Chapter 1 contains an Introduction to the role of metal complexes in functional assemblies. The remainder of the chapter is devoted to an Introduction to the

[Formulae and special characters can only be approximated here. Please see the pdf version of the Abstract for an accurate reproduction.] The kinetics for outer-sphere electron transfer between a series of cobalt(II) poly-aza cage ligand complexes and the iron(III) sarcophagine-type hexa-aza cage complex, [Fe(sar)]3+ (sar = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane), in aqueous solution have been investigated and the Marcus correlation is used to deduce the electron self-exchange rate constant for the [Fe(sar)]3+/2+ couple from these cross-reactions. The deduced electron self-exchange rate constant is in relatively good agreement with the experimentally determined rate constant (k ex calc = 4 ´ 10 5 M -1 s -1 ; k ex obs = 8 ´ 10 5 M -1 s -1 ). The successful application of the Marcus correlation to the electron transfer reactions of the Fe cage complex is consistent with the trend for the Co, Mn, Ni and Ru cage complexes which all follow the pattern of outer-sphere electron transfer reactivity expected from the Marcus-Hush formalism. A comparison of predictions based on the Marcus correlation with the experimentally determined kinetics of an extended series of cross reactions involving cobalt cage complexes with low-spin-high-spin cobalt(III)/(II) couples shows that electron transfer reactions involving large spin changes at the metal centre are not necessarily anomalous in the context of the adiabatic Marcus-Hush formalism. The results of this study also show that for suitable systems, the Marcus correlation can be used to reliably calculate the rates of outer-sphere electron transfer cross-reactions, with reaction free-energy changes spanning the range -6 to -41 kJ mol -1 and many different combinations of initial electronic configurations. Together, these results provide a coherent and internally consistent set of experimental data in support of the Marcus-Hush formalism for outer-sphere electron transfer. The results with the caged metal-ion systems also highlight the special nature of the mechanism of electron transfer in reactions of metal-aqua ions. ¶ A new range of symmetrically disubstituted hexa-aza sarcophagine-type cage ligand complexes are prepared in this study by the base-catalysed co-condensation of formaldehyde and a-methylene aliphatic aldehydes with cobalt(III) tris(1,2-diamine) precursors in acetonitrile solution. Encapsulation reactions based on the condensation of the weak carbon di-acids propanal and decanal with formaldehyde and the cobalt(III) tris(1,2-diamine) precursors, [Co(en)3 ] 3+ (en = 1,2-ethanediamine) and D-lel3 -[Co((R, R)-chxn)3 ] 3+ (chxn = 1,2-cyclohexanediamine), yield unsaturated cobalt(III) cage complexes with an endo-cyclic imine function in each cap. The Co III -coordinated endo-cyclic imine units of the cage ligands are reactive electrophiles that are readily reduced by the BH4 - ion to give the corresponding symmetrically di-substituted hexaamine macrobicyclic cage ligands. The nitromethane carbanion is also shown to add at the endo-cyclic imine function to yield a novel nitromethylated cage ligand complex. The latter reaction introduces a new method for the regioselective functionalisation of cage ligands at sites removed from the more commonly substituted bridgehead positions. The capping of cobalt(III) tris(1,2-diamine)-type complexes with weak CH-acids developed in this study introduces a new and more direct route to symmetrically di-substituted cage ligand complexes. ¶ A new range of cobalt(III) surfactant cage complexes, with linear octyl, dodecyl and hexadecyl hydrocarbon chains built directly into the bridgehead structure of the cage ligand, have been prepared by the base catalysed co-condensation of formaldehyde and long chain aliphatic aldehydes with the tripodal cobalt(III) hexaamine complex, [Co(sen)]3+ (sen = 4,4',4''-ethylidynetris(3-azabutan-1-amine)), in acetonitrile solution. Chiral surfactant cage complexes are obtained by capping reactions beginning with the optically pure L-[Co(sen)]3+ precursor complex. The cobalt(III) cage complexes with octyl to hexadecyl substituents are surface active and reduce the surface tension of water to levels approaching those of organic solvents. The dodecyl substituted cage complex forms micelles in aqueous solution when the concentration of cage complex is > 1 ´ 10 -3 mol dm -3 at 25 °C. The cobalt(III) cage head-group of these surfactants undergoes an electrochemically reversible one-electron reduction to the corresponding cobalt(II) cage complex. The reduction potential of the surfactant head group can be tuned to more positive potentials by replacing the bridgehead hydrocarbon chain substituent with an ether linked hydrocarbon chain. The cobalt(III) surfactant-cage