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Synthesis

Controlling Guests in Nanocapsules

Studies probe how guests become organized and oriented in self-assembled molecular containers

by MICHAEL FREEMANTLE, C&EN LONDON
January 3, 2005 | A version of this story appeared in Volume 83, Issue 1

Atwood
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Credit: COURTESY OF JERRY ATWOOD
Credit: COURTESY OF JERRY ATWOOD

Whenever people get together for social events, the rules of etiquette provide guidance for how guests and hosts should interact. In the supramolecular realm, however, the rules of engagement between guest molecules that are enclosed inside supramolecular hosts haven't yet been completely figured out by chemists.

To realize the full potential of these assemblies, several groups of supramolecular chemists are striving to gain insight into how guest molecules are arranged inside nanocapsules and to develop methods that may be used to manipulate these guests.

"A detailed understanding of the interplay and relative orientations of the constituent guest molecules has, until now, been restricted to a few instances of limited complexity," note chemistry professor Jerry L. Atwood and coworkers at the University of Missouri, Columbia, in a recent paper [Angew. Chem. Int. Ed., 43, 5263 (2004)].

The paper describes two important advances relating to nanocapsules with interior volumes in the 1,200–1,500-Å3 range, according to Atwood. "First, we show that it is possible to order the guests on the interior of our large free-standing capsules," he says. "Second, and most remarkably, we show that these large capsules communicate with each other, at least in the solid state and probably in solution, by the formation of intercapsule hydrogen bonds. This communication in turn leads to a completely different ordering of the guests within the capsules."

Atwood and colleagues studied three crystalline nanocapsule materials. The nanocapsules in each material are globular hexamers consisting of six macrocyclic building blocks bound together by 72 hydrogen bonds. The building blocks are pyrogallol[4]arene molecules having different alkyl chains for each of the three materials. The nanocapsules form when ethyl acetate is allowed to evaporate from an ethyl acetate solution of the macrocyclic blocks. Single-crystal X-ray diffraction reveals that each type of nanocapsule contains six ethyl acetate guest molecules and a single water guest molecule.

ENCLOSED
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Credit: IMAGES COURTESY OF LIAM A. PALMER
Pyrogallolarenes (X = OH) assemble themselves in dry organic solvents into hexameric capsules (left) that can hold four octane molecules. Resorcinarenes (X = H) require water to form hexamers (right) that can encapsulate eight benzene molecules.
Credit: IMAGES COURTESY OF LIAM A. PALMER
Pyrogallolarenes (X = OH) assemble themselves in dry organic solvents into hexameric capsules (left) that can hold four octane molecules. Resorcinarenes (X = H) require water to form hexamers (right) that can encapsulate eight benzene molecules.

"The paper presents a series of remarkable X-ray structures of hexameric molecular capsules," comments Yoram Cohen, a chemistry professor at Tel Aviv University, in Israel. The interactions between capsules are shown to affect how the ethyl acetates encapsulated in the cavity are oriented. "When there is no communication between the capsules, all six ethyl acetate molecules are oriented so that their methyl groups point toward the base of the macrocycles. However, when two neighboring capsules 'communicate'--that is, they are mutually engaged in hydrogen bonds--the encapsulated ethyl acetates reorient themselves. This phenomenon is also found in biological systems."

Cohen points out that interest in noncovalent molecular capsules, particularly those based on hydrogen bonds, stems from their ability to isolate reversibly the encapsulated guests from their surroundings. Hydrogen-bonded dimeric capsules based on substituted calixarenes were first reported in 1995 by chemistry professor Julius Rebek Jr.'s group at Massachusetts Institute of Technology. The following year, Rebek became director of Skaggs Institute for Chemical Biology at Scripps Research Institute and moved his research group there.


