pubs.acs.org/Langmuir © 2010 American Chemical Society
Biorefinery: A Design Tool for Molecular Gelators George John,* Balachandran Vijai Shankar, Swapnil R. Jadhav, and Praveen Kumar Vemula† Department of Chemistry, The City College of New York, The Graduate School and University Center of The City University of New York, The CUNY Institute for Macromolecular Assemblies (MMA), New York, New York 10031. †Present address: Kauffman Foundation Entrepreneur Postdoctoral Fellow, Harvard-MIT Division of Health Sciences & Technology, 65 Landsdowne Street, PRB 325, Cambridge, Massachusetts 02139. Received February 23, 2010. Revised Manuscript Received April 23, 2010 Molecular gels, the macroscopic products of a nanoscale bottom-up strategy, have emerged as a promising functional soft material. The prospects of tailoring the architecture of gelator molecules have led to the formation of unique, highly tunable gels for a wide spectrum of applications from medicine to electronics. Biorefinery is a concept that integrates the processes of converting biomass/renewable feedstock and the associated infrastructure used to produce chemicals and materials, which is analogous to petroleum-based refinery. The current review assimilates the successful efforts to demonstrate the prospects of the biorefinery concept for developing new amphiphiles as molecular gelators. Amphiphiles based on naturally available raw materials such as amygdalin, vitamin C, cardanol, arjunolic acid, and trehalose that possess specific functionality were synthesized using biocatalysis and/or chemical synthesis. The hydrogels and organogels obtained from such amphiphiles were conceptually demonstrated for diverse applications including drugdelivery systems and the templated synthesis of hybrid materials.
Introduction The ubiquity of functional soft materials in nature is best exemplified in the plethora of intriguing, naturally occurring jelly materials, common example being the jelly pith of the aloe vera plant that retains water (Figure 1) and the whole body of a jellyfish. Via an intricate yet proficient bottom-up strategy, the production of gels in natural systems occurs for diverse but essential biological functions. In the quest to develop man-made multifunctional gels, the materials research community is involved in mimicking such biological jelly materials as well as in extending the logistics to other solvent systems. The recent trend has been shifting toward the development of monomeric low-molecular-weight building blocks rather than polymers for crafting such gels.1 The gels resulting from such small molecules are called molecular gels. Increasing interest in such systems is evident from the ample variety of low-molecular-weight gelators being developed. The recent demonstrations of molecular gels in applications such as scaffolds for regenerative medicines, electronic and photonic applications, and art conservation illustrate their potential utility.2-4 The ability of molecular gelators (MGs) to immobilize solvent molecules (organic liquids or water) stems from the propensity to undergo supramolecular self-assembly processes. MGs hierarchically self-assemble to form a 3D self-assembled fibrillar network (SAFIN) by utilizing weak intermolecular forces such as hydrogen bonding, donor-acceptor interactions, π-π stacking, and van der Waals interactions in which the liquid medium is efficiently
Figure 1. Natural retreat of a hydrogel from an aloe vera plant.
*Corresponding author. Tel: (212) 650-8353. Fax: (212) 650-6107. E-mail:
[email protected].
entrapped by surface tension.5 This has proven to be a versatile, simple bottom-up fabrication strategy for generating not only novel but also unique, highly tunable materials.6,7 In addition, nature offers structurally diverse raw materials such as sugars, fatty acids, and lipids that can be exploited to tailor specific recognition events at the molecular level and in turn develop morphologically rich nanoscale architectures. Thus, diversity in nature can be utilized to control the gel network exquisitely for various uses. Gelators have been developed from plant-based materials such as ricinoleic acid, and hydroxy stearic acid obtained from castor oil is one of the successful large-scale vegetable-based thickening agents.8,9 In this context, over the past few years, we have developed various amphiphilic MGs from natural renewable resources; some of them have been explored in applications ranging from
(1) Fages, F. Low Molecular Mass Gelators: Design, Self-Assembly Function; Topics in Current Chemistry; Springer: New York, 2005; Vol 256. (2) (a) Xu, B. Langmuir 2009, 25, 8375. (b) Ajayagosh, A.; Praveen, V. K. Acc. Chem. Res. 2007, 40, 644. (c) Estroff, L.; Hamilton, A. D. Chem. Rev. 2004, 104, 1201. (d) Sangeetha, N. M.; Maitra, U. Chem. Soc. Rev. 2005, 34, 821. (e) van Esch, J. H.; Feringa, B. L. Angew. Chem., Int. Ed. 2000, 39, 2263. (3) (a) Hirst, A. R.; Escuder, B.; Miravet, J. F; Smith, D. K. Angew. Chem., Int. Ed. 2008, 47, 8002. (b) Zhao, F.; Mab, M. -L.; Xu, B. Chem. Soc. Rev. 2009, 38, 883. (4) Carretti, E.; Deia, L.; Weiss, R. G. Soft Matter 2005, 1, 17.
(5) Weiss, R. G., Terech, P., Eds. Molecular Gels: Materials with Self-Assembled Fibrillar Networks; Springer: Dordrecht, The Netherlands, 2005. (6) Whitesides, G. M.; Mathias, J. P.; Seto, C. T. Science 1991, 254, 1312. (7) Feiters, M. C.; Nolte, R. J. M. Advances in Supramolecular Chemistry; Gokel, G. W., Ed.; JAI Press: Greenwich, CT, 2000; pp 41-156. (8) Polishuk, A. T. J. Am. Soc. Lubr. Eng. 1977, 33, 133. (9) Uzu, Y. J. Jpn. Oil Chem. Soc. 1975, 24, 261.
