Helical versus Flat Bis-Ferrocenyl End-Capped Peptides: The Influence of the Molecular Skeleton on Redox Properties.

Despite the fact that peptide conjugates with a pendant ferrocenyl (Fc) have been widely investigated, bis-ferrocenyl end-capped peptides are rarely synthetized. In this paper, in addition to the full characterization of the Fc-CO-[L-Dap(Boc)]n-NH-Fc series, we report a comparison of the three series of bis-ferrocenyl homopeptides synthesized to date, to gain insights into the influence of α-amino isobutyric (Aib), 2,3-diamino propionic (Dap) and Cα,ß-didehydroalanine (ΔAla) amino acids on the peptide secondary structure and on the ferrocene redox properties. The results obtained by 2D NMR analysis and X-ray crystal structures, and further supported by electrochemical data, evidence different behaviors depending on the nature of the amino acid; that is, the formation of 310-helices or fully extended (2.05-helix) structures. In these foldamers, the orientation of the carbonyl groups in the peptide helix yields a macrodipole with the positive pole on the N-terminal amino acid and the negative pole on the C-terminal amino acid, so that oxidation of the Fc moieties takes place more or less easily depending on the orientation of the macrodipole moment as the peptide chain grows. Conversely, the fully extended conformation adopted by ΔAla flat peptides neither generates a macrodipole nor affects Fc oxidation. The utilization as electrochemical and optical (Circular Dichroism) probes of the two terminal Fc groups, bound to the same peptide chain, makes it possible to study the end-to-end effects of the positive charges produced by single and double oxidations, and to evidence the presence "exciton-coupled" CD among the two intramolecularly interacting Fc groups of the L-Dap(Boc) series.

Flat, Cα,ß -Didehydroalanine Foldamers with Ferrocene Pendants: Assessing the Role of α-Peptide Dipolar Moments.

The foldamer field is continuously expanding as it allows to produce molecules endowed with 3D-structures and functions never observed in nature. We synthesized flat foldamers based on the natural, but non-coded, Cα,ß -didehydroalanine α-amino acid, and covalently linked to them two ferrocene (Fc) moieties, as redox probes. These conjugates retain the flat and extended conformation of the 2.05 -helix, both in solution and in the crystal state (X-ray diffraction). Cyclic voltammetry measurements agree with the adoption of the 2.05 -helix, characterized by a negligible dipole moment. Thus, elongated α-peptide stretches of this type are insulators rather than charge conductors, the latter being constituted by peptide α-helices. Also, our homo-tetrapeptide has a N-to-C length of about 18.2 Å, almost double than that (9.7 Å) of an α-helical α-tetrapeptide.

Key multi(ferrocenyl) complexes in the interplay between electronic coupling and electrostatic interaction.

In this review, the properties of the most significant examples of multi(ferrocenyl) cations containing a number of ferrocenyl units from two to six are discussed and the results are compared with the outcomes of some of our recent studies on conjugated ferrocenyl complexes, in order to give an overview of how the nature of the bridging ligand, the distance between the redox-active centres, and the medium affect the electronic and electrostatic properties of the molecules.

New bis-ferrocenyl end-capped peptides: synthesis and charge transfer properties.

In this article, the successful preparation of a new series of 3(10) -helical peptides of different length containing two terminal ferrocenyl (Fc) units and based on the strongly foldameric α-aminoisobutyric (Aib) acid is reported. The synthesis of the Fc-CO-(Aib)(n) -NH-Fc (n = 1-5) homo-peptides was performed by solution methods. Moderate to good yields (26-85%) were obtained in each of the difficult coupling steps of Fc-COOH and the corresponding H-(Aib)(n)-NH-Fc compounds by C-activation with the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide/7-aza-1-hydroxy-1,2,3-benzotriazole method. Information on the C=O···H-N intramolecularly hydrogen-bonded networks was initially obtained from FT-IR absorption measurements. The N-H stretching (amide A) region allowed us to distinguish which amide protons are involved in intramolecular hydrogen bonds and indicates the formation of an incipient 3(10) -helix structure for peptides containing at least two Aib residues. This conclusion was confirmed by (1)H NMR titrations of the N-H groups of the peptides in CDCl(3) with dimethylsulfoxide and by crystallographic analysis of the N(α) -acylated Fc-CO-(Aib)(5)-NH-Fc pentapeptide amide. The two redox-active Fc groups covalently bound to the termini of the foldameric peptide architectures were used as electrochemical probes. The end-to-end effects of electron holes generated by single and double oxidations were analyzed by means of electrochemical and spectroelectrochemical techniques. The results of these studies indicate that charge transfer across the peptide main chain does occur in the five peptides. In particular, in the pentapeptide 5, charge is transferred through an intramolecular Fe···Fe separation of 14 Å.

Charge mapping in 3(10)-helical peptide chains by oxidation of the terminal ferrocenyl group.

Two series of 3(10)-helical peptides of different lengths and rigidity, based on the strongly foldameric α-aminoisobutyric acid and containing a terminal ferrocenyl unit, have been synthesized. Oxidation-state sensitive spectroscopic tags of helical peptides, the N-H groups, allowed mapping of the charge delocalization triggered by oxidation of the terminal ferrocenyl moiety and were monitored by IR spectroelectrochemistry.