Molecular Baskets: The Design of Functional Calixarenes

Ariane Vartanian Literature Seminar October 20, 2011

Although macrocycles derived from phenols and aldehydes have been around in some form since the late nineteenth century, it was not until molecular recognition became popular in the late 1970s that calixarenes began to cultivate a story of their own. C. David Gutsche coined the term for these vase-shaped molecules after the Greek word for chalice, sparking interest in the calixarenes versatile skeleton, straightforward synthesis, and remarkably sophisticated applications1. This report will highlight some interesting functions of calixarenes, from the most elegant models of supramolecular encapsulation to biomimetics and calixarene-studded nanoparticles. Molecular recognition is a common theme in calixarene chemistry, and virtually all applications exploit this property. Due to their inviting bowl shape, calixarenes make appealing characters in host-guest studies and are capable of encapsulating a variety of aliphatic, aromatic, and ionic guest molecules. The aromatic core is principal in directing the calixarenes molecular recognition behavior; it has high affinity for guest molecules through cation- interactions, - stacking, or hydrophobic effects. Cation- interactions in particular are curious, because they allow polar cationic molecules, such as amino acids and neurotransmitters, to bind strongly with the nonpolar corein essence serving as a nonpolar anion2,3. These interactions are still active in aqueous media: the electronrich ring can compete against the high energy cost of desolvating ions, and snatch a cation out of water and into a hydrophobic environment. This phenomenon of calixarenes is promising for applications in biological (and cation) sensing4,5. Various studies have shown the self-assembling, through hydrogen bonding of the hydroxyl units or functionalized rims, of calixarene or resorcinarene (resorcinol-derived) molecules into cages with spherical or oblong cavities6,7. These cavities, by virtue of their aromatic cores, favorably encapsulate nonpolar molecules, and the rims can also help tuck away those with polar functional groups. Many such models are reversible by introducing hydrogen bond competitors, allowing controlled release of guests, which may be useful for such applications as drug delivery or catalysis8,9. One particularly elegant study assembled calix[4]resorcinarenes into a spherical hexameric capsulesixty hydrogen bonds totalthat aptly mimics viral capsids10. The cavity on the hexamer was a mammoth 1,375 , the most spacious constructed at the time. In solution-state, the use of such protective interiors (molecular flasks) for reactions of labile molecules is wellestablished, but only recently has this concept been extended to the solid state11,12. Zheng and colleagues demonstrated E/Z photoisomerization of 3-chloroacrylic acid in a supramolecular C-ethylcalix[4]resorcinarene crystal13. Each void space permitted the dynamic motion of a single substrate so that the reaction proceeded in a single-crystal-tosingle-crystal fashion and the overall crystallinity was retained. From these results, it is not unthinkable that most solution-state reactions might be transferred to the solid state, and that molecular structures of intermediates and products can be characterized directly by X-ray crystallography in real-time.

The biomimetic objective of designing these tiny reaction vessels is to construct artificial enzymes that can rival the selectivity and efficiency of Nature. Enzymes combine superior molecular recognition with catalytic functionalities that can accelerate reactions by factors greater than 106. The calixarene has been engineered, in many examples, as a synthetic receptor14. For instance, Gissot and Rebek, Jr. demonstrated the aminolysis, accelerated by up to 16 times, of p-nitrophenyl choline carbonate (an acetylcholine analogue) by a pyridine-functionalized resorcinarene15. Although their catalytic performance is still not as efficient as their biological equivalents, calixarenes are especially suited for enzyme mimics in several ways. The shape and size of the cavity interior are easily tuned, and due to its programmable flexibility it can even shrink or expand to accommodate different guestsmuch like the induced-fit process of enzymesubstrate binding. Furthermore, the rims can be functionalized with metal-coordinating arms (such as imidazoles or histidines) that hold a metal catalyst above the binding pocket, imitating the active site of metalloenzymes; in some cases these arms can confer chirality to the host environment16. A new direction in calixarene chemistry has taken the form of calixarene-studded nanomaterials. There has been a recent surge of interest in fabricating self-assembled monolayers of calixarenes solid-supported on gold, silver, silicon, or quantum dots, such that the molecular recognition of calixarenes and novel optical properties of nanoparticles together give rise to myriad permutations of molecular sensors17. The focus herein is the sensing of biologically-active molecules, although the concept has been extended to other ions and environmentally-relevant species, such as polycyclic aromatic hydrocarbons.

Figure 1. Calixarene-modified gold nanoparticles serve as colorimetric amino acid sensors18.