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Invited Feature Article Chart 1. Schematic Representation of an Ideal Biorefinery Concepta
a Adapted from ref 16a. Biorefining refers to fractionating biomass into various separated products that possibily undergo further biological, (bio)chemical, physical, and/or thermal processing. It is an overall concept of a processing where biomass feedstock is converted and extracted into a spectrum of valuable chemical, fuel, and energy products analogous to petroleum refinery.17b Biomass/existing biomass refers to current agricultural crops, and future biomass refers to new agricultural crops.
drug delivery to hybrid nanomaterial synthesis.10,11 This feature article emphasizes our efforts and others’ to employ biorefinery in crafting molecular gels from amphiphiles and their successful use in the targeted area of applications. Biorefinery: A Tool for Developing Chemicals, Intermediates, and Products. The dawn of the 20th century witnessed the industrial production of solvents, fuels, synthetic fibers, and chemicals from plant/crop-based resources. However, after the 1950s, the production trend gradually shifted toward utilizing petroleum-based resources. Despite increasing reliance on petroleum products, serious questions about sustainability and problems addressing the ecological impact began to emerge. Because of economic and environmental concerns, the choice of raw materials from petrochemicals has been shifted back to crop-based renewable resources. Simultaneously, efficient processes for developing costeffective products from biobased resources has grown significantly.12,13 With a paradigm shift in process strategies, especially after the 1970 oil crisis, biobased industrial products started to reclaim their stand. This could be augmented by (1) focusing on fermentation byproducts and (2) developing processes for the conversion of biobased raw materials and waste products into value-added chemicals. Thanks to the concept of biorefinery or white biotechnology, where the knowledge of biochemical and enzymatic processes and related advances has been utilized in converting biomass into sugars and other value-added products.14,15 Biorefinery is a concept that integrates the processes of biomass conversion and associated infrastructure to produce fuels, power, and chemicals and is analogous to petroleum-based refineries. Nature provides an enormous variety of resources that can be converted into functional materials by devising efficient routes. (10) Vemula, P. K.; John, G. Acc. Chem. Res. 2008, 41, 769. (11) John, G.; Vemula, P. K. Soft Matter 2006, 2, 909. (12) van Wyk, J. P. H. Trends Biotechnol. 2001, 19, 172. (13) (a) Ragauskas, A. J.; Wiliams, C. K.; Davison, B. H.; Britovsek, G.; Cairney, J.; Eckert, C. A.; Frederick, W. J.; Hallett, J. P.; Leak, D. J.; Liotta, C. L.; Mielenz, L. R.; Murphy, R.; Templer, R.; Tschaplinski, T. Science 2006, 311, 484. (b) Metzger, J. O.; Bornscheuer, U. Appl. Microbiol. Biotechnol. 2006, 71, 13. (14) (a) Lorenz, P.; Zinke, H. Trends Biotechnol. 2005, 23, 570. (b) Metzger, J. O.; H€uttermann, A. Naturwissenschaften 2009, 96, 279. (15) Corma, A.; Iborra, S.; Velty, A. Chem. Rev. 2007, 107, 2411.
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John et al. Chart 2. Schematic Representation of the Utility of Biorefinery for Generating Self-Assembled Soft Materials
Several fermentation feedstocks such as starch, sucrose, cellulose, and food products can produce valuable products such as resins, chemicals, solvents, and fuels.16-18 An idealized concept of biorefinery is depicted16a in Chart 1. Furthermore, feedstocks such as sugars, proteins, and nucleotides are ubiquitous in nature and are excellent sources of raw materials in biorefinery. Although biomass supplies the raw materials, processes that efficiently transform them into valuable molecular entities are necessary. The process of choice should be selective, energetically efficient, high yielding, and environmentally benign. Enzymes function as biological catalysts in several industries such as food, specialty chemicals, and additives to name a few.19,20 They also find applications as the active components in detergents, laboratory reagents, diagnostic reagents, and digestive aids. Enzymes are highly regioselective and exhibit excellent control of the selfassembly process,21 and with their use, several hierarchically selfassembled materials have been realized.22-24 Therefore, one can envision that future processes may be dominated by strategies that employ microbial processes and enzymes for the production of commodity chemicals. In the following section, we address the recent advances in the utilization of a biorefinery approach for the development of novel amphiphiles and their potential use. Chart 2 summarizes our approach to generating self-assembled soft materials from renewable resources. Suitable building blocks (amphiphiles) with appropriate functional groups, which have the ability to promote intermolecular interactions, were systematically synthesized by careful design principles. The rationale for designing amphiphiles from plant-based starting materials was that they were either hydrophobic (e.g., cardanol) or hydrophilic (e.g., sugars) and were converted into an (16) (a) Herrera, S. Nat. Biotechnol. 2004, 22, 671. (b) Willems, P. A. Science 2009, 325, 707. (17) (a) Kamm, B.; Kamm, M. Appl. Microbiol. Biotechnol. 2004, 64, 137. (b) Kamm, B., Gruber, P. R., Kamm, M., Eds.; Biorefineries - Industrial Processes and Products: Status Quo and Future Directions; Wiley-VCH,: Weinheim, Germany, 2005. (18) (a) Bierman, U.; Friedt, W.; Lang, S.; Luhs, W.; Machmuller, G.; Metzger, J. O.; Ruschgen, M. K.; Schafer, H. J.; Schneider, M. P. Angew. Chem., Int. Ed. 2000, 39, 2206. (b) Koopmans, R. J. Soft Matter 2006, 2, 537. (19) Himmel, M. E.; Ding, S.-Y.; Johnson, D. K.; Adney, W. S.; Nimlos, M. R.; Brady, J. W.; Foust, T. D. Science 2007, 315, 804. (20) Committee on Biobased Industrial Products, Board on Biology, Commission on Life Sciences, National Research Council. Biobased Industrial Products: Priorities for Research and Commercialization; National Academy Press: Washington, DC, 2000. (21) Williams, R. J.; Mart, R. J.; Ulijin, R. V. Biopolymers 2010, 94, 107. (22) Das, A. K.; Collins, R.; Ulijn, R. V. Small 2008, 4, 279. (23) Wang, Q. G.; Yang, Z. M.; Gao, Y.; Ge, W. W.; Wang, L.; Xu, B. Soft Matter 2008, 4, 550. (24) Wang, Q. G.; Yang, Z. M.; Wang, L.; Ma, M. L.; Xu, B. Chem. Commun. 2007, 1032.
