Supramolecular PEG-co-Oligo(p-benzamide)s Prepared on a Peptide Synthesizer Hannah M. Ko ¨ nig, ² Tatiana Gorelik, ‡ Ute Kolb, ‡ and Andreas F. M. Kilbinger* ,² Contribution from the Institute of Organic Chemistry, Johannes Gutenberg-UniVersity Mainz, Duesbergweg 10-14, 55099 Mainz, Germany, and Institute of Physical Chemistry, Johannes Gutenberg-UniVersity Mainz, Jakob-Welder-Weg 11-15, 55128 Mainz, Germany Received October 11, 2006; E-mail: akilbing@uni-mainz.de Abstract: An automated synthesis protocol has been developed for the preparation of oligo(p-benzamide)s on solid support using a commercial peptide synthesizer employing a variation of standard Fmoc chemistry. Bis(trichloromethyl carbonate) in NMP was used to activate the aromatic carboxylic acids for acylation of secondary aromatic amines on solid support. N-Protected hepta(p-benzamide) was automatically prepared on solid support and manually converted to a solid supported block co-oligomer by attaching a poly(ethylene glycol) chain. Cleavage from the support could be achieved with minimal loss of the p-methoxybenzyl N-protective group. While the N-protected block co-oligomer was molecularly dissolved in nonpolar organic solvents, the N-deprotected block co-oligomer adopted a rod-coil conformation and showed strong aggregation as evidenced by gel permeation chromatography and transmission electron microscopy. Rigid rodlike aggregates could be observed in chloroform, toluene, as well as water. Introduction With the development of a broad range of living polymeri- zation techniques, chemists have been able to design well- defined polymers as well as block copolymers and gain insight into their solution- and solid-state organization. However, discrete molecular weights and monomer sequence control typically observed for biomacromolecules cannot be achieved with these polymerization techniques. In recent years, the boundary between classical multistep organic synthesis and polymer chemistry has been crossed by many groups with the aim of creating new block copolymer architectures in which at least one block is precisely defined. 1 The growing interest in self-assembled solution- and solid-state structures with dimen- sions on the nanometer scale is a driving force for the development of multistep polymer syntheses employing the tools of synthetic organic chemistry. One well-established way of preparing precisely defined oligomers and polymers is solid supported synthesis. The idea, which was first described by Merrifield, 2 has since been well- developed and automated for a variety of biologically relevant macromolecules. These include R- and -peptides, glycopep- tides, oligonucleotides, and oligosaccharides. 3 One of the first of very few examples where solid supported synthesis was employed for the preparation of materials were the liquid crystalline oligopeptides reported by Cormack et al. 4 Peptide/ polymer hybrids prepared on solid support have also been shown by the Klok group 5 and Wooley et al. 6,7 Our group recently reported the solid supported synthesis of oligo(p-benzamide)s (OPBA) up to the decamer. 8 Other non-natural oligomers have also been prepared on solid support. 9 The great advantage of solid supported syntheses is the potential for automation. This aspect has, however, only been addressed for non-natural oligomers in a few cases. 10-12 Commercial peptide synthesizers are typically laid out for the synthesis of Boc- or Fmoc-peptide synthesis (i.e., the synthesis of aliphatic amides with well-established coupling protocols). Repetitive syntheses of oligomers requiring reaction conditions drastically different from those preprogrammed into the peptide synthesizer are often not feasible to be carried out in these machines without major modifications. As a result, automation of oligomer syntheses, especially in the field of materials chemistry, is scarce. ² Institute of Organic Chemistry. ‡ Institute of Physical Chemistry. (1) Hawker, C. J.; Wooley, K. L. Science 2005, 309, 1200-1205. (2) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149-2154. (3) Seeberger, P. H.; Haase, W.-C. Chem. ReV. 2000, 100, 4349-4394. (4) (a) Cormack, P. A. G.; Moore, B. D.; Sherrington, D. C. Chem. Commun. 1996, 353-354. (b) Cormack, P. A. G.; Moore, B. D.; Sherrington, D. C. J. Mater. Chem. 1997, 7, 1977-1983. (5) Klok, H.-A. J. Polym. Sci., Part A: Polym. Chem. 2005, 43,1-17. (6) Becker, M. L.; Liu, J.; Wooley, K. L. Biomacromolecules 2005, 6, 220- 228. (7) Becker, M. L.; Liu, J.; Wooley, K. L. Chem. Commun. 2003, 180-181. (8) Ko ¨nig, H. M.; Abbel, R.; Schollmeyer, D.; Kilbinger, A. F. M. Org. Lett. 2006, 8, 1819-1822. (9) (a) Nelson, J. C.; Young, J. K.; Moore, J. S. J. Org. Chem. 1996, 61, 8160- 8168. (b) Young, J. K.; Nelson, J. C.; Moore, J. S. J. Am. Chem. Soc. 1994, 116, 10841-10842. (c) Huang, S.; Tour, J. M. J. Org. Chem. 1999, 64, 8898-8906. (d) Huang, S.; Tour, J. M. J. Am. Chem. Soc. 1999, 121, 4908-4909. (e) Jones, L.; Schumm, J. S.; Tour, J. M. J. Org. Chem. 1997, 62, 1388-1410. (f) Malenfant, P. R. L.; Frechet, J. M. Chem. Commun. 1998, 2657-2658. (g) Levin, C. G.; Schafmeister, C. E. J. Am. Chem. Soc. 2003, 125, 4702-4703. (h) Semetey, V.; Moustakas, D.; Whitesides, G. M. Angew. Chem., Int. Ed. 2006, 45, 588-591. (10) Wurtz, N. R.; Turner, J. M.; Baird, E. E.; Dervan, P. B. Org. Lett. 2001, 3, 1201-1203. (11) Belitsky, J. M.; Nguyen, D. H.; Wurtz, N. R.; Dervan, P. B. Bioorg. Med. Chem. 2002, 10, 2767-2774. (12) Hartmann, L.; Krause, E.; Antonietti, M.; Borner, H. G. Biomacromolecules 2006, 7, 1239-1244. Published on Web 12/23/2006 704 9 J. AM. CHEM. SOC. 2007, 129, 704-708 10.1021/ja0672831 CCC: $37.00 © 2007 American Chemical Society