One strategy for synthesising dinuclear biomimetic model complexes is to employ an organic scaffold which possesses both a bridging unit and covalently linked side arms, thus creating compartmental multidentate binding pockets. The resulting preorganised chelating ligand then favours the arrangement of two or more metal ions in close proximity, with metal separations largely depending on the bridging unit.69 The pyrazole heterocycle fulfils such a role upon deprotonation. It can then act as an anionic bridge reminiscent of a carboxylate group70,71 but with suitable sites at the 3- and 5- positions for further functionalisation (Scheme 1.12), allowing for formation of stable five- and/or six-membered chelate rings upon complexation.69
Scheme 1.12: Schematic representation of a dinuclear metal complex supported by a 3,5-substituted pyrazole-bridging ligand. Complexes with nickel(II), copper(II) and zinc(II) are known for the selected ligand depicted.
The pyrazole building block thus provides synthetic flexibility, and has been proven to preorganise two metal centres in a fashion which allows cooperativity.72 Variation of the chelating side arms allows the geometric and electronic properties to be manipulated, such as denticity, identity of donor atoms, and metal separation. The latter of these can be controlled by varying the length of the chelating side arms, short lengths favouring large intermetallic distances and vice versa, with typical metal separations of 3.5−4.5 Å.72 This versatility has allowed these ligand systems to be successfully applied in emulating dinuclear iron,73,74 nickel,75–77 copper78,79 and zinc80–82 metallobiosites.
1.4.1 Copper Chemistry Supported by 3,5-Disubstitued Pyrazole Ligands
Scheme 1.13: A series of related dinuclear copper(II) complexes with differing metal separations, used as functional models for the dinuclear copper(II) metalloenzyme, catechol oxidase (CO). Charges and counterions
are omitted. * Distance estimated from analogous nickel(II) complex.
The use of 3,5-disubstituted pyrazole scaffolds for biomimetic applications is well illustrated by their use as functional models of the T3-site in CO enzymes. These metallobiomolecules catalyse the copper-mediated oxidation of catechols to the corresponding quinones, referred to as catecholase activity. In this exemplary model study, a diverse set of pyrazole-based supporting scaffolds with differing nitrogen-donor atom types, numbers, and side arm lengths was prepared. These ligands were employed to engineer a series of related dinuclear copper(II) complexes with a range of redox potentials and metal separations (I−VIII, Scheme 1.13).78,79 The catecholase functionality of the resulting complexes was then investigated using the activated substrate 3,5-di-tert-butylcatechol. While both redox potential and Cu···Cu separation were found to influence activity, a general trend indicating that shorter metal-metal distances are favourable for catalytic ability could be established.
This example demonstrates the potential of pyrazole-based ligand scaffolds for systematic modulation of the properties of corresponding model complexes.
A significant part of the motivation for studying biological systems stems from the desire to utilise the knowledge gained to not only reproduce but also expand upon the chemistry observed in nature, allowing for novel molecules with valuable functionality to be produced.
The pyrazole unit has proven synthetically useful in this regard, for example, by condensing the features of two mononuclear metalloprotein active sites into a discrete ligand.83,84 For example, an expanded porphyrin scaffold made up of an organic framework with two adjacent metal binding pockets has recently been reported. This so-called siamese twin
porphyrin scaffold was then used to incorporate two adjacent copper(II) ions into a bioinspired hybrid complex (IX, Scheme 1.14) with unique physicochemical properties.85,86 In a related approach, the bridging capacity of pyrazole was exploited to merge two tetradentate tripodal metal-binding compartments. The corresponding dinuclear copper(II) complexes (X, XI, Scheme 1.14) supported by this ligand system were then shown to be capable of mediating both benzylic (X)87 and phenylic (XI)88 C−C coupling reactions. As X and XI demonstrate, the scaffolds employed combine two tris(aminoalkyl)amine binding pockets to bring two copper(II) ions into close proximity, with one binding site on each metal centre available for additional external co-ligands. This system can thus be thought of as a preorganised dinucleating analogue of the prominent TMPA and tren systems extensively utilised in studies of copper-mediated dioxygen activation (Section 1.3.1).
Scheme 1.14: Complexes illustrating the use of pyrazole to construct dinucleating analogues of prominent mononuclear metal binding sites.
As highlighted above, pyrazole-bridging ligands of the general type shown in Scheme 1.12 are particularly versatile, showing the potential to fuse discrete metal ion binding sites into binucleating compartmental scaffolds, and further enabling modulation of metal separations in the corresponding complexes. Despite finding considerable application in the field of bioinspired copper chemistry, the use of these systems to directly investigate copper-mediated dioxygen activation is extremely limited, with only a single example in the literature. In this example, a copper(I) complex was generated in situ from the bis-tridentate pyrazole ligand (HL1) depicted in Scheme 1.15. After ether layering and exposure to air at low temperature, a copper(II)-peroxo adduct could be isolated and crystallographically characterised.89 Although not strictly biologically relevant owing to its tetranuclear nature, this complex illustrates that pyrazole-based ligand systems are indeed suitably robust for investigations of this type of chemistry, and may even provide synthetic routes to novel copper-oxygen adducts.