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Table 1. Representative Amphiphiles Developed from Crop-Based Resources, Their Gelation Ability, and Their Potential Field of Application active molecules
synthesis protocol
type of gel
possible applications
amygdalin Tylenol ascorbic acid cardanol (phenolic lipids) arjunolic acid trehalose
biocatalysis chemical synthesis biocatalysis chemical synthesis chemical synthesis biocatalysis
hydro/organogel hydrogel hydrogel organogel organogel hydro/organogel
drug-delivery vehicles prodrugs, multiple drug-delivery vehicles metal ion reduction, template for making hybrid materials templating agent for developing controlled self-assembled nanostructures developing varied supramolecular architecture and nanomaterials potential food and tissue engineering application
Figure 2. (A) Enzyme -mediated synthesis of amygdalin-based gelators. (B) SEM images of (i) an organogel of Amy-4 and (ii) hydrogels of Amy-14. (The scale bar is 1 μm.) Reprinted with permission from ref 35. Copyright 2006 American Chemical Society.
amphiphilic form. The amphiphiles were then used to generate vivid self-assembled soft materials such as molecular gels and liquid crystals. Table 1 summarizes the molecules from which amphiphilic building blocks were generated. They were found to gel water as well as various organic solvents to form the respective hydro/ organogels. These soft materials exhibited their potential utility as drug-delivery systems and excellent templates for hybrid-nanomaterial synthesis. Molecular Gelators for Drug-Delivery Applications. Molecular gels have emerged as a logical alternative to current polymeric gels for controlled drug-delivery applications. Several hydrogels and organogels of low molecular weight amphiphiles have been widely employed as intelligent carriers in controlled drug-delivery systems.25-29 Self-assembled molecular gels from peptide-based amphiphiles have been successfully demonstrated for regenerative medicine by Stupp and co-workers.30,31 In addition, such peptides were amenable to further chemical modification for targeted use.32 However, the solubilization of hydrophobic drugs and the development of suitable delivery systems have (25) Peppas, N. A., Ed. Hydrogels in Medicine and Pharmacy; CRC Press: Boca Raton, FL, 1987. (26) Peppas, N. A.; Bures, P.; Leobandung, W.; Ichikawa, H. Eur. J. Pharm. Biopharm. 2000, 50, 27. (27) Podual, K.; Doyle, F. J.; Peppas, N. A. J. Controlled Release 2000, 61, 9. (28) Gupta, P.; Vermani, K.; Garg, S. Drug Discovery Today 2002, 7, 569. (29) Qiu, Y.; Park, K. Adv. Drug Delivery Rev. 2001, 53, 321. (30) Hartgerink, J. D.; Beniash, E.; Stupp, S. I. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 5133. (31) Cui, H.; Webber, M. J.; Stupp, S. I. Biopolymers 2010, 94, 1. (32) Webber, M. J.; Kessler, J. A.; Stupp., S. I. J. Intern. Med. 2010, 267, 71.
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remained challenging tasks.33 Such intelligent gel-based host systems have overcome the problem of hydrophobic drug insolubility and have also increased their efficiency by elevating their bioavailability. In the following examples, we demonstrate the ability of biobased amphiphiles to form various self-assembled hydro/organogels and the elegant utilization of such gels in applications such as controlled drug delivery.
Apricot/Peach Biomass: Amygdalin-Based Gelators Amygdalin, a naturally occurring glycoside found in apricot kernels, almonds, and apples, is used in the commercial preparation of laetrile.34 We have used an enzymatic route to synthesize amphiphilic molecules from amygdalin by tethering natural fatty acids with an enzyme-cleavable ester linkage (Figure 2). A lipaseassisted (Novozyme 435) biocatalytic reaction yielded regioselective esterification of the primary hydroxyl of amygdalin in nearly quantitative yield. The amygdalin-based amphiphiles were found to gel in a broad range of solvents, including both polar and nonpolar organic solvents in addition to water at extremely low concentrations35 (minimum gelation concentrations (MGC) were in the range of 0.05-0.2% w/v). A microscopy investigation of hydro/organogels of amygdalin amphiphiles revealed that they consist of rich morphologies such (33) Miyata, T.; Uragami, T.; Nakamae, K. Adv. Drug Delivery Rev. 2002, 54, 79. (34) Syrigos, K. N.; Rowlinson-Busza, G.; Epenetos, A. A. Int. J. Cancer 1998, 78, 712. (35) Vemula, P. K.; Li, J.; John, G. J. Am. Chem. Soc. 2006, 128, 8932.
