Synthesis and Mechanisms of Organo-Iridium Complexes as Catalysts and as Bioactive Agents.

The synthesis of chiral molecules is of great importance to the pharmaceutical, agrochemical, flavour and fragrance industries. The use of organo-iridium complexes has gained a reputation for its great utility in key enantioselective synthetic procedures. Prime examples include the catalytic reduction of carbonyls and imines; iridium-catalysed allylic substitution and catalysed enantioselective hydrogenation of unsaturated carboxylic acids. Important aspects in these processes are the reaction conditions such as the catalyst loading, metal-ion ligands, the substrate, solvent and the reaction times - all of which can affect the degree of enantioselectivity. Understanding the mechanisms of these reactions through kinetic and other studies makes a vital contribution to improving catalytic efficiency. Asymmetric transfer hydrogenation (ATH) is a prime example of a process that offers operational simplicity and has seen a surge in extensive mechanistic investigations encompassing both theoretical and experimental aspects.

This work offers new insights into the reaction mechanism of organo-iridium (III) catalysed ATH of imines, particularly that of α-fluorinated imines. The enantioselectivity of ATH has been previously noted to be a result of enantiomer formation following either zero or first-order kinetics. However, for the amine enantiomer formed with zero-order kinetics the consecutive introduction of fluorine α to the C=N bond leads to a decrease in nitrogen basicity, increasing the rate of product release as well as an increase in the electrophilicity of the carbon, facilitating nucleophilic attack. A result of changing the rate limiting step is that the reaction mechanism then proceeds to follow first-order kinetics in the formation of the enantiomeric products, with the almost complete removal of enantioselectivity. The strong electron withdrawing properties of fluorine retard the imine nitrogen’s basicity, consecutive fluorination results in a lowering of the concentration of protonated imine under the reaction conditions, confirming that the iminium ion is the reactive species in this process.

An expansion of the work on ATH is offered in the study of the acidity of the carbon acids which act as ligands for iridium. The catalytic species harbours a η6 pentamethylcyclopentadienyl ligand, forming multi-centred bonds to the metal centre; offering both stability, steric protection and significant electron density contribution to the metal centre. In order to estimate the importance of the basicity of this ligand on catalytic activity, the non-aromatic substituted cyclopentadienes were subjected to deuterium exchange, by exposing the Cp* ligand to NaOD in a DMSO-d6/D2O (9:1 v/v %) co-solvent system. The observed pseudo first-order rate constants for H/D exchange are then used to reveal relative acidities of a family of Cp* derivatives. Carboxy tetramethylcyclopentadiene undergoes H/D exchange by intramolecular general base catalysed removal of the acidic proton by the carboxylate anion. Additionally, the synthesis, characterisation and subsequent deuterium exchange experiments of an amido Cp* is discussed, showing sequential 1,5-sigmatropic rearrangements.

In an attempt to expand the library of synthetic methodologies for biologically active organo-iridium complexes, a microwave assisted method was developed. The newly furnished complexes feature a variety of Cp* tethered glucose units in an effort to enhance transport and recognition with regards to cell surface interactions. These derivatives were tested for anti-bacterial and anti-cancer activity.