Jeremy K. M. Sanders

Evolution of dynamic combinatorial chemistry.

Since its inception in the mid-1990s, dynamic combinatorial chemistry (DCC), the chemistry of complex systems under thermodynamic control, has proved valuable in identifying unexpected molecules with remarkable binding properties and in providing effective synthetic routes to complex species. Essentially, in this approach, one designs the experiment rather than the molecule. DCC has also provided us with insights into how some chemical systems respond to external stimuli. Using examples from the work of our laboratory and others, this Account shows how the concept of DCC, inspired by the evolution of living systems, has found an increasing range of applications in diverse areas and has evolved conceptually and experimentally. A dynamic combinatorial library (DCL) is a thermodynamically controlled mixture of interconverting species that can respond to various stimuli. The Cambridge version of dynamic combinatorial chemistry was initially inspired by the mammalian immune system and was conceived as a way to create and identify new unpredictable receptors. For example, an added template can select and stabilize a strongly binding member of the library which is then amplified at the expense of the unsuccessful library members, minimizing the free energy of the system. But researchers have exploited DCC in a variety of other ways: over the past two decades, this technique has contributed to the evolution of chemistry and to applications in the diverse fields of catalysis, fragrance release, and responsive materials. Among these applications, researchers have built intricate and well-defined architectures such as catenanes or hydrogen-bonded nanotubes, using the ability of complex chemical systems to reach a high level of organization. In addition, DCC has proved a powerful tool for the study of complex molecular networks and systems. The use of DCC is improving our understanding of chemical and biological systems. The study of folding or self-replicating macrocycles in DCLs has served as a model for appreciating how complex organisations such as life can emerge from a pool of simple chemicals. Today, DCC is no longer restricted to thermodynamic control, and new systems have recently appeared in which kinetic and thermodynamic control coexist. Expanding the realm of DCC to unexplored and promising new territories, these hybrid systems show that the concept of dynamic combinatorial chemistry continues to evolve.

Supramolecular Catalysis in Transition

Supramolecular chemistry is poised at a fascinating moment in its history. Advances in synthesis, structural techniques and computing allow us to devise and prepare complex systems at will, study their structures and dynamics in exquisite detail, and rationalise the observations afterwards. So why, amongst the myriad of new supramolecular building blocks and arrays, do we see so few effective catalysts? How is it that we can apparently understand so much and yet fail the practical test of producing even rudimentary catalysis in any reliable way?

Discovery of an organic trefoil knot.

An Organic Knot When people tie knots, they grasp both ends of a strand and loop them around each other. The task is rather more difficult at the molecular level, when there is no top-down organizing framework, and the strand needs to be coaxed into looping around itself. Recently, chemists have taken advantage of the tight geometrical restrictions of metal-ligand coordination to produce knot morphologies. Ponnuswamy et al. (p. 783; see the Perspective by Siegel) now demonstrate the spontaneous assembly of a trefoil knot from organic fragments without assistance from metal centers. The topology appears to be driven by hydrophobic interactions among aromatic segments that minimize exposure to surrounding water through their overlap. Hydrophobic interactions appear to steer three molecular fragments into a knot, rather than a simpler ring geometry. Molecular knots remain difficult to produce using the current synthetic methods of chemistry because of their topological complexity. We report here the near-quantitative self-assembly of a trefoil knot from a naphthalenediimide-based aqueous disulfide dynamic combinatorial library. The formation of the knot appears to be driven by the hydrophobic effect and leads to a structure in which the aromatic components are buried while the hydrophilic carboxylate groups remain exposed to the solvent. Moreover, the building block chirality constrains the topological conformation of the knot and results in its stereoselective synthesis. This work demonstrates that the hydrophobic effect provides a powerful strategy to direct the synthesis of entwined architectures.

Exciton coupling in porphyrin dimers

Abstract Exciton coupling in cofacial porphyrin dimers that exhibit small chromophore separations and various orientations is predicted using point-dipole and distributed transition-monopole treatments. For these systems, the transition-monopole treatment is shown to be superior in predicting the observed spectral properties of the dimers. The properties of the dimers are in some respects analogous to those of the “special pair” bacteriochlorophyll dimer in the photosynthetic reaction centre.

SELECTION APPROACHES TO CATALYTIC SYSTEMS

The key feature of enzymic catalysis is recognition of the transition state. Synthesis of designed systems rarely leads to successful catalysts as the rules for conformation and intermolecular interactions are to imperfectly understood. This review describes several current ‘selection’ approaches to the generation of systems that can recognise transitionstate analogues. Examples covered include catalytic antibodies, ribozymes, imprinted polymers. Combinatorial chemistry, and thermodynamic templating. All have the potential to yeild effective catalysts without prior design of every detail.

Molecular recognition and self-assembly special feature: Dynamic combinatorial synthesis of a catenane based on donor-acceptor interactions in water

A new type of neutral donor–acceptor [2]-catenane, containing both complementary units in the same ring was synthesized from a dynamic combinatorial library in water. The yield of the water soluble [2]-catenane is enhanced by increasing either building-block concentrations or ionic strength, or by the addition of an electron-rich template. NMR spectroscopy demonstrates that the template is intercalated between the 2 electron-deficient naphthalenediimide units of the catenane.

Dynamic combinatorial chemistry

A combinatorial library that responds to its target by increasing the concentration of strong binders at the expense of weak binders sounds ideal. Dynamic combinatorial chemistry has the potential to achieve exactly this. In this review, we will highlight the unique features that distinguish dynamic combinatorial chemistry from traditional combinatorial chemistry, and that could make a useful addition to the set of combinatorial techniques used in drug discovery.

Recent developments in dynamic combinatorial chemistry

Generating combinatorial libraries under equilibrium conditions has the important advantage that the libraries are adaptive (i.e. they can respond to exterior influences in the form of molecular recognition events). Thus, a ligand will direct and amplify the formation of its ideal receptor and vice versa. Proof of principle of this approach has been established using small libraries showing highly efficient amplification of selected receptors. The approach has recently been extended to address folding of macromolecules, including peptides.

Identification and Isolation of a Receptor for N-Methyl Alkylammonium Salts: Molecular Amplification in a Pseudo-peptide Dynamic Combinatorial Library

A cyclic pseudo-peptide receptor for acetylcholine has been amplified and isolated from a dynamic combinatorial library by virtue of templated stabilization under thermodynamic control (see scheme, TFA=trifluoroacetic acid). This is a demonstration of significant molecular amplification in dynamic systems to evolve a novel receptor.

Exploring the formation pathways of donor-acceptor catenanes in aqueous dynamic combinatorial libraries

The discovery through dynamic combinatorial chemistry (DCC) of a new generation of donor-acceptor [2]catenanes highlights the power of DCC to access unprecedented structures. While conventional thinking has limited the scope of donor-acceptor catenanes to strictly alternating stacks of donor (D) and acceptor (A) aromatic units, DCC is demonstrated in this paper to give access to unusual DAAD, DADD, and ADAA stacks. Each of these catenanes has specific structural requirements, allowing control of their formation. On the basis of these results, and on the observation that the catenanes represent kinetic bottlenecks in the reaction pathway, we propose a mechanism that explains and predicts the structures formed. Furthermore, the spontaneous assembly of catenanes in aqueous dynamic systems gives a fundamental insight into the role played by hydrophobic effect and donor-acceptor interactions when building such complex architectures.