Gels

Enantiomerically pure C₁₆‐alkyl amides derived from cis and trans cycloalkane‐1,2‐dicarboxylic acids, respectively, have been synthesized and their behavior as organogelators has been investigated. These compounds include cis/trans diastereomeric cyclobutane and cyclohexane derivatives with the aim to explore the influence of the ring size as well as the relative configuration in their hierarchical self‐assembly to form gels. High resolution ¹H NMR spectroscopy studies allowed the determination of the dynamics of the gelation process in [D₈]toluene and the sol‐gel transition temperature. The morphology and size of the aggregates have been investigated and results have shown that, in the case of cyclobutane derivatives, the cis/trans stereochemistry is not relevant for the gelation behavior and the properties of the soft‐materials obtained, but it is remarkable for cyclohexane diamides, which are better organogelators. The four compounds produce chiral aggregates despite that two of them are meso achiral molecules. We show herein that this fact is an example of stochastic symmetry breaking induced by sonication. The self‐assembly of these molecules has been modelled providing information and support about the structure and the chirality of the aggregates.

Some hybrid tetrapeptides consisting of (1R,2S)-2-aminocyclobutane-1-carboxylic acid and glycine, β-alanine, or γ-aminobutyric acid (GABA) joined in alternation, compounds 1–3, respectively, have been investigated to gain information on the non-covalent interactions responsible for their self-assembly to form ordered aggregates, as well as on parameters such as their morphology and size. All three peptides formed nice gels in many organic solvents and significant difference in their behaviour was not observed. Scanning electron microscopy (SEM) and circular dichroism (CD) pointed out that peptide 1, which contains the shortest C₂linear residue, presented the most defined fibril network and afforded nanoscale helical aggregates. Tetrapeptide 3, with C₄linear residues in its structure, also showed bundles of fibres whereas a homogeneous spherulitic network was observed for tetrapeptide 2, with a C₃ spacer between cyclobutane residues. Computational calculations for 1 allowed us to model the self-assembly of the molecules and suggested a head-to-head arrangement to give helical structures corresponding to hydrogen-bonded single chains. These features were corroborated by a high-resolution NMR spectroscopy study of the dynamics of the gelation process in toluene-d₈ which evidenced that molecules self-assemble to afford ordered aggregates with a supramolecular chirality.

Two chiral synthetic β‐dipeptides have been constructed, one with two trans‐cyclobutane residues and the other with one trans and one cis fragment, 1 and 2, respectively, and investigated to get insight into the non‐covalent interactions responsible for their self‐assembly to form ordered aggregates, as well into parameters such as their morphology and size. Experimental evidence of the formation of these assemblies was provided by spectroscopy, microscopy and X‐ray diffraction experiments that suggest the formation of nanoscale helical aggregates. This process involves a conformational change in the molecules of each dipeptide with respect to the preferred conformation of the isolated molecules in solution. A high‐resolution NMR spectroscopy study allowed the determination of the dynamics of the gelation process in [D₈]toluene and the sol–gel transition temperature, which was around 270 K in this solvent at a concentration of 15 mM. NMR spectroscopy experiments also provided some information about conformational changes involved in the sol–gel transition and also suggested a different gel packing for each dipeptide. These observations have been nicely explained by computational studies. The self‐assembly of the molecules has been modelled and suggested a head‐to‐head molecular arrangement for 1 and a head‐to‐tail arrangement for 2 to give helical structures corresponding to hydrogen‐bonded single chains. These chains interact with one another in an antiparallel way to afford bundles, the significant geometry parameters of which fit well to the main peaks observed in wide‐angle X‐ray diffraction spectra of the aggregates in the solid state.

Efficient and stereoselective synthetic routes have been developed for the preparation of chiral N-monoprotected cyclobutane bicyclic ureas in which one of the NH groups is protected as a benzyl or tert-butyl carbamate. Ureas in both enantiomeric forms were obtained from a common chiral precursor via the selective manipulation of functional groups. These compounds have been subjected to a structural study in solution and in the solid state. NMR, IR and TEM techniques evidence a strong tendency to aggregation in solution giving regular assemblies, which is a result of intermolecular urea N–H⋯OC hydrogen bonding. In the solid state, X-ray analysis shows that two urea molecules interact through only one hydrogen bond yielding infinite chains. This fact and the almost complete coplanarity of both the urea and the carbamate carbonyl groups determine the crystal packing to be formed by a parallel molecular arrangement. All these structural features are well supported by theoretical calculations that allow us to conclude that the formation of a network based on hydrogen bonding is energetically favourable.

Improved methodologies are provided to synthesize (1R,2S)-2-aminocyclobutane-1-carboxylic acid derivatives and their incorporation into β-peptides of 2–8 residues bearing different N-protecting groups. The conformational analysis of these oligomers has been carried out by using experimental techniques along with theoretical calculations. This study shows that these oligomers adopt preferentially a strand-type conformation in solution induced by the formation of intra-residue six-membered hydrogen-bonded rings, affording cis-fused [4.2.0]octane structural units that confer high rigidity on these β-peptides. Moreover, all of them are prone to self-assemble producing nano-sized fibres, as evidenced by TEM, AFM and SPFM, and, in some instances, they also form gels. These techniques and molecular modelling allowed us to suggest an aggregation model for the assembly structures in which a parallel molecular-arrangement is preferred and the conformation is similar to that observed in solution. According to this model, both hydrogen-bonding and hydrophobic interactions would account for formation of the assemblies.

The gelation of a designed gelator was investigated by different NMR methods, which showed a clear thermal hysteresis. Two very simple approaches for the NMR determination of the gelation point are suggested. One involves the observation of the NMR integral, and the other records the ratio of the diffusion coefficients between the gelator and the solvent. Differential behavior of the gelator protons are interpreted as a hint that a part of the gelator molecule might still be flexible as in the dissolved state.