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Foresight Update 26 (page 2)

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Table of Contents - Foresight Update 26

Recent Progress: Supramolecular Chemistry by J.-M. Lehn

by Jeffrey Soreff

(Editor's note: In this issue, Jeff Soreff focuses on an ambitious plan for advances in chemistry - as projected in Nobel chemist Jean-Marie Lehn's new book Supramolecular Chemistry - and its relationship to molecular nanotechnology.)

Jean-Marie Lehn, the winner of the 1987 Nobel Prize in chemistry, provides a broad overview of the chemistry of "soft bonds" in Supramolecular Chemistry. Lehn covers a broad variety of structures and functions. Lehn's goal for chemistry is stated clearly: creating "molecular and supramolecular devices."

From the perspective of molecular manufacturing, perhaps the most crucial is the effect on synthesis. As Lehn writes: "The contribution of supramolecular chemistry to chemical synthesis has two main aspects: the production of the non-covalent supramolecular species themselves and the use of supramolecular features to assist in the synthesis of covalent molecular structures." Both of these options can create atomically precise components useful in molecular mechanisms. Both can extend to larger 3D structures than are accessible through traditional synthetic techniques.

Amongst the types of supramolecular species, one of the distinctions that Lehn makes is between: "(1) supermolecules, well-defined, discrete oligomolecular species that result from the intermolecular association of a few components (a receptor and its substrate(s)) following a built-in "Aufbau" scheme based on the principles of molecular recognition; [and] (2) supramolecular assemblies, polymolecular entities that result from the spontaneous association of a large undefined number of components..." Supermolecules can therefore be atomically precise, while polymolecular entities are more similar to phases or polydisperse polymers.

The assembly of supermolecules requires well defined adhesion between selected molecules. Lehn sketches some of the factors necessary for selective binding: "1) steric (shape and size) complementarity... 2) interactional complementarity... 3) large contact areas... 4) multiple interaction sites... 5) strong overall binding..."

At many points in his book, Lehn emphasizes the importance of information in supramolecular systems, particularly information embedded in the constituent molecules during their synthesis. The selectivity of the binding sites in the molecules is a large part of this information.

In order to design large supermolecules, composed of a large number of molecules, each in a unique position, one needs to be able to construct a large variety of binding sites, each binding very specifically to its complement. At the end of chapter 2, Lehn writes: "The variety of hydrogen bonding patterns that may be envisaged makes these interactions a highly versatile tool for the recognition and orientation of molecules for both biomimetic and abiotic purposes." In chapters 2 and 3 these patterns are mostly turned inwards to bind small cations, anions, and neutral molecules. While these techniques may prove useful in molecular manufacturing as, for instance, tool holders, the examples in chapter 9 where the bonds are turned outwards to form larger supermolecules appear more promising for the construction of large structures.

A theme where Lehn's research program also applies to components for molecular manufacturing lies in the design of exoreceptors. Lehn describes the design of exoreceptors for control of crystal growth, and for the control of polymolecular structures. He writes "The fact that polymolecular assemblies define surfaces on which and through which processes can occur, again stresses the interest of designing exoreceptors operating at the interfaces, in addition to endoreceptors embedded in the bulk of the membranes." From our perspective, the exoreceptors are, in addition, useful as structural connections within large supermolecules. Success at the systematic design and synthesis of exoreceptors would be a substantial help in engineering large supermolecules.

In addition to selective binding, Lehn emphasizes that the self-assembly of well-defined structures must have a termination mechanism. This is essentially the difference between producing a supermolecule and producing a supramolecular polymer or phase. This is crucial if we are to use self-assembly for such tasks as building a strut out of a number of identical subunits. In Lehn's words "termination control presents a particular challenge."

The considerations described above are rather general. Lehn also describes a good deal of work with two specific structural motifs: macrocyclic and macropolycyclic ethers and amines on the one hand and metal helicates on the other.