ACCORDING TO Cohen, interest in larger capsules stems from a seminal paper by Atwood and Leonard R. MacGillivray, now assistant professor of chemistry at the University of Iowa [Nature, 389, 469 (1997)]. The two chemists showed that C-methylresorcin[4]arene forms a hexameric capsule with eight water molecules in the solid state and provided evidence that the capsule structure is maintained in solution. In 2001, Rebek's group showed that C-undecylresorcin[4]arene forms hexameric capsules containing ammonium salts in chloroform solution. Cohen's group is using diffusion nuclear magnetic resonance spectroscopy to study the structure of nanocapsules in solution and probe the encapsulation process. "Diffusion NMR is a powerful tool for the characterization of multicomponent superstructures, such as hexameric capsules, in solution," Cohen says. "We can probe the hexameric nature of these capsules, assess their relative stability and the role of water molecules in different assemblies, and determine the self-recognition in the self-assembly process."

Cohen
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Credit: COURTESY OF YORAM COHEN
OLYMPUS DIGITAL CAMERA
Credit: COURTESY OF YORAM COHEN

Cohen and graduate student Liat Avram have employed the technique to study the self-assembly and host-guest properties of resorcin[4]arenes and pyrogallol[4]arenes. "We showed, for example, that, contrary to previous belief, C-undecylresorcin[4]arene self-assembles spontaneously into a hexameric capsule in water-saturated chloroform solutions," Cohen says. "Diffusion measurements enabled us to determine unequivocally that eight water molecules form part of the hexameric capsule structure in analogy to the structure found in the solid state.

"Interestingly, we demonstrated with the same technique that when water-hexameric capsules encapsulate an ammonium salt such as tetrahexylammonium bromide, the eight water molecules leave the structure," Cohen continues. "We also showed that the isobutyl analog of the resorcin[4]arene and C-isobutylpyrogallol[4]arene and its undecyl analog all form hexameric capsules in solution. Water molecules are not part of the hexameric pyrogallol[4]arene capsule superstructure. The capsules encapsulate neutral tertiary alkylamines but not ammonium salts, whereas the resorcin[4]arene capsules encapsulate both amines and ammonium salts in chloroform solution."

In addition, diffusion NMR studies reveal that when the pyrogallol[4]arene capsules are protonated in a water-chloroform solution, the tertiary alkylamines are ejected and chloroform molecules enter the capsules. Cohen and Avram conclude that the alkyl chains on the hexameric capsules have little influence on the characteristics of the capsules, whereas the number of hydroxyl groups has a dramatic effect.

Cohen and Avram recently used diffusion NMR to investigate the self-assembly and self-recognition properties of capsules formed from two different macrocycles [J. Am. Chem. Soc., 126, 11556 (2004)]. They showed that heterohexameric capsules form over time or after heating from solutions of two resorcin[4]arenes or two pyrogallol[4]arenes.

"We found that heterohexamers are only formed when macrocycles of the same types are mixed," Cohen says. "When resorcin[4]arene capsules are mixed with pyrogallol[4]arene capsules, no heterohexamers are detected."

One of the reasons for the interest in resorcin[4]arene and pyrogallol[4]arene assemblies is their large size, remarks Bruce C. Gibb, associate professor of chemistry at the University of New Orleans. "They are the most capacious capsules reported to date," he says. "The larger capsules that are now available not only entrap a wider range of molecules, but they also simultaneously entrap larger numbers of molecules."

Gibb points out that the contents of a capsule can be described in terms of their orientational isomerism--that is, the relative orientation that two or more molecules have to one another--and their positional isomerism, which is the relative position that two or more molecules have to one another.

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Credit: COURTESY OF V. RAMAMURTHY
Ramamurthy
Credit: COURTESY OF V. RAMAMURTHY
Ramamurthy

"Controlling the constitution, position, and orientation of encapsulated guests is a function of capsule size," he explains. "The larger the capsule, the harder it is to control the contents because guests can be further removed from the capsule walls."

The nanocapsules prepared by his group are dimers formed by self-assembly of two basketlike molecules (cavitands) having a resorcinarene framework, an external coat of eight carboxylic acid groups, and an internal hydrophobic pocket. The dimeric capsules are smaller than the hexameric capsules described by the Atwood and Cohen groups.

The nanocapsules prepared by his group are dimers formed by self-assembly of two basketlike molecules (cavitands) having a resorcinarene framework, an external coat of eight carboxylic acid groups, and an internal hydrophobic pocket. The dimeric capsules are smaller than the hexameric capsules described by the Atwood and Cohen groups.