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Figure 3. (A) Schematic representation of the enzyme-mediated delivery of curcumin from hydrogels of amygdalin ester amphiphiles. (B) Amy-18 hydrogel with real-time images of the gel samples in contact with the lipase enzyme at different time intervals.
as helical ribbons and twisted fibers (Figure 2B). Furthermore, amygdalin amphiphiles, being esters of fatty acids, would be cleavable by lipase enzymes, allowing them to be explored for a conceptual approach of enzyme-triggered drug delivery. Previously, pioneering work on enzyme-mediated self-assembly and disassembly was elegantly demonstrated by Xu and co-workers with small-molecule amphiphiles.36 Amphiphiles of clinically active substances and other enzymatically responsive molecules were shown to form a supramolecular gel network by Ulijin’s group.37-39 We have successfully demonstrated the encapsulation of the model hydrophobic chemotherapeutic drug curcumin using amygdalin-based hydrogels while utilizing the inherent hydrophobic domains of the bilayer assembly in amygdalin-based hydrogels as reservoirs.35 Such hydrogels have the potential to increase the bioavailability of water-insoluble drugs while exhibiting excellent stability in the absence of a hydrolase enzyme without “leaking” the encapsulated drug. It is noteworthy to mention that these hydrogels undergo degradation under physiological conditions (∼37 °C), releasing the drug. Importantly, the drug-release kinetics could be modulated by altering both the enzyme concentration and/or the temperature (Figure 3). Encouraged by the exciting results from amygdalin-based amphiphiles, we have designed the next generation of drug-delivery vehicles by extending the concept to prodrug hydrogelators. It is important to note that when a gelator is to be degraded a detailed knowledge of the metabolic pathway of resulting fragments also becomes mandatory. However, this information is lacking for the majority of existing hydrogelators. This ambiguity could be resolved to some extent if a gelator is designed in such a way that the degraded products will be a mixture of known drugs and agents whose metabolic pathways are well documented and are known to be harmless and nontoxic. We have successfully demonstrated this approach by developing self-assembling amphiphiles from the common drug acetaminophen or N-(4-hydroxyphenyl)acetamide, sold under the brand name Tylenol. Acet(36) Yang, Z.; Liang, G.; Xu, B. Acc. Chem. Res. 2008, 41, 315. (37) Williams, R. J.; Smith, A. M.; Collins, R.; Hodson, N.; Das, A. K.; Ulijn, R. V. Nat. Nanotechnol. 2009, 4, 19. (38) Mart, R. J.; Osborne, R. D.; Stevens, M. M.; Ulijn, R. V. Soft Matter 2006, 2, 822. (39) Das, A. K.; Collins, R.; Ulijn, R. V. Small 2008, 4, 279.
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aminophen is a common analgesic and antipyretic drug used for the relief of fever and headache and has been determined to be safe for humans via extensive investigations. A series of amphiphiles and bola-amphiphiles have been synthesized from acetaminophen by appending a biocompatible fatty acid (Figure 4A), which subsequently underwent self-assembly in water to form stable hydrogels.40 Akin to amygdalin-based hydrogelators, an enzyme-degradable linker was inserted to promote hydrolase-mediated drug delivery. Prodrug Apn-6, upon the action of lipase enzyme, could be transformed into the active acetaminophen drug (Figure 4). In addition, upon incubation of Apn-6 hydrogels with mesenchymal stem cells, the viability, adhesion, proliferation, and adipogenic and osteogenic differentiation abilities of the cells were preserved, suggesting excellent biocompatibility of the molecular hydrogel.40 Furthermore, the hydrogel matrix was also able to encapsulate model hydrophobic drug curcumin. This approach had the advantage of offering multiple drug delivery and degradation into biocompatible components (Figure 4). The concept of an enzymatically triggered multiple drug-delivery system based on prodrug amphiphiles proved to be an excellent starting point for generating stimuli-sensitive drug-delivery vehicles using biobased resources. Gels for the Templated Synthesis of Nanoparticles. The design and development of inorganic nanostructures using organic scaffolds to generate organic-inorganic hybrid nanomaterials is a topic of heightened interest in nanotechnology.40-44 Thus the creation of morphologically rich organic scaffolds such as fibers, ribbons, tubules, and other interesting nanoarchitectures always remains intriguing. The process of creating such organic scaffolds should be synthetically less complex and should be convenient enough to create secondary inorganic nanostructures without encompassing laborious multistep processes. Amphiphiles generated with embedded functional moieties that are capable of (40) Vemula, P. K.; Cruikshank, G. A.; Karp, J. M.; John, G. Biomaterials 2009, 30, 383. (41) van Bommel, K. J. C.; Friggeri, A.; Shinkai, S. Angew. Chem., Int. Ed. 2003, 42, 980. (42) Shimizu, T.; Masuda, M.; Minamikawa, H. Chem. Rev. 2005, 105, 1401. (43) Shipway, A. N.; Katz, E.; Willner, I. Chem. Phys. Chem. 2000, 1, 18. (44) Llusar, M.; Sanchez, C. Chem. Mater. 2008, 20, 782.
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Figure 4. (A) Molecular structure and schematic representation of an acetaminophen-based amphiphile and enzymatic degradation of the hydrogel. (B) SEM and TEM micrographs of (i, ii) hydrogels from acetaminophen Apn-6 and (iii, iv) curcumin-loaded Apn-6 hydrogels.
forming self-assembled nanostructures that also dictate the in situ formation of metal nanostructures by acting as templates are highly advantageous.45 Furthermore, the utilization of abundant biobased resources to generate prolific scaffolds for hybrid nanomaterials would broaden the applications of biorefinery processes.
