Starting materials of an appropriate quality provide a solid foundation for any chemical study. Although already reported in the literature, the preparative procedures used to acquire the compartmental pyrazole ligands HL1, HL2 and HL3 have been adapted herein to obtain precursors of suitable purity for formation of stable copper(I) complexes. In addition
to the synthetic outcome of these modifications, several precursors could be crystallographically characterised. Structural determination of the intermediate AmdHL3 indirectly granted insight into the dynamic process responsible for broadening the NMR resonances of the corresponding final ligand, HL3, and this prototropy could then furthermore be demonstrated for the related ligand HL2 under anhydrous conditions.
Isolation of [NaL3] also led to a more detailed characterisation of this intermediate, revealing that Me2CO is an unsuitable solvent for the complexation strategy employed herein. In conclusion, the work described in this chapter has established a suitable basis for further investigation of bioinspired copper-mediated dioxygen activation chemistry supported by compartmental pyrazole ligand scaffolds.
3 Pyrazole-supported Copper(I) Complexes - Speciation in Solution
3.1 Introduction 3.1.1 Solution Stability
A general strategy for producing copper-oxygen adducts is to react cuprous complexes directly with dioxygen. A correlation exists between the structure of the copper(I) precursor and the type of adduct which results,14,15 thereby making detailed knowledge about the former invaluable. As reaction with dioxygen is typically carried out in solvent, significant efforts have been devoted herein to solution characterisation of the copper(I) complexes used in the current work. Owing to the oxygen sensitivity of these systems, all such undertakings were performed under inert conditions.
Scheme 3.1 Copper(I) disproportionation reaction. The equilibrium clearly lies far to the right at RT under aqueous conditions.
Copper(I) complexes are in some cases known to undergo spontaneous disproportionation into metallic copper and copper (II) species, a reaction which occurs readily under aqueous conditions at RT (Scheme 3.1).112,113 While the use of relatively soft aromatic nitrogen114 or nitrile115 donors can greatly attenuate this decomposition pathway, ligands employing aliphatic nitrogen donors not suitable for stabilising copper(I) may still suffer from this drawback. Systems illustrating this behaviour which are especially relevant to dioxygen activation chemistry include the unsubstituted tren ligand and its methylated derivative, Me6tren,116 as well as the hexamethylcyclam, Tet b.31 The corresponding copper(I) complexes of these ligands all undergo disproportionation, yet the latter two have been used to isolate and structurally characterise TP species despite this (Scheme 3.2).31,32
Scheme 3.2: Tetracoordinate copper(I) complexes susceptible to disproportionation, which have been used to isolate TP species. Metric parameters for the latter TP species can be found in Table 5.1.
In direct relation to the current work, it was reported in a previous investigation that the dinuclear copper(I) complex of HL3 was stable only below temperatures of −40 °C, rapidly
decomposing to a copper(II) species above this temperature.91 It was additionally shown in a separate study that copper(I) complexes of tetramethylethylenediamine (TMED), a mononucleating analogue related to HL1, also disproportionate.117 The TMED system was furthermore found to be sensitive toward the stoichiometry employed, with slight deviations leading to unstable copper(I) complexes.117 Initial copper(I) complex crystallisation trials employing crude ligands met with no success in the present study, which was largely attributed to the above mentioned complications. This impeded the application of crystallisation as a purification procedure, and further emphasised the need for organic starting materials of high purity. While the use of sufficiently pure ligands then allowed room temperature stable copper(I) complexes to be prepared, including those of HL3, crystalline material could not be successfully obtained. Evidence for the formation of these complexes therefore relies solely on characterisation in solution by NMR and MS
A general synthetic procedure was employed for producing the copper(I) complexes, [CuI2L1]X, [CuI2L2]X and [CuI2L3]X, with some modifications for specific purposes. Ligands were deprotonated using alkali metal tert-butoxide salts (MOtBu, M = Na+, K+) in RCN solvents (R = Me,Et). Tetrakis-acetonitrile salts ([Cu(MeCN)4]X) with various weakly coordinating counteranions (WCAs, X = PF6−
,BF4−
, ClO4−
, OTf− or B(C6F5)4−
) were employed as the copper(I) sources (Scheme 3.3). The volatile MeCN and tBuOH byproducts were then removed under vacuum, and the resulting residues re-dissolved in the solvent required for subsequent study (CD3CN, EtCN, etc.). However, as the complexes were not further isolated, it should be kept in mind that one equivalent of MX is generally present in the analyte solutions discussed herein. This also applies in the case of ligand HL1, where the sodium salt [NaL1] was used for preparation of the corresponding copper(I) complexes, and thus one equivalent of NaX is present. When the presence of these additional salts in solution is significant then they are specifically highlighted. Otherwise, when referring to each system in a general sense, the 'X' superscript is used as above.
Organonitriles are often employed as solvents for these systems, as they stabilise the copper(I) state due to their strong -donor and π-acceptor capabilities.115 Initial synthetic attempts were thus conducted with propionitrile (EtCN) as a solvent. While significantly more toxic than MeCN, EtCN has a sufficiently lower freezing point to enable the use of
temperatures down to and below −80 °C. Once it was established that the copper(I) complexes were indeed stable at RT, other solvents could be trialled. Acetone was not appropriate for copper(I) complex formation reactions due to its relatively high acidity (Section 2.4). Although dichloromethane (DCM) was employed in studies of some of these complexes in a previous work,90 it can be problematic with respect to chloride abstraction reactions.115,118–121
Even in the absence of such unwanted reactivity, residual chloride can interact strongly with copper centres, blocking binding sites and attenuating subsequent reactivity toward substrates.122 In fact, literature evidence exists to suggest that chloride can competitively inhibit pyrazole-bridged dinuclear copper models of T3 active sites,79 and halide ions are furthermore known to act as inhibitors of the native Tyr itself.123 Chlorinated solvents were therefore avoided in the current work, and EtCN generally showed the best results in synthetic procedures. The main exception to this was the use of MeCN, which was widely employed for characterisation.
3.1.3 Speciation and Dynamic Processes of Relevance to Characterisation
The speciation of copper(I) complexes with tetradentate or tridentate nitrogen donor ligands in solution can be complicated. Dynamic processes such as dissociation and re-association of nitrogen donor atoms can occur, and dimeric species are also frequently observed despite the use of mononucleating tri- or tetradentate ligands. This applies even in the cases of relatively prevalent copper(I) complexes with highly symmetric ligands like TMPA115,121 and trispyrazolylborate (HB(Pz)3),124 and their derivatives.125,126 Binucleating organic scaffolds can lead to yet higher oligomeric structures.64 Ligands with pyrazole units capable of occupying a bridging position are especially well known for forming cyclic trimeric and tetrameric assemblies,127–129 which can furthermore exhibit fluxional behaviour in solution.130,131 With respect to bis-tridentate pyrazole-bridging chelates of the type employed in the synthesis of [CuI2L1]X, a binuclear copper(I) complex has been reported which shows interconversion at RT between cis- and trans- isomers (Scheme 3.4).132 The dynamic behaviour in the above described systems is generally identified by broadening of resonances in the corresponding NMR spectra. Several of the aforementioned fluxional processes are considered in interpreting the characterisation data discussed in this chapter.
Scheme 3.4: Interconversion between cis- and trans- isomers in a pyrazole-bridged copper (I) complex. The enantiomer of the trans- isomer is not depicted above but would also be part of the equilibrium. L = P(CH3)3.
Charges and counterions are omittied.