Chemical Topology and Interlocking Molecules

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Science  28 May 2004:
Vol. 304, Issue 5675, pp. 1256-1258
DOI: 10.1126/science.1099216

Complex molecular topologies rarely occur in nature outside the area of biopolymers. As such they are supreme targets for chemical synthesis of nonnatural products. About 40 years ago, two industrial chemists, Wasserman at Bell labs and Pedersen at Dupont, made independent esoteric discoveries that were later joined into one of the most powerful methods for the design and synthesis of topologically complex molecules. Wasserman performed the synthesis of a large ring compound that resulted in the stochastic production of a small amount of product with two interlocked rings, called “catenanes” (1, 2). From there, he contemplated the design of chemical topologies in general. A few years later, Pedersen noticed the templating effect of cations on the formation of cyclic polyethers and laid the basis for the field of ion-controlled macrocylizations (3), the precursor to modern template-controlled syntheses (4). Sauvage's high-yield synthesis of catenanes via coordination-metal intermediates combined topology with templation and opened the way for consideration of higher order chemical links, among them multiple-linked catenanes and an exceptional linked topology of three rings in which no two rings are concatenated (the Borromean link) (5). Recently, topology and templation merged in the work of groups from the University of Mainz and the University of California at Los Angeles, who have completed elegant syntheses of a complex interwoven [8]catenane and a Borromean link, respectively (6, 7).

As they report on page 1312 of this issue, Wang et al. used the calix[4]arene scaffold to present an array of urea fingers, which aggregate through hydrogen bonds to form an interdigitated cup-to-cup dimer (6). Through olefin metathesis, the fingers of each cup are bonded together, thus forming an [8]catenane (see the figure). Chichak et al. report on page 1308 that they combined the equilibrium-based methods of imine formation with the templation power of zinc ions to effect an elegant one-step total synthesis of a Borromean link from 18 precursors (7). Their strategy uses a set of endo- and exo-oriented ligands designed to form an oriented trigonal bipyramidal unit around zinc ions, six of which assemble into the Borromean link.

Rings within rings.

Schematic assembly through a template intermediate of a simple [2]catenane, a multithreaded cyclic [8]catenane, and a Borromean link.

The intricacies of topological architectures stir something in the human soul. Their symmetry and complexity appeal broadly to the scientific as well as the artistic mind. Topological concepts influence fields ranging from nuclear physics to theology. Biochemical examples of chemical topology are found in micrographs of knotted and supercoiled DNA (8). The biological activity of such DNA is controlled “topologically” by the action of topoisomerases. Broad discussion has ensued about the conformation of certain proteins as pseudo-knots, that is, knots lacking closure of the ends (9).

In mechanical engineering, links form the basis for many devices. Furthermore, whether in simple chains, flexible networks of chain mail, or interlocked gridworks, the link plays an important role in structural engineering. It is natural then to contemplate the construction of microlinks in the push for mechanical miniaturization. The bottom-up enterprise of nanotechnology and associated engineering sciences anticipates the need for efficient ways to prepare nanolinks of controllable complexity. Pursuits in the area of chemical topology provide such technology: Clever use of molecular biology by Seeman produced a bio-Borromean link as part of a general program in nanoengineered DNA scaffolds (10); and micromolding of polysilicones by Whitesides has afforded micro-Borromean links and chains (11).

The Borromean link also has a rich iconographic history (12). The novelty of a link among three rings that precludes a linkage between any two conjures many an image of intrigue (see the figure). Three Italian families, the Sforza, Visconti, and Borromea, provide the 14th-century origin of the symbol in family heraldry. Christian iconography places it earlier as an illumination of the trinity in a medieval bible from Chartres. Pagan and Nordic mythology connect it to the text of Snorri as the symbol of the heart of a giant named Hrungnir, which became the Viking and Celtic “knot of the fallen.” Even mosaics of antiquity and ancient Asian engravings bear witness to this symbol as a quasi-landmark of Jungian philosophy.

All in the family.

Three geometric variations on the Venn representation of the Borromean link (23): Trinity in circles, Hrungnir's heart in triangles, and Japanese “mon” (family crest) in hexagons.

Catenanes have a rich chemical history (5, 13). Wilstätter is purported to have lectured on the topic in Zurich no later than 1912, but Mark and co-workers evidently were the first to publish on this topic about 40 years later. Lüttringhaus discussed a number of approaches to interlocked ring topologies in 1958. Three rings in a chain, [3]catenane, has been prepared by Sauvage to illustrate the general utility of metal-template methods, and the current record of five links in a chain, olympiadane, was prepared by Stoddart using the aromatic-stack template he discovered. Very recently, as part of a program on conducting materials, Bauerle prepared a catenane of two fully conjugated cycles (14).

An important illustration of the syntheses of the Böhmer and Stoddart groups is the general power of thermodynamic assembly as a way to direct chemical synthesis. In the high-energy syntheses of carbon-rich species spanning diamond, fullerenes, dodecahedrane, and adamantane, thermodynamic assembly equals or outperforms the classical bond-construction strategy. Under ambient conditions, more kinetically labile bond types such as metal coordination or hydrogen bonding are effective for preparing thermodynamically assembled catenane or knot precursors, which can then be locked into place, as seen in the independent syntheses by Vögtle, Hunter, and Leigh (1517). Independently, Fujita and Sanders use metal coordination as a constitutive part of each ring to make dynamic catenation possible (18, 19). Biological templating of a protein dimer led Dawson and co-workers to design and synthesize a “protein catenane” (20).

Less often mentioned are the complex chemical topologies that result during crystal formation. Crystal nucleation is a sublime form of templation. The crystal structures of trimesic acid and adamantane tetracarboxylic acid are classic marvels of complex linked topologies spontaneously assembling during crystal growth (21, 22). Kahn described several inorganic coordination networks by their spontaneously formed topologies (5).

Despite the power and appeal of combining template control with thermodynamic assembly for one-step molecular syntheses (4), the directed bond-construction approach offers control over specifics of structure impossible to reach by thermodynamic assembly routes. The directed strategy has already provided an efficient route to a threaded two-ring precursor of a Borromean link with differentiated rings (23). Such tailor-made strategies will no doubt complement the one-step transformations in the synthesis of a wide spectrum of complicated molecular links. Engineers in the area of nanoscale technologies will benefit from access to a diversity of methodologies, and both strategies will be engines for chemical discovery.

Links and knots have multiple transannular interactions and a complex stereochemistry enforced by entwinement akin to the interactions of disparate amino acid residues enforced by the folding in proteins. Effectively, the folding and secondary structure encoded in the primary sequence and constrained by the conformational preferences of the amino acids are analogous to the crossing character and template groups in a topological isomer. The phase relationship among the crossings of a topological structure ensures cooperativity among the steric and functional parts of the molecule, and such cooperativity can express itself as allostery or amplification. Indeed, molecules of complex topology will inherently display emerging properties not seen in their parts and will likely mimic the character of biomolecules.

Chemistry is a science that creates its own object; therefore, only once chemical synthesis of a class of objects is mastered can one begin to judge the potential new chemical phenomena that will emerge. Topological chemistry is now reaching the stage where chemists can confidently design and synthesize molecules of complex topology. The flurry of activity directed toward new topological chemical objects signals that the time is ripe for exploiting their functional potential.

References and Notes

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