Investigation of Factors Influencing the Chemoenzymatic Synthesis of Block Copolymers Matthijs de Geus, Joris Peeters, ‡ Martin Wolffs, ‡ Thomas Hermans, ‡ Anja R. A. Palmans, ‡ Cor E. Koning, and Andreas Heise* , Department of Polymer Chemistry and Department of Macromolecular and Organic Chemistry, Technische Universiteit Eindhoven, Den Dolech 2, P.O. Box 513, 5600 MB Eindhoven, The Netherlands Received December 20, 2004; Revised Manuscript Received March 24, 2005 ABSTRACT: The chemoenzymatic synthesis of block copolymers from a bifunctional initiator using enzymatic ring-opening polymerization (eROP) and ATRP in two consecutive steps was investigated. First, a polycaprolactone (PCL) macroinitiator was obtained via an enzymatic ring-opening polymerization initiated by the bifunctional initiator. By carefully managing the water activity in the system, the amount of PCL not initiated by the bifunctional initiator was reduced to <5%. Moreover, comparison of the results from 1 H NMR and MALDI-ToF of PCL obtained from different bifunctional initiators revealed an influence of the initiator structure on the initiation behavior in the enzymatic reaction. Block copolymers were obtained in a subsequent ATRP. The combination of various characterization techniques such as GPC, GPEC, and DSC provided clear evidence of the block structure of the polymers. Introduction Biocatalytic approaches in polymer science are ex- pected to further increase the diversity of polymeric materials. Major progress has been achieved over the past years in applying enzyme catalysis in polymer science. 1,2 The application of enzymes in polymer syn- thesis and transformation is attractive due to their ability to function under mild conditions with high enantio- and regioselectivity. The stability of lipases in organic media and their ability to promote transesteri- fication and condensation reactions on a broad range of low and high molar mass substrates have been shown in many examples. In particular, immobilized Lipase B from Candida Antarctica (Novozym 435) has shown exceptional activity for a range of polymer forming reactions, including the ring-opening polymerization of cyclic monomers (e.g., lactones, carbonates). 3 The application of enzymes as catalysts in a nonnatu- ral environment was until now predominantly the domain of organic chemistry. 4 The development of biocatalytic methods in this field on both academic and industrial levels, however, offers interesting opportuni- ties for the use of these technologies in polymer chem- istry. 5 However, the full exploitation of biocatalysis in polymer science will require the development of mutu- ally compatible chemo- and biocatalytic methods. 6-9 In our laboratory, we therefore explore the integration of biocatalytic and traditional polymer synthesis. Our goal is the development of chemoenzymatic cascade polym- erization reactions, i.e., combined catalytic reactions without an intermediate recovery step. We believe that this new concept can eventually lead to the development of new materials and a sustainable technology, once its versatility has been demonstrated on the fundamental level. The synthesis of block copolymers is particularly suited to investigate the combination of two fundamen- tally different synthetic techniques, since the marriage of two chemically different building blocks often requires a considerable synthetic effort. Block copolymers with building blocks, based on two intrinsically different polymerization mechanisms, e.g., polyester and poly- methacrylate, can be obtained either by chemically linking two preformed polymer blocks or, alternatively, in two consecutive polymerizations using macroinitia- tors. With respect to the latter case, the majority requires an intermediate transformation step in order to convert the end group of the first block into an active initiator for the second polymerization. A very powerful and elegant synthetic pathway to block copolymers is the use of an initiator combining two fundamentally different initiating groups in one molecule. This allows two consecutive polymerizations without an intermedi- ate transformation step. The feasibility of this approach has been successfully demonstrated for the combination of various chemical polymerization techniques. 10-15 Moreover, we recently reported the first example of a one-pot chemoenzymatic cascade polymerization com- bining nitroxide-mediated radical polymerization (NMP) and enzymatic ring-opening polymerization (eROP). 16 Here, we report the synthesis of block copolymers combining atom transfer radical polymerization (ATRP) and eROP from a bifunctional initiator. In previous studies, we found that block copolymers can be obtained using this strategy. 17,18 In this paper we report the findings from our detailed investigation into the key factors for obtaining a high block copolymer yield in a chemoenzymatic ATRP-eROP procedure. While this paper is focused on the optimization of the enzymatic polymerization and the synthesis of block copolymers in two consecutive steps, a subsequent paper will report the simultaneous polymerization with special view on the compatibility in a one-pot approach (Scheme 1). With respect to the first point, our goal was to obtain a well-controlled lipase-catalyzed polymerization by (i) carefully managing the water activity in the system, (ii) selecting a bifunctional initiator that shows fast and complete initiator consumption with fast polymerization Department of Polymer Chemistry. ‡ Department of Macromolecular and Organic Chemistry. * Corresponding author: e-mail a.heise@tue.nl; Tel 0031-(0)40 2473012; Fax 0031-(0)40 2463966. 4220 Macromolecules 2005, 38, 4220-4225 10.1021/ma0473871 CCC: $30.25 © 2005 American Chemical Society Published on Web 04/22/2005