Biomass from Citrus Plants: Vitamin C-Based Amphiphiles Ascorbic acid, also known as vitamin C, is a sugar-based building block abundantly found in citrus fruits and plants. Its derivatives are used as antioxidants and food additives. Importantly, ascorbic acid has the ability to reduce metal ions to their zero oxidation state. An example is the ascorbic acid-mediated reduction of Au(III) to Au(0) that results in the formation of gold nanoparticles (GNPs). In addition, vitamin C amphiphiles are known to self-assemble in water to form nanotubes and other nanostructures.46 Therefore, it is reasonable to conceive that vitamin C amphiphiles could serve the dual purpose of (i) self-assembling to form soft organic nanomaterials and (ii) generating metal nanoparticles within soft nanomaterials. The synthesis of monoesters of ascorbic acid could potentially be nontrivial because of the presence of multiple (primary and secondary) hydroxyl groups. To overcome this, an enzyme-mediated regioselective esterification of ascorbic acid was employed as shown in Figure 5. Ascorbic acid-based amphiphiles Asc-8, Asc-12, and Asc-18 exhibited excellent self-assembly properties to generate hydro/ organogels and formed liquid crystals.47 Interestingly, while retaining their ability to self-assemble, ascorbic acid-based amphiphiles were able to reduce Au(III) metal ions to generate GNPs without utilizing an external reducing agent. The scanning electron microscopy (SEM) and transmission electron microscopy (TEM) investigation of GNP-embedded hydrogels showed GNPs (∼18 nm) embedded in sheetlike morphologies. The formation of GNPs within the hydrogel matrix did not affect the inherent morphology of the gel, whereas earlier studies by external doping of GNPs in hydrogels (45) Vemula, P. K.; John, G. Chem. Commun. 2006, 2218. (46) Bhattacharya, S.; Srivatsava, A.; Pal, A. Angew. Chem, Int. Ed. 2006, 45, 2934. (47) Vemula, P. K.; Aslam, U.; Mallia, V. A.; John, G. Chem. Mater. 2007, 19, 138.
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resulted in drastic changes of the gel native morphology.48 Thus, the current approach of the in situ synthesis of organic-inorganic hybrid materials was found to be a versatile method because the matrix itself acts as both a reducing agent and a stabilizing agent. Besides acting as templates, the ascorbic acid amphiphiles also formed liquid crystals that could be exploited for templating applications. Nanoparticles embedded in liquid crystals have enormous potential in a wide range of applications such as photonics and electronic displays. However, external doping of NPs in liquid crystals may have potential disadvantages because of the formation of nonhomogenous hybrid materials, which are often unstable. The formation of the smectic A (SmA*) phase by Asc-18 at 112.9 °C has been identified from the characteristic focal conic textures using polarizing optical microscopy images (Figure 6). The preparation of liquid crystals in the presence of Au(III) metal ions resulted in the formation of GNP-embedded liquid crystals with the SmA* phase at 120 °C, akin to the native amphiphile. Interestingly, the optical properties of GNP-embedded liquid crystals did not change over time, suggesting that these hybrid materials were indeed homogeneous and stable in nature. Taken together, this is yet another example of the utilization of biobased molecules to generate various value-added novel materials that could find potential applications. Cashew Nut Shell Liquid and Cardanol-Based Amphiphiles. The processing of cashew nuts produces an enormous amount of cashew nut shells, which is a potential industrial waste that on thermal treatment yields an oily substance called cashew nut shell liquid (CNSL). Cardanol, present in the CNSL, has been extensively used in varied materials such as resins, coatings, frictional materials, and surfactants.49 Hence, it is considered to be one of the chief plant-derived renewable resources. It consists of a rich mixture of phenolic lipids: 5% 3-(pentadecyl)-phenol, 49% 3-(8Z-pentadecenyl)-phenol, 17% 3-(8Z,11Z-pentadecadienyl)-phenol, and 29% 3-(8Z,11Z,14-pentadecatrienyl)-phenol. (48) Ambrosi, M.; Fratini, E.; Alfredsson, V.; Ninham, B. W.; Giorgi, R.; Lo Nostro, P.; Baglioni, P. J. Am. Chem. Soc. 2006, 128, 7209 and references therein . (49) (a) John, G.; Pillai, C. K. S. Macromol. Chem. Rapid Commun. 1992, 13, 255. (b) Saminathan, M.; Pillai, C. K. S. Polymer 2000, 41, 3103. (c) Saladino, R.; Neri, V.; Mincione, E.; Marini, S.; Coletta, M.; Fiorucci, C.; Filippone, P. J. Chem. Soc., Perkin Trans. 2000, 1, 281.
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Figure 5. (A) Enzyme-catalyzed synthesis of ascorbic acid amphiphiles. (B) (i) SEM micrograph of the Asc-18 organogel. (ii) TEM micrograph of the Asc-18 hydrogel with Au nanoparticles with their corresponding bilayer arrangement. Reprinted with permission from ref 47. Copyright 2007 American Chemical Society.
Figure 6. (i) SmA* phase of Asc-18 at 132.7 °C. (ii) SmA* phase
of Asc-18/GNPs at 120 °C. (iii) TEM image of GNPs in the Asc18 liquid-crystalline phase. (The scale bar is 100 nm.) Reprinted with permission from ref 47. Copyright 2007 American Chemical Society.