In one representative study, Patel and Menon designed water-soluble psulfonatocalix[4]arene thiol-modified gold nanoparticles which exhibited a distinct redto-purple color change in aqueous solutions of lysine, arginine, and histidine, but not in the presence of other amino acids18. These three amino acids feature a positively-charged NH3+ in the side chain, as well as the NH3+ characteristic of all protonated amino acids. Cation- interactions between the cations and cavities induce aggregation of the calixcapped nanoparticles. The surface plasmon absorbances of the gold nanoparticles couple as the nanoparticles come into proximity, and a distinct color change is observed as the wavelength shifts from 524 nm to the 550 nm region. Similarly, cadmium-selenide quantum dots have been coated with p-sulfonatocalix[n]arene (n = 4, 6) to afford highly fluorescent probes for the detection of acetylcholine, methionine, and phenylalanine19,20.

Calixarenes remain a popular cavitand in materials chemistry research. The creative design of calixarenes with functional rims and shape-selective cavities has led to a diverse spectrum of innovative materials, spanning the fields of supramolecular chemistry, biomimetics and analytical sensing.
1 2 3 4 5 6 7 8 9 10 11 12 Gutsche, C. David. Calixarenes: An Introduction, 2nd ed.; Royal Society of Chemistry: Cambridge, 2008. Dougherty, D. Cation-pi interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp. Science 1996, 271, 163-168. Lehn, J.; Meric, R.; Vigneron, J.; Cesario, M.; Guilhem, J.; Pascard, C.; Asfari, Z.; Vicens, J. Supramol. Chem. 1995, 5, 97-103. Mutihac, L.; Lee, J. H.; Kim, J. S.; Vicens, J. Recognition of amino acids by functionalized calixarenes. Chem. Soc. Rev. 2011, 40, 2777-2796. Perret, F.; Lazar, A. N.; Coleman, A. W. Biochemistry of the para-sulfonatocalix[n]arenes. Chem. Comm. 2006, 2425-2438. Atwood, J. L.; Barbour, L. J.; Jerga, A. Organization of the interior of molecular capsules by hydrogen bonding. PNAS 2002, 99, 4837-4841. Hof, F.; Craig, S.; Nuckolls, C.; Rebek, Jr., J. Molecular encapsulation. Angew. Chem. Int. Ed. 2002, 41, 1488-1508. Shimizu, K.; Rebek, Jr., J. Synthesis and assembly of self-complementary calix[4]arenes. PNAS 1995, 92, 12403-12407. Rebek, Jr., J. Host-guest chemistry of calixarene capsules. Chem. Comm. 2000, 637-643. MacGillivray, L. R.; Atwood, J. L. A chiral spherical molecular assembly held together by 60 hydrogen bonds. Nature 1997, 389, 469-472. Inokuma, Y.; Kawano, M.; Fujita, M. Crystalline molecular flasks. Nat. Chem. 2011, 3, 349-358. Legrand, Y.; van der Lee, A.; Barboiu, M. Single-crystal X-ray structure of 1,3dimethylcyclobutadiene by confinement in a crystalline matrix. Science 2010, 329, 299302. Zheng, S.; Messerschmidt, M.; Coppens, P. Single-crystal-to-single-crystal E Z and Z E isomerizations of 3-chloroacrylic acid within the nanocavities of a supramolecular framework. Chem. Comm. 2007, 2735-2737. Reinaud, O.; Le Mest, Y.; Jabin, I. Models of Metallo-enzyme Active Sites. In Calixarenes in the Nanoworld; Vicens, J., Harrowfield, J., Eds.; Springer: The Netherlands, 2007. Gissot, A; Rebek, Jr., J. A functionalized, deep cavitand catalyzes the aminolysis of a choline derivative. J. Am. Chem. Soc. 2004, 126, 7424-7425. Coquiere, D.; Le Gac, S.; Darbost, U.; Seneque, O.; Jabin, I.; Reinaud, O. Biomimetic and self-assembled calix[6]arene-based receptors for neutral molecules. Org. Biomol. Chem. 2009, 7, 2485-2500. Kim, H. J.; Lee, M. H.; Mutihac, L.; Vicens, J.; Kim, J. S. Host-guest sensing by calixarenes on the surfaces. Chem. Soc. Rev. 2012, 41, advance article. Patel, G.; Menon, S. Recognition of lysine, arginine, and histidine by novel psulfonatocalix[4]arene thiol functionalized gold nanoparticles in aqueous solution. Chem. Comm. 2009, 3563-3565. Jin, T.; Fujii, F.; Sakata, H.; Tamura, M.; Kinjo, M. Amphiphilic psulfonatocalix[4]arene-coated CdSe/ZnS quantum dots for the optical detection of the neurotransmitter acetylcholine. Chem. Comm. 2005, 4300-4302. Wang, X.; Wu, J.; Li, F.; Li, H. Synthesis of water-soluble CdSe quantum dots by ligand exchange with p-sulfonatocalix[n]arene (n = 4, 6) as fluorescent probes for amino acids. Nanotech. 2008, 19, 205501-205510.

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