Lehn's goal is stated clearly:
molecular and supramolecular devices

The macrocyclic ethers are variations on crown ethers. Lehn describes a large number of cases where they bind substrates specifically. In one case, "Receptor molecules possessing two binding subunits located at the two poles of the structure will complex preferentially substrates bearing two appropriate functional groups at a distance compatible with the separation of the subunits. The distance complementarity amounts to a recognition of molecular length of the substrate by the receptor. Such linear recognition by ditopic receptors has been achieved for both dicationic and dianionic substrates, diammonium and dicarboxylate ions respectively; it corresponds to the binding modes illustrated in 50 and 51." In this case both the substrate and the binding site have an obvious tunable element, so it is quite clear that a variety of specific bindings are feasible.

The metal helicates that Lehn built are strands of bipyridine ligands, strung together with alkane or ether linkages and wound around metal ions. Lehn designed the strands so that a single strand does not wind around all of the coordination sites of a single metal ion, but rather two or three strands wind around a line of metal ions.

Lehn writes: "One may draw an analogy between nucleic acids and helicates, with on one side the polynucleotide strands and their interaction through hydrogen bonding and on the other side the oligobipyridine strands and their binding together via metal ion coordination." Another way to view the analogy is that in both cases the noncovalent interactions wind fairly flexible, readily synthesized, covalent structures into more densely interconnected, less flexible, 3D structures with very predictable "secondary structure." Perhaps the metal helicates might one day be used to build structures similar to Nadrian Seeman's DNA polyhedra. Lehn has already used these structures to place substituents on the bipyridine strands into well defined positions in space.

A crucial feature of nucleic acids is their sequence specific binding. Seeman's polyhedra use this, and a general use of Lehn's metal helicates for 3D structures would require some similar specificity. Since the bipyridine sequences in the helicates bind to each other through intermediate metal atoms, this requires that there be sufficiently specific binding of at least two different types of metal atoms to two different type of bipyridine sites. Lehn describes an experimental demonstration of the selectivity of metal ion assembly of helicate structures with: "Similarly, when a mixture of the two tris-bipyridine ligands 129 and 148 is allowed to react simultaneously with copper(I) and nickel(II) ions, only the double helicate 132 and the triple helicate 149 are formed (Figure 49). Thus, parallel operation of two programmed molecular systems leads to the clean self-assembly of two well-defined helical complexes from a mixture of four components in a process involving the assembly of altogether 11 particles of four different types into two supramolecular species."

Lehn describes a number of advantages of metal-centered supermolecule design in general. He favors it because, amongst other features, 1) It allows a wide range of bond strengths. 2) It allows several coordination geometries, with well-defined orientation of the ligands within each choice of geometry.

In describing supramolecular assistance to covalent synthesis, Lehn describes a number of selective catalysts, primarily drawing examples from his group's macrocycle work. He shows examples of chiral recognition and regiospecificity. Since the catalysts that he shows have their geometry defined by covalent bonds rather than by the hydrophobic effects that contribute to the folding of protein enzymes, one might expect these new catalysts to be more useful in a machine phase environment than proteins are. Lehn writes: "Supramolecular catalysts are by nature abiotic chemical reagents that may perform the same overall processes as enzymes, without following the detailed pathway by which enzymes actually effect them or under the conditions in which enzymes do not operate. Furthermore and most significantly, this chemistry may develop systems realizing processes that enzymes do not perform while displaying comparable high efficiencies and selectivities."

For construction of large structures, nanotechnology requires catalysis of bond formation rather than bond cleavage. Lehn writes that "To this end, the presence of several binding and reactive groups is essential," since at least two substrates must be bound. Lehn demonstrated this in a macrocycle that catalyzes the formation of pyrophosphate from two separate substrates bound at two sites in the macrocycle. This showed that, while there is a minimum complexity required in a catalyst for bond formation, this is achievable.

In addition to synthetic techniques, there are a number of other areas of commonality between Lehn's research program and the program needed for molecular manufacturing.

