A long-standing aim in molecular self-assembly is the development of synthetic nanopores capable of mimicking the mass-transport characteristics of biological channels and pores. Here we report a strategy for enforcing the nanotubular assembly of rigid macrocycles in both the solid state and solution based on the interplay of multiple hydrogen-bonding and aromatic π − π stacking interactions. The resultant nanotubes have modifiable surfaces and inner pores of a uniform diameter defined by the constituent macrocycles. The self-assembling hydrophobic nanopores can mediate not only highly selective transmembrane ion transport, unprecedented for a synthetic nanopore, but also highly efficient transmembrane water permeability. These results establish a solid foundation for developing synthetically accessible, robust nanostructured systems with broad applications such as reconstituted mimicry of defined functions solely achieved by biological nanostructures, molecular sensing, and the fabrication of porous materials required for water purification and molecular separations.

This paper describes the design, synthesis, and characterization of a hydrogen-bonded molecular duplex (3‚4). Two oligoamide molecular strands, 3 and 4, with the complementary hydrogen-bonding sequences ADAADA and DADDAD, respectively, were found to form an extremely stable (K a ) (1.3 ( 0.7) × 10 9 M -1 ) molecular duplex (3‚4) in chloroform. Evidence from 1D and 2D 1 H NMR spectroscopy, isothermal titration calorimetry, and thin-layer chromatography confirmed the formation and the high stability of the duplex. The exceptional stability is explained by positive cooperativity among the numerous hydrogen-bonding and van der Waals interactions and the preorganization of the individual strands by intramolecular hydrogen bonds. This design has opened a new avenue to supramolecular recognition units with programmable specificities and stabilities.

This Account reviews the progress made by us on creating porous molecular crescents, helices, and macrocycles based on aromatic oligoamides. Inspired by natural pore- or cavity-containing secondary structures, work described in this Account stemmed from the development of foldamers consisting of benzene rings linked by secondary amide groups. Highly stable, three-center intramolecular hydrogen bonds involving the amide linkages are incorporated into these aromatic oligoamides, which, along with meta-linked benzene units that introduce curvatures into the corresponding backbones, leads to tape-like, curved backbones. Depending on their chain lengths, aromatic oligoamides that fold into crescent and helical conformations have been obtained. Combining results from modeling and experimentally measured data indicates that the folding of these oligomers is readily predictable, determined by the localized intramolecular three-center H-bonds and is independent of side-chain substitution. As a result, a variety of reliably folded, modifiable scaffolds can now be constructed. The well-defined crescent or helical conformations contain noncollapsible internal cavities having multiple introverted amide oxygen atoms. Changing the backbone curvature by tuning the ratio of meta- to para-linked benzene units leads to crescents or helices with cavities of tunable sizes. For example, oligoamides consisting of meta-linked units contain cavities of approximately 9 A across, while those with alternating meta- and para-linked units have cavities of over 30 A across. The generality of such a folding and cavity-creating strategy has also been demonstrated by the enforced folding of other types of aromatic oligomers such as oligo(phenylene ethynylene)s, aromatic oligoureas, and aromatic oligosulfonamides. More recently, the folding of aromatic oligoamides was found to assist efficient macrocyclization reactions, which has provided a convenient method for preparing a new class of large shape-persistent macrocycles in high yields. The folded and cyclic structures were extensively characterized based on multiple techniques such as one- and two-dimensional NMR, mass spectrometry, and X-ray crystallography, as well as theoretical calculations. The enforced folding and folding-assisted cyclization of oligomers have provided a predictable strategy for developing crescent, helical, and cyclic structures containing nanosized voids that are mostly associated with the tertiary and quaternary structures of proteins. The availability of these porous molecules has supplied a new class of nanosized building blocks that provide both opportunities and challenges for creating the next-generation nanostructures capable of presenting multiple introverted functional groups, forming various pores and channels, and finally, developing protein-like pockets.

