Synthesis and Self-Assembling Properties of Diacetylene-Containing Glycolipids Xiaoping Nie and Guijun Wang* Department of Chemistry, UniVersity of New Orleans, New Orleans, Louisiana 70148
[email protected] ReceiVed NoVember 8, 2005
Diacetylene-containing glycolipids are interesting molecules that have many potential applications. The polydiacetylenes formed by the cross-linking of the diacetylene lipids are new stimuli-responsive materials. In particular, diacetylene lipids that can form gels in aqueous solution are of great interest in designing functional biocompatible materials. We have synthesized a series of diacetylene-containing sugar lipids with different chain lengths, substituents, and positions of diyne and studied their self-assembling properties in several solvents including hexane, ethanol, and ethanol/water mixture. Among the 24 diacetylenecontaining glycolipids synthesized, many of them exhibited excellent gelation properties in ethanol or ethanol/water mixture. Typically very long chain diacetylene lipids formed gels in ethanol and hexane. Shorter chain diacetylene lipids and compounds with one free hydroxyl group can form gels in aqueous solution. The position of the diyne and chain length affect the self-assembling properties significantly. The systematic study of the gelation properties for diacetylene lipids with different lipid chains can help us to understand the structure requirement for the desired physical properties. Optical microscopy studies showed that the molecules form interesting architectures such as tubules, rods, sheets, and belts. The resulting organogels can also be cross-linked and give different colored polymerized gels depending on their structures.
Introduction Polydiacetylenes (PDAs) are important conjugate polymers that have drawn great attention over the past few decades. PDAs exhibit a unique blue to red color transition in the presence of heat, mechanical stress, pH change, and binding to biological agents.1-3 Extensive studies of polymerizable diacetylenes have been carried out in crystals,4,5 thin films,6,7 vesicles,8,9 and at air-water interfaces.10,11 The optical electronic properties and * Address correspondence to this author. Phone: 504 280-1258. Fax: 504 280-6860.
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the unique color transitions of polydiacetylenes lend themselves to many applications in optical electronic devices, chemosensors, and biosensors.12-16 To cross-link diacetylene groups, the monomer diacetylenes must be aligned at specific distances and (5) Tachibana, H.; Kumai, R.; Hosaka, N.; Tokura, Y. Chem. Mater. 2001, 13, 155-158. (6) Barentsen, H. M.; van Dijk, M.; Zuilhof, H.; Sudho¨lter, E. J. R. Macromolecules 2000, 33, 766-774. (7) Mosley, D. W.; Sellmyer, M. A.; Daida, E. J.; Jacobson, J. M. J. Am. Chem. Soc. 2003, 125, 10532-10533. (8) Ma, G.; Cheng, Q. Langmuir 2005, 21, 6123-6126 (9) Kolusheva, S.; Shahal, T.; Jelinek, R. J. Am. Chem. Soc. 2000, 122, 776-780. (10) Niwa, M.; Shibahara, S.; Higashi, N. J. Mater. Chem. 2000, 26472651. (11) Ma, Z.; Li, J.; Li, H.; Jiang, L. New J. Chem. 2000, 313-316. (12) Kolusheva, S.; Shahal, T.; Jelinek, R. J. Am. Chem. Soc. 2000, 122, 776-780. (13) Sarkar, A.; Okada, S.; Matsuzawa, H.; Matsuda, H.; Nakanishi, H. J. Mater. Chem. 2000, 819-828. 10.1021/jo052317t CCC: $33.50 © 2006 American Chemical Society
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Published on Web 05/27/2006
Diacetylene-Containing Glycolipids SCHEME 1. The Topochemical Polymerization of Diacetylene and the Color Transition Mechanism
orientations to their neighbors. This strict topochemical requirement for polymerization can be used to probe the molecular aggregation structures of the monomers. It is generally accepted that the color transition is due to the conformation change of the PDA side chains (Scheme 1). The preparation of processable PDAs is important for the exploration of their further applications. Diacetylene-containing phospholipids are interesting molecules that can self-assemble and form tubules, nanotubules, and ribbons.17-19 Membrane lipid mimetics have been used to achieve favorable alignment of diacetylene groups and form useful supramolecular structures including liposome, tubules, ribbons, and thin films.20-22 The self-assembling of small molecules to form supramolecular gels in organic solvent (organogels) or water (hydrogels) is an interesting