A closer look at the chemical structure of cardanol (Figure 7) reveals that it encompasses the appropriate structural moieties to generate a library of amphiphilic molecules using a limited number of synthetic steps. The uniqueness of its structure is that it contains (i) hydrophobic saturated/unsaturated hydrocarbon chains, (ii) alkyl chains with odd numbers of carbons, (iii) unsaturated isomers with varying degrees of nonisoprenoic cis double bonds, and (iv) a meta-alkylated phenolic group. Such an assortment of structural features reveals the amenability of cardanol to introduce diverse structural and functional entities in the framework of building blocks, which makes it a resourceful option for developing functional soft materials. The structural motifs present in cardanol are viable for hydrophobic interactions such as van der Waals forces (alkyl chains) and π-π stacking (aromatic ring). Consequently, the facile derivatization of the phenolic group with a hydrophilic moiety would impart amphiphilic character. The development of cardanol-based amphiphiles, besides being a tool for creating functional soft materials, would also provide an opportunity to systematically study the influence of hydrophobic groups, such as the unsaturation of the hydrocarbon chain on the self-assembly of amphiphiles. The systematic alteration of the hydrophobic groups has a profound effect 17848 DOI: 10.1021/la100785r
Figure 7. Cashew nut shell liquid (CNSL) from which cardanol is derived and its components.
on tuning the morphology of the aggregates. With such a purview and our continued interest in designing novel molecular gelators by employing the biorefinery concept, we envisioned that carbohydrate-derivatized cardanol might be an appropriate candidate because both the hydrophobic and hydrophilic segments stem from renewable raw materials.
Cardanol-Glycolipid Molecular Gelators Carbohydrate-derived glycolipids can be envisaged as appropriate candidates for molecular gelators that are synthesized from natural renewable raw materials.50,51 Therefore, cardanyl glycosides CG1 and CG2 were synthesized by attaching glucopyranoside to the phenolic functional group of cardanol (Figure 8). Interestingly, the self-assembly of CG1 and CG2 in organic solvents leads to the formation of fibrous structures that were further transformed into higher-order assemblies, progressively developing into a 3D network, thus inducing gelation.52 The topical morphologies of the gels obtained from CG1 and CG2, as analyzed by electron microscopy, were found to be a network of intertwisted and (50) (a) Fuhrhop, J.-H.; Schnieder, P.; Boekema, E.; Helfrich, W. J. Am. Chem. Soc. 1988, 110, 2861. (b) Fuhrhop, J.-H.; Boettcher, C. J. Am. Chem. Soc. 1990, 112, 1768. (c) Fuhrhop, J.-H.; Svenson, S.; Boettcher, C.; Roessler, E.; Vieth, H.-M. J. Am. Chem. Soc. 1990, 112, 4307. (51) Aveyard, R.; Binko, B. P.; Chen, J.; Esquena, J.; Fletcher, P. D. J.; Buscall, R.; Davies, S. Langmuir 1998, 14, 4699. (52) John, G.; Jung, J. H.; Masuda, M.; Shimizu, T. Langmuir 2004, 20, 2060.
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Figure 8. (A) Synthesis of cardanyl glycosides. (B) Molecular structures of cardanol glycoside amphiphiles. (C) SEM micrographs of monoene derivative a in (i) a water/ethanol mixture, (ii) cyclohexane, and (iii) a cyclohexane gel of saturated derivative d, CG2. Reprinted with permission from ref 52. Copyright 2004 American Chemical Society.
interlocked fibers with a width of 20-30 nm and a pitch of 150-300 nm. The presence of unsaturation to the cardanol side chain played a vital role in determining the strength of self-assembled gels, which was evinced through the formation of stronger gels from saturated CG2 and self-assembled nanofibers from unsaturated CG1 analogues. Cardanyl glycoside CG2 displayed efficient gelling ability in a wide range of organic solvents, water, and protic solvent (1:1) mixtures whereas CG1 formed fibrous nanostructures as opposed to stronger gels (Figure 8). Because of interest in the disparity between the cardanyl glycosides’ (CG1) ability to gel different solvents (organic or aqueous) and the morphologically rich self-assembly characteristics, the mixture of cardanyl glycosides was meticulously fractionated into its individual components to investigate their gelation tendencies.53,54 The diene and triene components b and c of the cardanyl glycosides in their fully hydrated state formed fluid nanostructures at room temperature and could not self-assemble to form gels. Monoene glycoside a was able to gel most of the tested organic solvents similar to CG2, including toluene, cyclohexane, glycerol, and mixtures of solvents such as water/ethanol, water/THF, and water/acetone. Although the gelation tendency and gel morphologies for monoene glycoside were consistent with that of CG2, the average Tgel for monoene glycoside was ∼43% lower (30 °C) than that of CG2 (70 °C). In addition, the X-ray diffraction of the water/protic polar solvent gels showed a higher Bragg peak for monoene glycoside a than did the CG1 mixture, suggesting both a lower packing efficiency and gel stability when compared to those of CG2. Monoene glycoside a in an aqueous solution self-assembled to form nanotubes. It is hypothesized that the presence of the double bond induced the twist (helicity) in the flat fibers and spiral-cord-like structures, which resulted in the formation of tubular structures. It is interesting to observe that the insertion of one double bond in the side chain can drastically influence the nature of self-assembly
to result in the formation of hollow nanotubes instead of solid, fibrous structures. A systematic study of doping monoene amphiphile a into saturated amphiphile d yielded interesting results. Significant effects on the twisted morphology of CG2 were observed only after 50% doping, with the equimolar (1:1) composition giving loosely coiled ribbon morphology.55 Furthermore, with increasing monoene content, the helical pitch progressively decreased to give tubular morphologies with helical markings. These studies demonstrate the flexibility of cardanol-derived amphiphiles to fine tune their self-assembled structures, a prerequisite for making tailor-made assemblies. The cis allylic double bonds in CG1 introduce “kinks” into the alkyl chain to increase its fluidity. A combination of hydrogen bonding (-OH of glucose), π-π interactions (phenyl moiety), and other hydrophobic forces (alkyl chains) were found to be the driving forces behind the self-assembly process as revealed by spectroscopic methods. In summary, one could regulate the structure and stability of a gel system with subtle structural variations. Binary self-assembly of the saturated and monoene derivatives provided a rationale for the control of self-assembled helical structures. Molecular Gelators from Triterpenes. Triterpenes are an important class of secondary plant metabolites that exhibit numerous therapeutic properties and find applications in many pharmaceutical formulations.56 The tricyclic structure of triterpenoids displays rich variations not only in the chemical functionality but also in the basic carbon skeleton. Such a resourceful framework is amenable to developing building blocks with a wide variety of structural modifications capable of forming supramolecular architectures and nanomaterials. As a result, they have emerged as a prospective biobased building block comparable to conventional carbohydrates, proteins, and fats.