There is a common dependence on computation in both areas of research. Certain functional features, notably allostery, require at least one flexible degree of freedom in a receptor molecule. Lehn writes "Such designed dynamics are more difficult to control than mere rigidity, and the developments in computer-assisted molecular design methods, allowing the exploration of both structural and dynamical features, may greatly help [1.38-1.50]." This is essentially the same reason that molecular dynamics is employed in analysis of diamondoid mechanisms. It permits explorations of dynamics which are an essential part of the functions of the mechanisms.

Lehn presents an architecture for transferring molecular information across a membrane via "molecular transmembrane rods". This proposal shares some important common features with rod logic, albeit in the analog domain. Both proposals pack desired degrees of freedom very densely, with separate channels for each rod. The packing of information is somewhat similar to the design of a binding surface, but, unlike the binding surface case, the information isn't frozen at the time of covalent synthesis. As Lehn writes: "Indeed with only a few molecular rods an extremely large amount of information may be expressed since the set of rods can adopt a very high number of topographies defined by in-plane configurations and out-of-plane displacements."

Lehn writes of the desirability of "the development of chemo-mechanical actuators for the conversion of light, electrical, or chemical energy into mechanical energy and motion, a major goal being, as already pointed out, to achieve controlled oriented motion." This goal is equally important in the development of molecular manufacturing systems, since they require mechanical energy for mechanosynthesis and other applications.

Some of the experimental work that Lehn describes may already allow an experimental check on some of the calculated properties of certain pieces of molecular machinery. Lehn writes: "...the relaxation data for the free and complexed species, indicate that complexes of alpha-cyclodextrin present weak dynamic coupling between substrate and receptor... Potential energy calculations have shown that there are small or no barriers to rotation of a substrate inside the cavity of alpha-, beta-, or gamma-cyclodextrin." The cyclodextrin complexes may therefore provide an experimentally accessible system for demonstrating the low barriers predicted for certain types of bearings useful in nanotechnology. The existence of these complexes is helpful in showing that the intermolecular potentials required for low rotational barriers are compatible with high enough net binding to form stable complexes.

In this book, Lehn shows himself to be a vigorous advocate of the self-assembly path to nanoscale structures, responding to the classic Feynman quote "there's plenty of room at the bottom," with his own view that in "reaching higher levels of organization and behaviour, it is clear that through supramolecular chemistry "there's even more room at the top!" Foresight members interested in the self-assembly route to molecular nanotechnology will want to watch for further results from this visionary chemist.

Supramolecular Chemistry. Concepts and Perspectives. Jean-Marie Lehn. VCH. Weinheim, New York, Basel, Cambridge, Tokyo 1995 271 pp, ISBN 3-527-29311-6, paper $39.95

Table of Contents - Foresight Update 26

Book Review: Quotes from Jean-Marie Lehn

Nobel prizewinning chemist Jean-Marie Lehn gives his views on the future of chemistry in his new book Supramolecular Chemistry: Concepts and Perspectives. (See adjoining review by Jeff Soreff.) Foresight director Chris Peterson presents her favorite quotes from the book as part of the review.
"Recent lines of investigation concern self-processes (self-assembly, self-organization, replication) and the design of programmed supramolecular systems." page 7

"The combination of receptors, carriers and catalysts, handling electrons, ions, and molecular substrates, with polymolecular organized assemblies, opens the way to the design of molecular and supramolecular devices and to the elaboration of chemical microreactors and artificial cells." page 87

"Positional changes of atoms in a molecule or supermolecule correspond on the molecular scale to mechanical processes at the macroscopic level. One may therefore imagine the engineering of molecular "machines" that would be thermally, photochemically or electrochemically activated" [references, including Nanosystems]. page 135

"The formation of photonic, electronic, ionic switching devices from molecular components and their incorporation into well-defined organized assemblies represents the next step towards the development of circuitry and functional materials at the nanometric scale...The controlled build-up of such architectures requires the ability to direct self-assembly and self-organization processes through explicit instructed procedures."
pages 137-8

"In addition, temporal information may be involved if the progressive build-up of the final superstructure occurs through a defined sequence of molecular instructions and algorithms, a given component or recognition event coming into play at a well-defined stage in the overall process...Such sequential self-assembly represents the next step in the design of artificial systems presenting higher levels of complexity." page 144