phenomenon. These small molecules, which are termed as organogelators or hydrogelators, respectively, have great potential in preparing novel functional materials.23-26 Biocompatible functional small molecule organogelators such as carbohydrates and amino acid derivatives are very interesting because they have potential applications in drug delivery, tissue engineering, and as biocompatible materials. Polysaccharides have been widely utilized in polymer gels for separation and immobilization of enzymes, etc. Some glycolipids and other small sugar derivatives have been found to be able to form gels in organic solvents and sometimes in water.27-30 The formation of various supramolecular assemblies including liposomes, crystals, or gels in solvents can provide insight in understanding structure influences on the molecular self-assembling process. The advantages of forming supramolecular gels is that the structures of the gelators can be modified and synthesized readily, also the gels formed by noncovalent forces are revers-
ible. Polymer gels have the advantage of being more stable but their structures are not flexible. Supramolecular gels such as organogels formed by a small molecule offer a direct and effective way of organizing molecular subunits in the gel state, cross-linking the diacetylene in the gel state can produce novel polydiacetylene gels. The gelation by small molecule has been barely used to prepare novel polydiacetylenes, and especially no systematic studies have been conducted. A few earlier studies have employed gelation in preparing polydiacetylenes, either involving a diacetylene dicholesteryl ester with two urethanes,27,28 a diaminocyclohexane-based system,29 or diacetylene-containing amides.30 The diacetylene-containing organogels may have interesting properties of color transition combined with gel-solution phase transition in response to external stimuli. These compounds can be useful in designing biosensors or chemosensors. Sugarcontaining amphiphilic molecules are cell membrane mimics and are expected to be biocompatible. As part of our goal to discover carbohydrate-based stimuli-responsive functional materials that are useful in enzyme purification, protein and DNA immobilization, drug and gene delivery carriers, and as scaffolding material for tissue engineering, we have designed, synthesized, and tested a series of monosaccharide lipids containing diacetylene functional groups. Here we report the systematic synthesis and characterization of a series of diacetylene-containing monosaccharide lipids. Their self-assembling properties in hexane, ethanol, and an ethanol/water mixture are also studied. The synthesis can be carried out efficiently and we found several molecules with excellent gelation abilities for hexane and the ethanol/water mixture. Results and Discussions
(14) Lu, Y.; Yang, Y.; Sellinger, A.; Lu, M.; Huang, J.; Fan, H.; Haddad, R.; Lopez, G.; Burns, A. R.; Sasaki, D. Y.; Shelnutt, J.; Brinker, C. J. Nature 2001, 410, 913-917. (15) Charych, D.; Nagy, J.; Spevak, W.; Bednarski, M. Science 1993, 261, 585-588. (16) Gill, I.; Ballesteros, A. Angew. Chem., Int. Ed. 2003, 42, 32643267. (17) Georger, J. H.; Singh, A.; Price, R. R.; Schnur, J. M.; Yager, P.; Schoen, P. E. J. Am. Chem. Soc. 1987, 109, 6169-6175 (18) Thomas, B. N.; Lindemann, C. M.; Corcoran, R. C.; Cotant, C. L.; Kirsch, J. E.; Persichini, P. J. J. Am. Chem. Soc. 2002, 124, 1227-1233. (19) Spector, M. S.; Singh, A.; Messersmith, P. B.; Schnur, J. M. Nano Lett. 2001, 1, 375-378. (20) Wang, G.; Hollingsworth, R. I. Langmuir 1999, 15, 6135-6138. (21) Wang, G.; Hollingsworth, R. I. AdV. Mater. 2000, 12, 871-874. (22) Wang, G.; Hollingsworth, R. I. Langmuir 1999, 15, 5, 3062-3069. (23) Terech, P.; Weiss, R. G. Chem. ReV. 1997, 97, 3133-3159. (24) Abdallah, D. J.; Weiss, R. G. AdV. Mater. 2000, 12, 1237-1247. (25) Si, C.; Huang, Z.; Kilic, S.; Xu, J.; Enick, R. M.; Beckman, E. J.; Carr, A. J.; Melendez, R. E.; Hamilton, A. D. Science 1999, 289, 15401543. (26) Estroff, L. A.; Hamilton, A. D. Chem. ReV. 2004, 104, 1201-1217. (27) Inoue, K.; Ono, Y.; Kanekiyo, Y.; Hanabusa, K.; Shinkai, S. Chem. Lett. 1999, 5, 429-430. (28) Tamaoki, N.; Shimada, S.; Okada, Y.; Belaissaoui, A.; Kruk, G.; Yase, K.; Matsuda, H. Langmuir 2000, 16, 7545-7547. (29) Nagasawa, J.; Kudo, M.; Hayashi, S.; Tamaoki, N. Langmuir 2004, 20, 7907-7916. (30) George, M.; Weiss, R. G. Chem. Mater. 2003, 15, 2879-2888.