(53) John, G.; Jung, J. H.; Minamikawa, H.; Yoshida, K.; Shimizu, T. Chem.; Eur. J. 2002, 8, 5495. (54) Jung, J. H.; John, G.; Masuda, M.; Yoshida, K.; Shinkai, S.; Shimizu, T. Langmuir 2001, 17, 7229.
(55) John, G.; Masuda, M.; Okada, Y.; Yase, K.; Shimizu, T. Adv. Mater. 2001, 13, 715. (56) Bag, B. G.; Dey, P. P.; Dinda, S. K.; Sheldrick, W. S.; Oppel, I. M. Beilstein J. Org. Chem. 2008, 4, 24.
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Figure 9. (A) Synthesis of arjunolic acid esters. (B) SEM micrographs of (i) the C4 ester of arjunolic acid in an o-xylene gel, (ii) a nitrobenzene derivative in toluene, and (iii) a TEM micrograph of a methyl arjunolate xerogel from o-xylene. Reprinted with permission from ref 57. Copyright 2009 American Chemical Society.
Biomass from the Arjuna Tree: Arjunolic Acid Amphiphiles Recently, arjunolic acid, a 6,6,6,6,6-pentacyclic triterpenoid obtained from Terminalia arjuna, has been utilized to develop soft materials.57-60 The presence of hydroxyl and carboxyl functionalities in arjunolic acid provides an excellent opportunity for its facile functionalization. Accordingly, a diverse set of potential molecular gelators was developed (Figure 9). Typically, the acid group was esterified to yield a series of n-alkylated (1 e n e 18) (4-nitrophenyl)methyl arjunolates. Short-chain esters, ethyl arjunolate, and n-butyl arjunolate, in particular, were observed to possess optimum amphiphilic character to induce the self-assembly of arjunolic acid derivatives in a wide range of aliphatic (acyclic and cyclic) and aromatic organic solvents, thereby forming organogels. Among the series of MGs, (4-nirophenyl)methyl arjunolate was found to be the most efficient because it was able to form gels in most of the tested organic liquids with appreciably low MGC values (∼0.2-3 wt %/v). Irrespective of the type of organic liquid or the MG structure present in the gel, it consisted of a similar spherulitic-type fibrillar network that was composed of intertwined fibers with micrometer-range length and nanometer-range diameter, as observed by optical and electron microscopy analyses. In addition, righthanded helices were observed for several fibers indicating the expression of molecular chirality on the supramolecular assemblies. The absence of sharp peaks in X-ray diffractograms for both the neat and self-assembled states of ethyl and (4-nitrophenyl)methylnitrophenylmethyl arjunolate, along with very small heat changes for gel-to-sol transitions observed in DSC thermograms, indicated the highly disordered packing of aurjunolate esters in the gel state. The growth kinetics of a 1/1 (w/w) chloroform/ cyclohexane gel analyzed by the Avrami equation suggested the 1D growth of fibers and the thermodynamic driving force for phase separation as the major factor dominating the rates of nucleation and fiber growth. The demonstration of imparting (57) Braja, B. G.; Dinda, S. K.; Dey, P. P.; Mallia, V. A.; Weiss, R. G. Langmuir 2009, 25, 8663. (58) Bag, B. G.; Maity, G. C.; Dinda, S. K. Org. Lett. 2006, 8, 5457. (59) Bag, B. G.; Maity, G. C.; Pramanik, S. R. Supramol. Chem. 2005, 17, 383. (60) Bag, B. G.; Maity, G. C.; Pramanik, S. R. Pramana 2005, 925.
