No abstract

Self-assembly of cyclic peptides is an attractive strategy for making hollow tubular structures. [1][2][3][4] Stacking of ring-shaped molecules of flat conformation can be stabilized by intermolecular hydrogen bonds formed between the amide groups. Cyclic peptides of rationally designed chemical structures can form nanotubes of different internal diameters and structures, which may find applications in biology and materials sciences. [2,5,6] Generally, the self-assembly process occurs in solution, is often triggered by a change in solubility of the peptide in organic solvents, and results in crystals organized by nanotubes. Herein, we report on the observation of selfassembled structures of a cyclic peptide in a nematic liquid crystal (LC). Hexagonal hollow tubes that have diameters in the order of micrometers and reaching several millimetres in length were observed. Strong experimental evidence suggests the occurrence of a hierarchical and self-similar-structured self-assembly of the cyclic peptide. That is, individual molecules of hexagonal conformation stack up into hexagonal nanotubes, which then self-organize into larger aggregates with the same appearance. Each molecule provides both intra-and intertube H bonding that ensure the molecular stacking within and the packing of nanotubes. To the best of our knowledge, this is the first work exploring the use of liquid crystals for the self-assembly of cyclic peptides, and the results show the surprising impact of the liquid crystalline medium.Previous work showed that the lipophilic macrolactam cyclo-(NHCH 2 CH=CHCH 2 CO) 3 (E olefin) is soluble in ethanol and can be crystallized by diffusion of diethyl ether.[4] The crystal structure determined by X-ray crystallography shows the stacking of macrocycles, which have a

The synthesis of four C(n) symmetric macrocyclic lactams cyclo-[NH-CH(2)-CH=CH-CH(2)-CO](n) (1, n=2; 2, n=3; 3, n=4) and cyclo-[NH-CH(2)-CH(2)-CH=CH-CO](3) (4) has been achieved by two approaches. A linear route leads to precursors that are subsequently macrocyclized in a separate step. The second, convergent approach relies on the symmetry of the targets: it includes suitably activated subunits, which are subjected to macrocyclization conditions. The subunits first oligomerize, then cyclize to form either pure macrolactams or mixtures. The macrolactam units 1, 2 and 4 stack on top each other through weak interactions (hydrogen bond and van der Waals), to form endless square, rectangular and triangular prisms, respectively. These stacks are further packed side by side in crystals grown from isotropic media. The overall dipoles in the crystals from lactams 1 and 4, which result mostly from the alignment of amide groups, are zero and large, respectively. Macrolactam 2 displays an astonishing isomorphism when allowed to cool down in anisotropic liquid crystal solutions. Large hollow hexagonal tubes are then obtained through a fractal process. Contrary to the three previous rings, 3 yields crystals where prisms of any shape are absent.

Syntheses of supermolecules rely on the stabilization provided by noncovalent interactions between recognition sites in each unit. [1±3] The construction of new supramolecular architectures with well-defined shape and size by using tube building blocks is an important subject in organic materials chemistry because novel electronic and photonic properties can result from their three-dimensional (3D) organization (Figure 1 a). [2] These tubular structures have also attracted considerable interest because of their utility as models for biological channels. [4±9] It is also thought that in tubes built from stacked cyclic peptides, uniform alignment of amide groups could give rise to a macrodipole moment such as that of an a-helix. [10] Voltage gating and current rectification are important expected new properties for such channel structures. [11] To date, all attempts to grow crystals of a useful size were frustrated by the inherent insolubility of these materials. [12±15] compared to the barriers for the respective ammine proton transfer reactions results from the increased distortion of the core structures in the transition states and the lower acidity of the amide protons. Zero point vibration and entropic contributions lower the Gibbs free energy barrier difference between the two pathways to 54 ± 63 kJ mol À1 by destabilizing the highly ordered ammine proton transfer transition states 12, 18, and 24. This difference could well be overcome by steric congestion induced by bulky substituents of amines and unsaturated hydrocarbon substrates. For comparison, the steric destabilization for complexes with three 2,6-dimethylanilide ligands at a titanium center such as in 4 a and 5 a has been computed to be 67 ± 78 kJ mol À1 .In allene and ethyne hydroamination with the simplified [CpTiNH(NH 2 )] system, where proton transfer takes place after initial amine coordination, the transition state for the cycloaddition is the highest point in the catalytic pathway and thus is rate-determining. However, it remains unclear whether the zero-order dependence on the 2,6-dimethylaniline concentration derived from the kinetic data for allene hydroamination [4] results from a rate-determining [22] cycloaddition or a rate-determining proton transfer from an amide ligand. A first-order dependence on the amine concentration can occur if the Gibbs free activation energy for the amine coordination plus proton transfer pathway is higher than the barrier for the initial [22] cycloaddition, but lower than the barrier for a competing amide proton transfer. A ratedetermining amide ligand exchange with free amine could also result in such a rate law (see Supporting Information for computed ligand exchange pathways).For alkene hydroamination, our model calculations predict that both the ammine and the amide proton transfer to the TiÀC bond have Gibbs free activation energies that are more than 50 kJ mol À1 higher than the cycloaddition step ( Figure 4 and 5 c). This explains the relative ease of allene and alkyne hydroamination compared to...