Synthesis of Diacetylene Fatty Acids. To synthesize a series of diacetylene-containing sugar lipids, the most straightforward method is esterification of free hydroxyl groups on the sugar with a diacetylene-containing fatty acid. The diacetylene acyl compounds can be prepared by coupling reactions of two acetylene-containing entities. Some long-chain diacetylenecontaining fatty acids are also commercially available. The synthesis of diacetylene fatty acids is shown in Scheme 2. Treating the alkynes 1a-d with NBS and silver nitrate afforded alkynyl bromides 2a-d in almost quantitative yield. The bromo acetylenes 2a-d were then coupled with terminal alkynes under a modified Cadiot-Chodkiewicz reaction condition,31 using butylamine, hydroxylamine, and cuprous chloride to give the diacetylene-containing fatty acids 4a-d in high yields. Terminal diacetylene fatty acid 5 can be prepared from fatty acid 4c in 90% yield by removal of the TES group with TBAF. Synthesis of Diacetylene Lipids. To understand the structure influence of diacetylene the lipid tails on the gelation process, we synthesized a series of compounds with the same headgroup with either two acyl chains or one acyl chain. We can obtain (31) Marino, J. P.; Nguyen, H. N. J. Org. Chem. 2002, 67, 6841-6844.
J. Org. Chem, Vol. 71, No. 13, 2006 4735
Nie and Wang SCHEME 2. Acids
Synthesis of Diacetylene-Containing Fatty
SCHEME 3. Synthesis of Diacetylene-Containing Lipids Type A, Type B, and Type C
the relationship of alkyl chain lengths and positions of diacetylene groups with their gelation and polymerization properties. The synthesis is shown in Scheme 3. The diacetylene acids 4a-d and 5 were converted to the corresponding acid chlorides by treating them with oxalyl chloride in dichloromethane. Esterification of sugar headgroup 6 with diacetylene-containing acid chlorides can give the desired diacetylene-containing lipids. The strategy is to synthesize three types of lipids A, B, and C in a one-pot reaction and isolate them by flash chromatography. When 0.75 equiv of sugar headgroups were used, the 2-monoesters type B were obtained as major products, type A and type C were minor products. The structures of type A compounds are shown in Figure 1 (for type B and type C, the compounds with the same numbers have the same fatty acyl structures). Screening for their gelation properties in various solvents would allow us to find promising gelators. The advantage of this strategy is that we can build up a small library quickly and investigate their structure activity relationship. The compounds with excellent gelation properties can be resynthesized in good yields and larger quantities under optimized reaction condition. To synthesize only the A compound, we just need to use slightly more than 2 equiv of acid; to obtain type B product only, slightly more than 1 equiv of acid can be used and the reaction can be done under kinetic controlled conditions to maximize the yield; to synthesize type C product only, a protecting group that is bulky and has good selectivity at the 2-position can be used, and after esterification at the 3-positions, the protecting group can be removed. Gelation Properties Studies. The preliminary gel testing results are shown in Table 1. The compounds showing positive gelation properties are highlighted in bold. Several diesters (type A compounds) can form gels in ethanol; the longest chain compound 7A is the most efficient one that forms gels at a concentration of 7 mg/mL (∼1 wt %). Compound 8A is two 4736 J. Org. Chem., Vol. 71, No. 13, 2006
carbons shorter; it formed stable translucent gels in ethanol at 0 °C at a similar concentration. The rigid phenyl acetylene derivative 13A also formed gels in ethanol. In a water and ethanol mixture, compound 11A formed unstable gels (precipitated after hours of standing) at 10 mg/mL, and the others precipitated out of solution. The diesters typically do not form gels in hexane. The 2-esters (type B compounds) are not gelators for hexane or ethanol; however, most of them formed stable gels in ethanol/water mixture at a very low concentration (