17850 DOI: 10.1021/la100785r
self-assembling and gelation properties to arjunolic acid by facile functionalization indicated the capability of triterpenoids, in general, to act as precursors for developing building blocks for MGs.57
Trehalose as Biomass for Molecular Gelators Trehalose is a nonreducing disaccharide that consists of two glucose units linked by an R,R-1,1-glycoside bond. The use of trehalose in food as a good source of energy has even been referred to in the Old Testament. The manna, a sweet tasting trehalose-rich substance, eaten by the Israelites during their journey in the desert is described in the book of Exodus.61 The use of trehalose extends from food to pharmaceutical and cosmetic applications.62 It can be produced from starch by inexpensive methods in large quantities.63 In nature, trehalose is found in cactus plants, invertebrates, and microorganisms and is used for the preservation of their membrane under anhydrobiotic conditions and for antioxidant capabilities.64 Selaginella lepidophylla, also commonly known as the resurrection plant, is composed of about 12.5% trehalose (dry weight), and a completely dried selaginella blossoms to life again when rehydrated.65 Disaccharide-based amphiphiles have been reported to exhibit gelation tendencies in a wide range of solvents.66 Trehalose, a disaccharide with two primary hydroxyl groups, provides an opportunity to attach hydrophobic fatty acids through a biocatalytic procedure in a single step. A series of symmetrical diester amphiphiles were synthesized from trehalose by employing regioselective enzyme catalysis (Figure 10). The symmetrical 6,60 -diester exhibited unprecedented gelation efficiency in organic solvents such as ethylacetate, isopropanol, acetone, and xylene with MGCs as low as 0.04 wt %/v, which is the lowest value reported for sugar ester gelators.67 As evidenced by SEM, the morphology of the gels was (61) Richards, A. B.; Krakowkab, S.; Dexterc, L. B.; Schmidd, H.; Wolterbeeke, A. P. M.; Waalkens-Berendsene, D. H.; Shigoyukif, A.; Kurimoto., M. Food Chem. Toxicol. 2002, 40, 871. (62) (a) Higashiyama, T. Pure Appl. Chem. 2002, 74, 1263. (b) Elbein, A. D.; Pan, Y. T.; Pastuszak, I.; Carroll, D. Glycobiology 2003, 13, 17R–27R. (63) Sugimoto, T. Shokuhin Kogyo 1995, 38, 34. (64) Crowe, J. H.; Crowe, L. M. Nat. Biotechnol. 2000, 18, 145. (65) Adams, R. P.; Kendall, E.; Kartha, K. K. Biochem. Syst. Ecol. 1990, 18, 107. (66) Bhattacharya, S.; Acharya, S. N. G. Chem. Mater. 1999, 11, 3504. (67) John, G.; Zhu, G.; Li, J.; Dordick, J. S. Angew. Chem., Int. Ed. 2006, 45, 4772.
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Invited Feature Article
Figure 10. (A) Synthesis of trehalose diesters from enzymatic catalysis. (B) (i) SEM micrograph of an organogel (ethylacetate) of Tre-acry; the inset is a real image of the gel; (ii) cross-linked xerogel in ethylacetate; and (iii) self-standing film of gel upon soaking in water. Reprinted with permission from ref 67. Copyright 2006 Wiley-VCH.
fibrous in nature, of several micrometers in length and with diameters in the range of 10-500 nm. The extensive hydrogen bonding of the sugar moieties of trehalose was the dominant intermolecular interaction that formed a rigid 3D network. The presence of 6,60 -symmetrical alkyl chains was necessary for gelation, which could be specifically produced only by using enzymatic catalysis. Gels containing polymerizable functional groups such as acrylate could be further extended for a postgelation process by cross-linking the network.68,69 Molecular gels of the diacrylate derivatives of trehalose upon exposure to UV light in the presence of a photoinitiator formed excellent self-supporting transparent films. Typically, the gelation process was carried out with trehalose diacrylate (Tre-acry) in ethylacetate in the presence of a photoinitiator, and the resultant gel was subsequently irradiated with UV light. After lyophilization, the free-standing scaffold was immersed in water to produce a self-supporting transparent hydrogel. The water gelation tendency of such scaffolds was similar to the phenomenon occurring in the cell walls of organisms and plants where trehalose forms a gel phase under the extreme desiccant conditions of nature and preserves the water content, thereby preventing cell disruption. Such a phenomenon observed in synthetic trehalose systems could be an initial step toward generating excellent scaffolds for tissue engineering applications. In addition to common organic solvents, the diesters of trehalose exhibited gelation for cooking oils such as olive oil. Such a tendency shows the potential for trehalose-based amphiphiles to be used as vegetable oil structuring agents. Oil structuring is a process that involves the alteration of the physical properties of vegetable oil with or without altering its chemical properties. Structured oil finds applications in the cosmetics, confectionary, and baking industries. Trehalose didecanoate was able to gel vegetable oils at extremely low concentration (MGC ≈ 0.09 wt %/v). (68) De Loos, M.; van Esch, J.; Stokroos, I.; Kellog, R. M.; Feringa, B. L. J. Am. Chem. Soc. 1997, 119, 12675. (69) Smith, D. K. Adv. Mater. 2006, 18, 2773.
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The amphiphile, when degraded in the body, is expected to produce products that are biocompatible, such as trehalose and capric acid. As a result, derivatives of trehalose are projected to be suitable for such food-based applications, consequently expanding the use of trehalose in foods and cosmetic formulations.
Conclusions and Perspectives The present review enumerates and exemplifies small-molecularweight hydrogelators and organogelators obtained by judicially combining the concepts of biorefinery and the principles of supramolecular assembly with a vision of green chemistry. Enzymatic or simple chemical transformations are applied to naturally available raw materials such as vitamin C, amygdalin, trehalose, cardanol, and arjunolic acid to produce a wide range of amphiphiles and their self-assembled molecular gels. The gels have been found to be materials of interest with potential use as drug-delivery vehicles, templates for nanomaterial synthesis, and food structuring agents. Importantly, biocatalysis has been successfully utilized to generate the building blocks in quantitative yields with precise control of regioselectivity. The swift integration of ideas from biorefinery and materials chemistry is a welcome approach that paves the way for new advances in the development of materials, chemicals, and new energy sources. Therefore, we envision that the collective efforts and responsible practices of biorefinery will offer opportunities for growth and will provide promise for a sustainable future. Acknowledgment. This work was supported by the ACS Petroleum Research Fund, grant GCI-PRF no. 48124-GCI. We also thank Dr. C. K. S. Pillai, Dr. Toshimi Shimizu, and Dr. Jonathan Dordick for their encouraging support. We thank the reviewers for their suggestions that enriched this review. We thank Mr. Greg Cruickshank for his critical reading of the manuscript. P.K.V. thanks the Kauffman Foundation for an entrepreneur postdoctoral fellowship.
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