Cyclic Polylactides by Imidazole-Catalyzed Polymerization of L-Lactide Hans R. Kricheldorf,* Nino Lomadze, and Gert Schwarz Institut fu ¨r Technische and Makromolekulare Chemie der UniVersita ¨t Hamburg, Bundesstrasse 45, D-20146 Hamburg, Germany ReceiVed July 8, 2008; ReVised Manuscript ReceiVed August 22, 2008 ABSTRACT: Heating of L-lactide with imidazole to 98-100 °C resulted in complete polymerization within 48 h. Even-numbered cycles resulting from end-to-end cyclization were the only reaction products after 4 h, but the polymerization process was accompanied by intensive racemization. Longer reaction times favored equilibration reactions with formation of odd-numbered cycles. Variation of the monomer-initiator ratio at 120 °C had little influence on the molecular weight. After 8 h at 150 °C, equal quantities of odd- and even-numbered cycles were found, indicating complete equilibration. Other protic heterocycles such as 1,2,4-triazole, benzimidazolyl acetonitrile, uracile, or hypoxanthine were not active as initiators/catalysts at 120 °C. However, the tertiary amine N-methylimidazole also catalyzes the formation of cyclic polylactides together with several byproducts. The reaction mechanisms are discussed. Introduction The term “ring-opening polymerization” (ROP) is usually understood as a process yielding linear polymers by a sequence of reaction steps involving the ring-opening of a cyclic monomer. This view is certainly correct for the majority of ROPs, but it is based on two requirements. First, the initiation step produces a stable (dead) endgroup, and, second, formation of cycles by “back-biting” equilibration is absent or inefficient. Three scenarios may yield cyclic oligomers and polymers as the endproducts of a ROP. The first is ROPs involving rapid equilibration reactions including back-biting. According to the theory of Jacobson and Stockmayer, 1,2 such a process should mainly yield linear chains with a small weight fraction (e.g., 2.5%) of cycles, 1,3,4 when conducted in bulk, but 100% cycles at low concentration. Yet, according to the theory of Kricheldorf, an efficient ring equilibration should mainly yield cyclic oligomers and polymers with a small percentage of linear chain (depending on the monomer-initiator ratio, if an initiator was used at all) at all concentrations. The second scenario (II) is based on a kinetically controlled ROP involving a cyclic initiator, that is, a ring expansion polymerization. Numerous examples illustrating this scenario have recently been pub- lished, 5-9 and the vast majority of such polymerizations were summarized in a review article. 8 The third scenario (III), which is particularly relevant for the present work, is based on kinetically controlled ROPs generating linear chains with two different reactive endgroups. Quite analogous to a step-growth polymerization, 10 these chains have the choice to continue the chain-growth by intermolecular reactions or to undergo cycliza- tion. Several examples of ROPs yielding cyclic polymers via a kinetically controlled chain-growth process involving end-to- end cyclization have recently been published. 11-15 For L- or D,L-lactide as monomers, Culkin et al. 15 have shown that initiation with a nucleophilic carbene yields cyclic polylactides, but due to intensive equilibration it was not clear if the cycles were mainly the consequence of a thermodynamically controlled back-biting process (scenario I) or of a kinetically controlled process according to scenario III. The purpose of the present work was to study imidazole- initiated ROPs of L-lactide. In contrast to most other amide groups, imidazolides are so electrophilic that they react with amino groups at low temperature or with alcohol groups at higher temperatures. Therefore, it was found that imidazole- initiated polymerizations of R-amino acid NCAs produce cyclic polypeptides. 12 In this case, equilibration reactions are excluded, due to the stability of peptide groups below 100 °C. The present work should answer three questions. First, does imidazole indeed initiate a relatively clean polymerization process? Second, are cyclic polylactides formed via a kinetically controlled polym- erization with end-to-end cyclization (e.g., according to Scheme 1)? Third, are cyclic polylactides formed via thermodynamically controlled equilibration reactions? Experimental Section Materials. L-Lactide (S-grade) was kindly supplied by Boeh- ringer GmbH & Co. (Ingelheim, Germany). It was twice recrystal- lized from dry ethyl acetate and stored over P 4 O 10 in a desiccator. Imidazole, N-methyl imidazole, 1,2,4-triazole, benzimidazolyl ac- etonitrile, hypoxanthum, and uracil were purchased from Alpha Aesar (Karlsruhe, Germany). Imidazole was distilled in vacuo and stored over P 4 O 10 . All other heterocycles were used after drying over P 4 O 10 . N-Methylimidazole was distilled over freshly powdered calcium hydride in vacuo. Polymerizations. A. With Imidazole (Nos. 1-4, Table 1). L-Lactide (40 mmol) and imidazole (2 mmol) were weighed under dry argon into a 25 mL Erlenmeyer flask having silanized glass walls (pretreated with Me 2 SiCl 2 ). The reaction vessel was closed with a glass-stopper and steel spring. The closed reaction vessel was almost completely immersed into a preheated oil bath. Finally, the cold reaction product was characterized. All other polymerizations catalyzed by imidazole or other protic heterocycles were performed analogously. B. With N-Methylimidazole (Nos. 5-8, Table 1). L-Lactide (40 mmol) was weighed under dry argon into a 25 mL Erlenmeyer flask having silanized glass walls. After injection of N-methylimi- dazole (2 mmol), the reaction vessel was closed with a glass-stopper and steel spring and immersed into a preheated oil bath. Measurements. The inherent viscosities were measured in CH 2 Cl 2 with an automated Ubbelohde viscometer thermostatted at 20 °C. The 400 MHz 1 H NMR spectra and the 100.4 MHz 13 C NMR spectra were recorded with a Bruker “Avance 400” FT NMT spectrometer in 5 mm o.d. sample tubes. CDCl 3 containing TMS served as solvent. The MALDI-TOF mass spectra (MT) were measured with a Bruker Biflex III mass spectrometer equipped with a nitrogen laser (λ ) 337 nm). All spectra were recorded in the * To whom correspondence should be addressed. E-mail: kricheld@ chemie.uni-hamburg.de. 7812 Macromolecules 2008, 41, 7812-7816 10.1021/ma801519t CCC: $40.75  2008 American Chemical Society Published on Web 10/08/2008