Pyromellitamide Aggregates and Their Response to Anion Stimuli James E. A. Webb, Maxwell J. Crossley, Peter Turner, and Pall Thordarson* Contribution from the School of Chemistry, The UniVersity of Sydney NSW 2006, Australia Received February 27, 2007; E-mail: p.thordarson@chem.usyd.edu.au Abstract: The N,N′,N′′,N′′′-1,2,4,5-tetra(ethylhexanoate) pyromellitamide is found to be capable of both intermolecular aggregation and binding to small anions. It is synthesized by aminolysis of pyromellitic anhydride with ethanolamine, followed by a reaction with hexanoyl chloride. The single-crystal X-ray structure of the pyromellitamide shows that it forms one-dimensional columnar stacks through an intermolecular hydrogen-bonding network. It also forms self-assembled gels in nonpolar solvents, presumably by a hydrogen-bonding network similar to the solid-state structure as shown by IR and XRD studies. Aggregation by intermolecular hydrogen bonding of the pyromellitamide is also observed by NMR and IR in solution. Fitting of NMR dilution data for pyromellitamide in d6-acetone to a cooperative aggregation model gave KE ) 232 M -1 and positive cooperativity of aggregation (F) 0.22). The pyromellitamide binds to a range of small anions with the binding strength decreasing in the order chloride > acetate > bromide > nitrate ≈ iodide. The data indicate that the pyromellitamide binds two anions and that it displays negative cooperativity. The intermolecular aggregation of the pyromellitamide can also be altered using small anion stimuli; anion addition to preformed self-assembled pyromellitamide gels causes their collapse. The kinetics of anion- induced gel collapse are qualitatively correlated to the binding affinities of the same anions in solution. The cooperative anion binding properties and the sensitivity of the self-assembled gels formed by pyromellitamide toward anions could be useful in the development of sensors and switching/releasing devices. Introduction Stimuli responsive biological systems provide some of the most elegant demonstrations of the importance of supramo- lecular interactions in nature. A well-known example is the cooperative binding of small ligands to multivalent hosts, as in the case of allosteric 1 oxygen binding to hemoglobin, 2 where successive binding of the ligand(s) changes the structure and/ or function of the host in a nonlinear fashion. External stimuli can also be used to influence intermolecular interactions as in the case of self-assembled protein filaments, where the structure can be modulated in vivo and in vitro with various small- molecule effectors. For instance, iodide is known to cause the depolymerization (collapse) of actin filaments (F-actin) 3 and the corresponding transition from a gel-like to solution state (gel f sol transition), possibly by influencing the unique hydration shell that is thought to surround and stabilize the F-actin polymer. 4 Much effort has been directed toward mimicking biological systems that respond to external stimuli. There are numerous examples of simple synthetic allosteric host-guest systems. 5,6 The vast majority of these concern the use of cationic or neutral guests (effectors), while relatively few discrete multivalent hosts displaying cooperative binding toward anions have been reported. 6c,7 The intermolecular interactions of synthetic self- assembled systems, including macroscopic self-assembled mo- lecular gels, 8 can also be tuned using small ionic or molecular effectors. Self-assembled molecular gels are showing increased potential for applications in biomedicine for drug delivery 9 and in tissue engineering 10 (e.g., by stimulating nerve regrowth in spinal injuries). 11 To date, there have been reports on molecular (1) (a) Monod, J.; Changeux, J.-P.; Jacob, F. J. Mol. Biol. 1963, 6, 306. (b) Monod, J.; Wyman, J.; Changeux, J.-P. J. Mol. Biol. 1965, 12, 88. (2) (a) Ackers, G. K.; Doyle, M. L.; Myers, D.; Daugherty, M. A. Science 1992, 255, 54. (b) Huang, Y.; Doyle, M. L.; Ackers, G. K. Biophys. J. 1996, 71, 2094. (c) Johnson, M. L. Methods Enzymol. 2000, 323, 124. (3) (a) Straub, F. B. Stud. Inst. Med. Chem. UniV. Szeged 1942, 2, 4. (b) Straub, F. B. Stud. Inst. Med. Chem. UniV. Szeged 1942, 2, 7. (c) Guba, F. Nature 1950, 165, 439. (4) Kabir, S. R.; Yokoyama, K.; Mihashi, K.; Kodama, T. Biophys. J. 2003, 85, 3154. (5) For reviews, see: (a) Rebek, J., Jr. Acc. Chem. Res. 1984, 17, 258. (b) Shinkai, S.; Ikeda, M.; Sugasaki, A.; Takeuchi, M. Acc. Chem. 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