"With increasing control being achieved over molecular programming of supramolecular structure generation through hydrogen bonding, the self-assembly of a variety of linear, two- or three-dimensional architectures may be realized...Designed self-assembly thus opens roads towards the generation of organized entities in the liquid phase." page 165

"By increasing the size of its entities, nanochemistry works its way upward towards microlithography and microphysical engineering, which, by further and further miniaturization, strive to produce ever smaller elements." page 195

"'Intelligent', functional supramolecular materials, network engineering and polymolecular patterning are the subject of increasing activity in chemical research. The development of advanced materials may take full advantage of the control provided by information-dependent supramolecular processes for the production of large scale architectures in a sort of molecular and supramolecular tectonics...leading to a nanotechnology and nanomaterials or organic or inorganic nature" [references, including Nanosystems]. page 195

"It is important to note that technologies resorting to self-organization processes should in principle be able to bypass microfabrication procedures by making use of the spontaneous formation of the desired superstructures and devices from suitably instructed and functional building blocks. There is indeed a rich palette of structures and properties to be generated by blending supramolecular chemistry with materials science!"
page 195

"Components and molecular devices such as molecular wires, channels, resistors, rectifiers, diodes, and photosensitive elements might be assembled into nanocircuits and combined with organised polymolecular assemblies to yield systems capable ultimately of performing functions of storage, detection, processing, amplification, and transfer of signals and information..." page 196

"The reading of molecular information and the operation of molecular devices require ways and means of addressing molecular and supramolecular species. Despite the difficult problem that one may apprehend, encouraging and exciting developments may be anticipated. Indeed, scanning tunneling microscopy (STM) and atomic force microscopy (AFM) are providing extraordinary manipulative power at the atomic and molecular scale..." page 196

"The chemist finds illustration, inspiration and stimulation in natural processes, as well as confidence and reassurance since they are proof that such highly complex systems can indeed be achieved on the basis of molecular components." page 205

"Questions have been addressed about which one may speculate, let one's imagination wander, perhaps even set paths for future investigations. However, where the answers lie is not clear at present and future chemical research towards ever more complex systems will uncover new modes of thinking and new ways of acting that we at present do not know and may even be unable to imagine." pages 205-6

"The perspectives are definitely very (too?) wide and it will be necessary to distinguish the daring and visionary from the utopic and illusionary! On the other hand, we may feel like progressing in a countryside of high mountains: the peaks, the goals are visible and identifiable or may become so as progress is made, but we do not yet know how to reach them. We may find landslides, rockfalls, deep crevices, tumultuous streams along the way, we may have to turn around and try again, but we must be confident that we will eventually get there. We will need the courage to match the risks, the persistence to fill in the abyss of our ignorances and the ambition to meet the challenges, remembering that 'Who sits at the bottom of a well to contemplate the sky, will find it small'"(Han Yu, 768-824). pages 205-6

This last quotation from Lehn is good advice for those of us pursuing molecular nanotechnology. The path is unclear, but our goal is clear. Being reminded of the need for persistence by a Nobel chemist is reason alone to keep this book on our shelves.

--Chris Peterson

Table of Contents - Foresight Update 26


Special thanks this issue go to Gayle Pergamit for advising on the Senior Associates Gathering program; Russell Whitaker, Ted Kaehler, Wayne Gramlich, and Paul Haeberli for Web Enhancement code or software evaluation; Dale Amon for providing a mirror site in Europe for Foresight's web site; Al Globus for briefing us on nanotechnology at NASA; and Toru Yao for news on nanotechnology in Japan.

For sending information, we thank Jeff Cavener, Dave Forrest, G.A. Houston, Marie-Louise Kagan, Tom McKendree, John McPherson, John Papiewski, Patrick Salsbury, PC Theriault.

--Chris Peterson, Director

Table of Contents
- Foresight Update 26

From Foresight Update 26, originally published 15 September 1996.
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