In recent work, the research groups of Gibb and chemistry professor Vaidhyanathan Ramamurthy at Tulane University, New Orleans, used fluorescence spectrometry and photochemistry to examine the interiors of their dimeric capsules and investigate the capsules' ability to influence the outcome of photoreactions of encapsulated guests [J. Am. Chem. Soc., 126, 14366 (2004)].

"We use the hydrophobic effect to self-assemble our capsules in water," Gibb says. "We then carry out photolysis reactions inside these capsules. The radicals thus generated reorient themselves to pack the cavity more efficiently, before recombining to give products that cannot form in free solution."

Most organic compounds are generally less soluble or insoluble in water, notes Ramamurthy, who is moving this month to the University of Miami as chairman of the chemistry department. "Water-soluble hosts, such as the octa acid host, act as a carrier to solubilize the organic compounds in water and thus facilitate selective chemistry under environmentally friendly conditions," he says. "Our objective is to make use of light and water to control the behavior of organic molecules during photochemical reactions."

Gibb, Ramamurthy, and coworkers note that the nanoenvironment inside the capsule formed from the two cavitand molecules is essentially dry and leak-proof on the photolysis timescale of excited states of reactant molecules. The capsules not only allow photolysis reactions to be carried out in water but also control the reaction outcome with selectivities comparable to those in the solid state.

IN RECENT WORK, Rebek and coworkers investigated how the mechanical rotation of a guest molecule in a hydrogen-bonded dimeric capsule is influenced by the presence of a different guest molecule [J. Am. Chem. Soc., 126, 12728 (2004)]. They coencapsulated [2,2]-paracyclophane molecules with molecules of different sizes, such as chloroform or cyclohexane, in capsules consisting of two resorcinarene tetraimide subunits. They tentatively conclude, from the limited data available so far, that larger coguests apply brakes to the spinning rate of the paracyclophane guest. "Conversely, attractive forces between coguests could accelerate spinning by pulling [2,2]-paracyclophane closer to the center of the capsule," the authors note.

In related work, Rebek and postdoc Toru Amaya used NMR to investigate the kinetics and thermodynamics of the hydrogen-bonded encapsulation process in protic solvents using the same hydrogen-bonded capsule and various hydrocarbon guests such as dodecane and naphthalene [J. Am. Chem. Soc., 126, 14149 (2004)]. The two chemists showed that the rates of dissociation-association of the capsule are comparable to the rates for the in-out exchange of large guests. The results suggest that guest exchange occurs by complete dissociation of the capsule in protic solvents, Rebek and Amaya note.

A recent article on the "ins and outs of molecular encapsulation" by Rebek and graduate student Liam C. Palmer considers the mechanism of guest exchange with reversibly formed capsules in nonprotic organic solvents [Org. Biomol. Chem., 2, 3051 (2004)]. "The earliest proposals that involved the complete dissociation of the assembly, exchange with solutes or solvents, then recombination are unlikely to be correct," the authors conclude.

Rebek and Palmer suggest that the guest-exchange mechanism is likely to involve the opening of flaps on the cavitands that bond together to form the capsules.

According to Atwood, the future of capsule work lies in three areas: delivery technology, materials, and models for cell and viral behavior. "The use of nanocapsules for delivery technology can be envisaged for drugs in the most elegant applications and also for herbicides, pesticides, and cosmetics, for example," he says. "Much of our work is focused on the encapsulation of small-molecule drugs," with site-specific delivery being accomplished by derivatizing the exterior of the capsules. "There is the potential to revolutionize drug therapy with such capsules, but this is definitely down the road.

"Capsules may also contain well-defined chunks of magnetic material," Atwood continues. "The manner in which the capsules pack then becomes the key issue in the organization of the magnetic substances. We also have new discoveries on the development of large spherical assemblies with diameters of about 80 nm and large tubes with diameters of about 20 nm and lengths of as much as 500 nm. These assemblies are based on capsules as building blocks."

Finally, Atwood says, model systems are urgently needed for studying complex cell and viral systems. "The capsules are poised to make an important contribution. The bottom line is that applications are still in the future, but they are on the way."

 

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