea-sibility of using automated reagent dispenserseven when extremely accurate reagent ratios areneeded. Comparison of automated and manualsynthesis for 10 and 45 polymethacrylates demon-strated that for small sets of polymers, the advan-tages of automated synthesis are improved repro-ducibility, but not necessarily reduced labor. Theability of automated synthesis to significantlyaccelerate project timelines becomes more pro-nounced when a larger number of polymers needto be synthesized. An additional use of the auto-mated synthesizer is to explore different reactionconditions in parallel. Finally, one of the most sig-nificant advantages of automated synthesis is thepreservation of ‘‘know-how’’: Once a workflow hasbeen optimized and archived, even minimallytrained personnel can precisely reproduce thesynthetic results obtained initially by highlytrained chemists. In summary, the automatedsynthesizer does not replace the chemist; rather,the chemist’s expertise is needed for designing aneffective workflow, which is then available forindefinite reuse.

The authors thank Chemspeed Technologies for helpfulconversations while pursuing this work. We also thankRoss Zimnisky for his assistance in editing the manu-script. This workwas supported by RESBIO (IntegratedTechnology Resource for Polymeric Biomaterials)funded by National Institutes of Health (NIBIB andNCMHD) under grant P41 EB001046. The content issolely the responsibility of the authors and does notnecessarily represent the official views of the NIH,NIBIB, or NCMHD. Additional financial support wasprovided by the New Jersey Center for Biomaterials.

REFERENCES AND NOTES

1. Zhang, H.; Hoogenboom, R.; Meier, M. A. R.;Schubert, U. S. Meas Sci Technol 2005, 203–211.



2. Webster, D. C. Macromol Chem Phys 2008, 209,237–246.

3. Rajan, K. Annu Rev Mater Res 2008, 38, 299–322.4. Petersen, L. K.; Narasimhan, B. Expert Opin

Drug Delivery 2008, 5, 837–846.5. Goldberg, M.; Mahon, K.; Anderson, D. Adv Drug

Delivery Rev 2008, 60, 971–978.6. Voorn, D. J.; Fijten, M. W. M.; Meuldijk, J.; Schu-

bert, U. S.; Van Herk, A. M. Macromol RapidCommun 2003, 24, 320–324.

7. Schmatloch, S.; Van den Berg, A. M. J.; Fijten,M. W. M.; Schubert, U. S. Macromol Rapid Com-mun 2004, 25, 321–325.

8. Nasrullah, M. J.; Roesler, R. R.; Schmitt, P.;Bahr, J. A.; Gallagher-Lein, C.; Webster, D. C. InACS Polymer Prepr; American Chemical Society:Chicago, IL, 2007; pp 175–176.

9. Klos, J.; Wurm, F.; Koenig, H. M.; Kilbinger, A. F.M. Macromolecules 2007, 40, 7827–7833.

10. Hoogenboom, R.; Fijten, M. W. M.; Paulus, R. M.;Thijs, H. M. L.; Hoeppener, S.; Kickelbick, G.;Schubert, U. S. Polymer 2006, 47, 75–84.

11. Hartmann, L.; Krause, E.; Antonietti, M.; Borner,H. G. Biomacromolecules 2006, 7, 1239–1244.

12. Guerrero-Sanchez, C.; Abeln, C.; Schubert, U. S. JPolymSci Part A: PolymChem2005, 43, 4151–4160.

13. Fijten, M. W. M.; Paulus, R. M.; Schubert, U. S. JPolymSci Part A: PolymChem2005, 43, 3831–3839.

14. Ekin, A.; Webster, D. C. Macromolecules 2006, 39,8659–8668.

15. Atallah, P.; Wilson, J.; Gonzalez, I.; Chavanne, J.;Bacquet, G.; Destarac, M. In ACS Polymer Prepr;American Chemical Society: Philadelphia, PA,2008; pp 175–176.

16. Remzi Becer, C.; Groth, A. M.; Hoogenboom, R.;Paulus, R. M.; Schubert, U. S. QSAR Comb Sci2008, 27, 977–983.

17. Moore, J. S.; Stupp, S. I. Macromolecules 1990,23, 65–70.

18. Fiordeliso, J.; Bron, S.; Kohn, J. J Biomater SciPolym Ed 1994, 5, 497–510.

19. Brocchini, S.; James, K.; Tangpasuthadol, V.;Kohn, J. J Am Chem Soc 1997, 119, 4553–4554.

20. Pulapura, S.; Kohn, J. Biopolymers 1992, 32,411–417.

21. Hooper, K. A.; Kohn, J. J Bioact Compat Polym1995, 10, 327–340.

22. Benaglia, M.; Rizzardo, E.; Alberti, A.; Guerra,M. Macromolecules 2005, 38, 3129–3140.

23. Mikolajczyk, M.; Kielbasinski, P. Tetrahedron1981, 37, 233–284.

24. Cotarca, L.; Eckert, H. Phosgenations: A Hand-book; Wiley-VCH: Weinheim, Great Britain, 2004.

25. Odian, G. Principles of Polymerization; Wiley:New York, 1981.

26. Moad, G.; Soloman, D. H. The Chemistry of FreeRadical Polymerization; Elsevier Science: Oxford,1995.

27. Moad, G.; Rizzardo, E.; Thang, S. H. Aust JChem 2005, 58, 379–410.

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