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The complexes in this work bear either a monodentate chlorido or iodido ligand bound to the iridium centre. The solution chemistry of the azpyNMe2 com- plexes1 and 4was investigated, revealing that the chlorido complexes readily hydrolyse in aqueous solution, reaching an equilibrium between chloride-bound and OH/OH2-bound analogues (Figure 3.16, pg. 102). The iodido complex, however, was inert to hydrolysis (Figure 3.17, pg. 103). In biological testings, the complexes were dissolved in cell medium containing 120 mM chloride. This was shown to suppress hydrolysis completely, indicating that complexes1 – 3 would remain in their chloride-bound form during cell tests. Once they enter the cells, the chloride concentration decreases and aquation may be possible. The iodido complex4 showed 40% I!Cl exchange over 24 h in solution with 120 mM chloride (Table 3.11, pg. 104), therefore a significant proportion of complex4 could be converted to complex 3 by the time it reaches cells.

The 1_{H-NMR spectra show that addition of chloride 24 h after hydrolysis} causes the disappearance of some, but not all, of the new peaks that ap- pear during hydrolysis of complex 1 (Figure 3.18, pg. 105). This indi- cates that, whilst aquation is suppressible and reversible by chloride, cer- tain species form during aquation that are una↵ected by addition of chloride post-hydrolysis. High chloride concentration would likely shift the equilibrium between OH/OH2-bound and Cl-bound Ir species, reverting the Ir-OH/OH2 species in the solution back to almost entirely Cl-bound complex. This suggests that species other than OH/OH2-adducts are forming, possibly hydroxido- bridged dimers. This has implications to the form the complex takes in cells, as chloride concentration varies depending on the intracellular location. More extensive investigations into the e↵ect of biologically-relevant chloride concen- trations on complex1 are carried out in Chapter 4.

The reactivities of Ir-Cl and Ir-OH/OH2 species are likely to di↵er. In the case of CDDP, the OH/OH2-bound Pt species can react with many o↵-target molecules, reducing the amount of complex that reaches the target site and

therefore also the efficacy of the drug. That complexes 1 – 3 remain their original Ir-Cl species in a solution at the chloride concentration of cell medium in an encouraging result, as it may mean that they are less likely to prematurely hydrolyse and bind o↵-target molecules in cells.

The halido ligand has a profound e↵ect on not only the hydrolysis, but also the stability of the chiral enantiomers of azpyNMe2 organoiridium complexes. Whilst separation by chiral HPLC with excellent resolution was possible for complexes1 – 4(Figure 3.19, pg. 108 and Table 3.12, pg. 110), the separated enantiomers of the chlorido complexes revert readily to a racemic mixture. Separated enantiomers of the iodido complex, however, remained optically pure. There are slight shifts in the retention times of some of the separated peaks, however, this is more likely to be due to slight erroneous variation in the flow speeds between runs rather than any significant chemical changes. This is the first time successful separation and/or isolation of stable enantiomers of an organoiridium iodido complex of this family has been reported. Separation of stable enantiomers has previously been possible for an organoosmium iodido complex bearing the same azpyNMe2 bidentate ligand.103

For the chlorido complexes to interconvert, there must be a mechanism facili- tating it. Given that the aquation results prove the bound chlorides are labile in aqueous solution, a likely mechanism is simply the approach of a free chlo- ride to the opposite face of the complex to which a chloride is already bound, resulting in the binding of the new chloride and the leaving of the previously- bound chloride (in the manner of an SN2 reaction). The net result of this would be the conversion from one enantiomer to the other. The iodide has been shown to be non-labile, and therefore interconversion does not occur for separated enantiomers of iodido complex 4. Pharmacological development of therapeutics tends to favour enantiomerically pure substances, meaning that this is a promising result for complex 4. Future drug development of similar organoiridium complexes with iodido ligands are likely to have stable, isolat- able enantiomers which can be tested for di↵ering biological properties. This is discussed further in Chapter 6.

unexpected. Cl is more electronegative than I and so it may be expected that the bond with the highly electropositive iridium(III) centre would be stronger with chlorine. Additionally, comparison of the x-ray crystal structures show that the Ir-I bond is longer than Ir-Cl bond in similar complexes (Table 3.9, pg. 90), this is in agreement with literature on similar complexes.94 _The strength of the Ir-I bond may come from the larger van der Waals dispersion forces associated with bonds with large atoms such as iodine. The hydrolysis of the Ru-halide bonds of ruthenium arene complexes has been studied, revealing that in such systems, Ru-I bonds also hydrolyse less readily than Ru-Cl bonds. Calculations of the related reaction energies and reaction barriers to aquation confirmed that the resistance of Ru-I bonds to hydrolysis was due to the higher activation energies inherent in Ru-I hydrolysis relative to Ru-Cl.114 _{This may} also be the case for Ir-halides.