Accelerating the Living Polymerization of 2-Nonyl-2-oxazoline by Implementing a Microwave Synthesizer into a High-Throughput Experimentation Workflow Richard Hoogenboom, Frank Wiesbrock, Mark A. M. Leenen, Michael A. R. Meier, and Ulrich S. Schubert* Laboratory of Macromolecular Chemistry and Nanoscience, EindhoVen UniVersity of Technology and Dutch Polymer Institute (DPI), PO Box 513, 5600 MB EindhoVen, The Netherlands ReceiVed September 28, 2004 Introduction. During the past decade, the field of high- throughput and combinatorial polymer research has grown rapidly. 1-3 Many different polymerization techniques, varying from polycondensation to anionic polymerizations, have been performed in an automated parallel fashion. To analyze the increasing amount of samples, various characterization techniques have been automated 4 or accelerated, as well. 5 Another very recent development in organic chemical research is the introduction of (monomodal) microwave synthesizers. 6 Performing reactions under microwave irradia- tion instead of conventional heating results in increased reaction speeds and reduced occurrence of side reactions; however, the driving force (thermal or nonthermal microwave effects) for these improvements is still under debate. 6-9 Microwave synthesizers were also applied for combinatorial approaches in organic chemistry. 10,11 The commercially available microwave synthesizers for combinatorial and high- throughput synthesis from the major suppliers were described recently in equipment reviews. 12-14 Although microwave- assisted synthesis is quite common in organic synthesis nowadays, its application in polymer chemistry is only in its infancy. 15,16 The effect of microwave irradiation has been mainly investigated for step-growth polymerizations, 17,18 ring- opening polymerizations, 19,20 and for both free and controlled radical polymerizations; 21,22 however, many of the reported investigations were performed utilizing domestic microwave ovens without full temperature and pressure control, making the reproducibility doubtful. 16 In this contribution, we describe the implementation of a monomodal microwave synthesizer into a high-throughput workflow (including high-throughput screening (HTS) with GC, GPC and MALDI-TOF MS) for combinatorial material research for the first time. This setup was utilized to screen solvent mixtures of acetonitrile and dichloromethane for the accelerated cationic ring-opening polymerization of 2-nonyl- 2-oxazoline under microwave irradiation. 23 In addition, detailed kinetic investigations were performed for the po- lymerization of 2-nonyl-2-oxazoline in dichloromethane. Results and Discussion. To combine the advantages of both microwave-assisted polymer synthesis and high- throughput polymer synthesis, the implementation of a microwave synthesizer (Emrys Liberator, Biotage) 24 into a high-throughput workflow was investigated. Even though this microwave system comprises a liquid handling system, a more modular approach was needed to fulfill the different automated filling and sampling tasks. In addition, for many reactions it is required to handle the stock solutions under an inert atmosphere. Both the inert atmosphere and the flexible modular approach were found in an ASW2000 synthesis robot. 25 The standard racks for the microwave synthesizer were programmed as customized rack in the ASW2000 software, enabling the incorporation of the microwave vials into the previously established high- throughput workflow around the ASW2000 robot. 4,25 The extended workflow with the microwave synthesizer is schematically depicted in Figure 1, where all arrows going outside or inside the synthesis robot represent manual transportation of the racks to the appropriate equipment. The new workflow consists of three major steps, as depicted by the numbers in Figure 1: (1) Automated preparation of the reaction mixtures by dispensing stock solutions with the ASW2000 (under inert atmosphere, if required). (2) Trans- portation of the microwave vials to the microwave synthe- sizer and subsequent polymerization of the reaction mixtures utilizing the microwave robot arm for automated sequential irradiation of the vials (quenching can also be done auto- matically if required). When all polymerizations are finished, the rack is placed back into the ASW2000 robot. (3) Samples for, for example, gas chromatography (GC) and gel perme- ation chromatography (GPC) can be taken automatically from all polymerization mixtures. After manual transportation of * To whom correspondence should be addressed. E-mail: u.s.schubert@ tue.nl. Figure 1. Schematic representation of the automated workflow, including the microwave synthesizer and the peripheral character- ization equipment. All arrows going outside or inside the ASW2000 synthesis robot (synthesizer) represent manual steps. 10 J. Comb. Chem. 2005, 7, 10-13 10.1021/cc049846f CCC: $30.25 © 2005 American Chemical Society Published on Web 12/21/2004