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The assembly of well-defined protein secondary structures, leads to a bewildering array of tertiary structures. 1 As the first step toward developing artificial oligomers and polymers that fold like biomacromolecules, there is currently an intense interest in designing unnatural building blocks that adopt well-defined secondary structures. 2,3 Here we report a new class of oligoamides with backbones that adopt well-defined, crescent conformations.Our design is based on diaryl amide oligomers, shown as 1. The presence of the three-center hydrogen bonding system consisting of the S(5) and S(6) type 4 intramolecularly hydrogen bonded rings should lead to rigidification of the amide linkage. Oligoamides containing such amide linkages should have a rigid backbone. With the two amide linkages on the same benzene ring being meta to each other, the resulting oligomer should have a crescent conformation. 5 Ab initio molecular orbital calculations (in vacuo) were performed on amide 2. 6 Conformations 2a-b are constrained to be planar. The relative energy of each conformation is shown in parentheses. The computational results indicated significant differences in the relative energies of the four conformations: 2 was overwhelmingly favored over the alternative conformations 2a,b. The desired conformation, 2, was planar and had two strong intramolecular hydrogen bonds with O‚‚‚H ) 1.87 Å (S(6)) and 2.14 Å (S(5)), respectively.

A general strategy for creating nanocavities with tunable sizes based on the folding of unnatural oligomers is presented. The backbones of these oligomers are rigidified by localized, three-center intramolecular hydrogen bonds, which lead to well-defined hollow helical conformations. Changing the curvature of the oligomer backbone leads to the adjustment of the interior cavity size. Helices with interior cavities of 10 Å to >30 Å across, the largest thus far formed by the folding of unnatural foldamers, are generated. Cavities of these sizes are usually seen at the tertiary and quaternary structural levels of proteins. The ability to tune molecular dimensions without altering the underlying topology is seen in few natural and unnatural foldamer systems

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The transport of molecules and ions across nanometer-scaled pores, created by natural or artificial molecules, is a phenomenon of both fundamental and practical significance. Biological channels are the most remarkable examples of mass transport across membranes and demonstrate nearly exclusive selectivity and high efficiency with a diverse collection of molecules. These channels are critical for many basic biological functions, such as membrane potential, signal transduction, and osmotic homeostasis. If such highly specific and efficient mass transport or separation could be achieved with artificial nanostructures under controlled conditions, they could create revolutionary technologies in a variety of areas. For this reason, investigators from diverse disciplines have vigorously studied small nondeformable nanopores. The most exciting studies have focused on carbon nanotubes (CNTs), which have exhibited fast mass transport and high ion selectivity despite their very simple structure. However, the limitations of CNTs and the dearth of other small (≤2 nm) nanopores have severely hampered the systematic investigation of nanopore-mediated mass transport, which will be essential for designing artificial nanopores with desired functions en masse. Researchers can overcome the difficulties associated with CNT and other artificial pores by stacking macrocyclic building blocks with persistent shapes to construct tunable, self-assembling organic pores. This effort started when we discovered a highly efficient, one-pot macrocyclization process to efficiently prepare several classes of macrocycles with rigid backbones containing nondeformable cavities. Such macrocycles, if stacked atop one another, should lead to nanotubular assemblies with defined inner pores determined by their constituent macrocycles. One class of macrocycles with aromatic oligoamide backbones had a very high propensity for directional assembly, forming nanotubular structures containing nanometer and sub-nanometer hydrophilic pores. These self-assembling hydrophilic pores can form ion channels in lipid membranes with very large ion conductances. To control the assembly, we have further introduced multiple hydrogen-bonding side chains to enforce the stacking of rigid macrocycles into self-assembling nanotubes. This strategy has produced a self-assembling, sub-nanometer hydrophobic pore that not only acted as a transmembrane channel with surprisingly high ion selectivity, but also mediated a significant transmembrane water flux. The stacking of rigid macrocycles that can be chemically modified in either the lumen or the exterior surface can produce self-assembling organic nanotubes with inner pores of defined sizes. The combination of our approach with the availability and synthetic tunability of various rigid macrocycles should produce a variety of organic nanopores. Such structures would allow researchers to systematically explore mass transport in the sub-nanometer regime. Further advances should lead to novel applications such as biosensing, materials ...