complexes are biologically active and are lethal to the tapeworm Hymenolepis diminuta, and the vaginal parasites, Trichomonas vaginalis and Tritrichomonas foetus. The surfactant cage complexes also cause lysis in red-blood cell membranes at concentrations as low 10 -5 mol dm -3 . Their biological activity is linked to the high head-group charge (3+) and size which cause distortions in biological membranes when the membrane is treated with these molecules. The combination of the chemically reversible outer-sphere redox properties of the cobalt cage head-groups and the chirality of the head group introduces a new and possibly unique series of chiral surfactant coordination complexes which are also redox active. ¶ The chiral carboxylic-acid ionophore, lasalocid A, has been used to promote the selective supramolecular transport and extraction of cobalt(III) hexa-aza cage cations and related tripodal cobalt(III) complexes. The conjugate base anion of lasalocid A forms stoichiometric outer-sphere complexes with the cobalt(III) cage and tripod complexes. These outer-sphere complexes are highly lipophilic and partition strongly from water into a chloroform phase. The extraction of the dissymmetric cobalt(III) complexes by the chiral polyether anion is enantioselective for many systems and results in the partial resolution of initially racemic complexes in the aqueous phase. A strong structural preference was demonstrated by the ionophore for symmetrically disubstituted cobalt(III) hexa-aza cage cations with a D-absolute configuration of the ligand about the metal-ion and an R configuration of the coordinated secondary amine N-H groups. The lasalocid A anion was also shown to promote the transport of the complexes, intact, across a chloroform bulk-liquid membrane against an NH4 + concentration gradient. The transport of the cobalt(III) complexes was also enantioselective and resulted in partial resolution of the initially racemic aqueous phase. The most efficiently transported enantiomer of each complex was also the most efficiently extracted isomer in all systems examined, consistent with a transport process limited by interfacial diffusion. The magnitude of the enantiomer separation obtained in some systems was sufficient to indicate that lasalocid A mediated extraction and transport may become a practical method for the resolution of particular types of kinetically-inert chiral metal-amine complexes.

Coordination of transition metals to peptides, either through the incorporation of unnatural chelating groups or amino acid ligating side-chains, expands the utility of peptides for biological studies. The first part of this project describes induction of α-helical secondary structure in pentapeptides upon side-chain coordination of inert transition metal ions. The second part of this project describes the syntheses of biologically active peptide species that contain a macrobicyclic hexaamine ligand that can complex radioactive metal ions for diagnostic imaging purposes. / Short peptide sequences do not form thermodynamically stable α-helices in water. The capacity of two metal clips, cis-[Ru(NH3)4(solvent)2]2+ and cis [Pd(en)(solvent)2]2+ to induce α-helicity in peptides that are five amino acids long, Ac HARAH NH2 and Ac MARAM-NH2 has been explored. In all cases at pH < 5, the metal ions bind to the side-chains of amino acid residues at positions i, i+4 of the pentapeptides resulting in formation of bidentate macrocyclic species. Circular dichroism and 1H nuclear magnetic resonance data indicate that the metal complexes of Ac-MARAM-NH2 are highly α helical in water, and in the most spectacular case, coordination of Ac-MARAM-NH2 to cis-[Ru(NH3)4(solvent)2]2+ results in up to 80% α-helicity. In contrast, metal complexes of Ac-HARAH-NH2 exhibit significantly less α-helicity in water. / 64Cu-radiolabelled peptides have been investigated for their ability to target specific tissue or cell types. These peptides require a chelating group that binds copper ions strongly. Macrobicyclic hexaamine ligands, based on the compound commonly referred to as “sarcophagine”, have demonstrated extremely high stability under biological conditions. Here we describe the synthesis of diaminosarcophagine chelators with carboxylate groups for conjugation to peptides. These new chelators have been attached to the N-terminus or lysine side-chain of biologically-active peptides, including Tyr3 octreotate, Lys3-bombesin and an integrin targeting peptide. Spectroscopic and voltammetric studies of these species suggest that the conjugated sarcophagine group retains the high metal binding affinity and structural properties of the parent species, diaminosarcophagine. These are among the first sarcophagine-peptide compounds that have been properly characterised. The new sarcophagine-peptide conjugates can be easily radiolabelled with 64Cu2+ over a wide pH range at ambient temperature.