Scheme 1.15: Isolation of a novel tetranuclear copper(II)-peroxo adduct, [(CuII2L1)2(O2)(OH)2], supported by a binucleating pyrazole-based ligand scaffold. Electron and mass balance are not properly accounted for here
(discussed in detail in Section 4.2).
The complex cation depicted in Scheme 1.15, [(CuII2L1)2(O2)(OH)2], consists of two pyrazolate-bridged dinuclear copper(II) fragments linked by two flanking hydroxide units and a central µ4-peroxide core, a rare motif in copper-oxygen chemistry. Although there is uncertainty about the mechanistic details of formation (Section 4.2), it is evident from geometric considerations that this type of ligand can support complexes bridged simultaneously by both a pyrazolate and µ-1,2-peroxide moiety. Assuming the copper(I) precursor complex is indeed dinuclear, the predicted metal separation would make a reaction pathway which proceeds through a cis-µ-1,2-peroxide intermediate plausible (Scheme 1.16). Furthermore, it is likely that the high flexibility and low steric demand of HL1, together with the free binding sites on each of the two resulting copper(II) atoms, make this system susceptible to dimerisation. Selection of an appropriately 3,5-disubstituted pyrazole scaffold which takes all of these factors into account may thus provide a strategy for hindering the dimerisation process, and isolating a novel dicopper(II)-cis-µ-1,2-peroxide (CP) motif.
Scheme 1.16: A plausible reaction pathway for formation of [(CuII2L1)2(O2)(OH)2]. The proposed intermediate, [CuII2L1(O2)], is potentially a novel type of Cu2O2 adduct.
1.4.2 Towards a novel Cu
2O
2core - Focus of this work
A considerable number of multidentate pyrazole-bridging ligand systems capable of supporting copper-mediated reactivity have been developed, as mentioned above (Section 1.4.1). By drawing on this established knowledge it is evident that several of the organic scaffolds which chelate the complexes depicted in Scheme 1.13 hold potential as suitable candidates for isolating the elusive dicopper(II)-cis-µ-1,2-peroxide species. In order to retain
a metal-metal separation similar to that promoted by HL1, only scaffolds with shorter side arms capable of forming five-membered rings were considered. To hinder association of external co-ligands other than dioxygen, additional donor atoms are also required. The most appropriate ligands were thus deemed to be those serving as chelates in the complexes VII and VIII, HL2 and HL3, respectively. In fact, preliminary studies of the dioxygen reactivity of copper(I) complexes formed with these two sterically bulky, bis-tetradentate scaffolds have previously shown considerable promise.90,91 These prior contributions provide a starting point for the in-depth investigations detailed in the current work, and are briefly described in each of the relevant sections. In addition, many open questions remain with respect to the formation and properties of the tetranuclear [(CuII2L1)2(O2)(OH)2] species supported by HL1, and thus this system was also further investigated herein.
In the majority of previous cases established procedures for pyrazole-bridging ligand synthesis provided material of sufficient purity to isolate the corresponding metal complexes directly. These synthetic strategies were therefore initially adopted herein.
However, over the course of the current work it became evident that even though these existing routes gave the desired chelating ligand scaffolds in good yields, the presence of trace organic impurities had an especially significant negative influence on the stability of the resulting copper(I) complexes and their corresponding copper(II)-dioxygen adducts. Due to these complications, the established procedures for ligand synthesis were then re-investigated. Strategies could thereby be developed for obtaining precursor materials which allowed for substantial enhancements in the stability of the resulting copper(I) and copper(II)-dioxygen species, which in turn greatly aided in facilitating characterisation of these complexes.
The above described re-investigation of ligand synthetic procedures proved to have a significant effect on the outcome of further experiments involving the corresponding copper complexes. Therefore, although not the principal focus of the current work, findings with respect to the isolation and characterisation of precursor materials which form the foundation of this investigation are discussed in the subsequent sections, comprising Chapter 2. Particulars regarding the synthesis and characterisation of the corresponding copper(I) complexes and their associated copper(II)-dioxygen adducts are considered in Chapters 3 and 4, respectively. As isolation of a dinuclear monomeric CP adduct is the primary goal of the current work, these chapters have specific emphasis placed on assessing the nuclearity and association states of the copper(I) and copper(II)-dioxygen species in solution. Chapter 5 contains further detailed studies pertaining to the dioxygen-adduct supported by HL3. In Chapter 6 the decomposition pathway of said species is investigated, and the reactivity of the copper(II)-dioxygen adducts supported by both HL2 and HL3 toward a selection of external substrates is examined. Chapter 7 contains a summary of all findings.