2. Results and Discussion
2.6. Conclusion and Outlook
This work was based on the synthesis of new binuclear zinc complexes that mimic the active centres of zinc containing enzymes. In addition to the imidazole containing and literature known ligand L1,[43d] three novel ligands were designed, which bear biomimetic functional groups, like benzimidazole, imidazole and carboxylate (L2−L4). In addition, the length of the side chains of the ligands containing benzimidazole moieties was modified (L2 and L3) to obtain zinc complexes, which vary in their zinc-zinc separations (8 and 9).
Two complexes (4a and 4b) were obtained that differ considerably in their Zn···Zn distances, although based on the same ligand (L1). This is due to the different nucleophiles that bridge the zinc atoms: a methanol-methanolate moiety in case of 4a and a methanol group in 4b. In addition, a µ−OH bridged complex (8) was obtained in solid state with the benzimidazole containing ligand L2. ESI-MS analysis of 8 revealed the formation of a (H3O2)-bridged complex, which was the only species in solution. These results indicated the flexibility of the pyrazole ligand scaffold, which is substituted in 3 and 5 positions with aromatic N-donor moieties. In addition, complex 4b is most likely active towards the cleavage of acetonitrile, as [Zn2H−1L1(CN)](ClO4)2 was the only species found in ESI-MS.
In accordance with potentiometric investigations, various complexes were obtained in the synthesis and characterised: [ZnH2L1]4+ (1), [Zn2H−1L1]3+ (2, 3), [Zn2H−2L1]2+ (4a, 4b and 5a) and [Zn4H−5(L1)2]3+ (7). The Zn···Zn separations for these complexes differ between 3.38(1) Å (4b) and 4.25(1) Å (3).
In addition to the binuclear complexes (2−5), a tetranuclear complex (19) was obtained by diffusion of atmospheric CO2 into the complex solution. The resulting carbonate moiety bridges two binuclear subunits in a µ4−η2:η1:η1 binding fashion. The same binding motif was observed when the complex solution was exposed directly to CO2. A second tetranuclear complex (7) was obtained that represented species [Zn4H−5(L1)2]3+. This complex bears a µ-oxo-µ-hydroxo bridge, which is uncommon for zinc and has not been reported so far for zinc containing complexes.
The synthesised complexes were furthermore investigated in catalytic reactions to activate CO2 or to cleave chemical bonds (i.e., P−O bond of phosphate diesters and phosphate triesters and the C−N bond of β-lactam antibiotic drugs).
Activation of CO2 was studied in the copolymerisation reaction with cyclohexene oxide and in the formation of propylene oxide with 1,2-propylene glycol. In these reactions 2 was used as catalyst. Since this complex bears no nucleophile, an additional equivalent of base was added to ensure nucleophilicity that is necessary for activity. Although 2 did not catalyse both reactions, the reason might be not due to the inactivity of the complex rather than the used conditions. Since both experiments were performed at 1 atm CO2 pressure, additional experiments under high CO2 pressure might increase the efficacy of 2 to activate CO2. In addition, increasing the catalyst concentration might also provide a higher activity.
The activity of the complexes to cleave chemical bonds was investigated by means of phosphate esters. 4 was found to be slightly active in the hydrolysis/transesterification reaction of 2-hydroxypropyl-p-nitrophenyl phosphate (HPNP). Compared to the uncatalysed reaction, a 21-fold rate enhancement was observed at pH 8.0 and a 12-fold acceleration at pH 8.5. In addition to this, complexes 2, 4, 5a and 12 were explored in hydrolytic experiments to cleave Paraoxon, a phosphate triester. Due to the co-ligand acetate, which strongly binds to the zinc atoms and does not allow coordination of the substrate, 5a and 12 were not active to hydrolyse Paraoxon. The hydrolytic activity of 2 and 4 was examined in buffered solutions. As demonstrated by 31P NMR spectroscopy, the substrate was cleaved after several days (probably due to background hydrolysis) and the free diethyl phosphate was present in solution. Different results were obtained in unbuffered solutions. In these reactions, the hydrolysed diethyl phosphate coordinated to the zinc atoms of the complexes as it was demonstrated by 31P NMR and X-ray analysis.
It could thus be proven that the used sulfonic acid buffers inhibit the complexes in the coordination of the substrate. Further experiments in other buffer systems, which do not interact with the complexes, would be of interest to explore the activity of the complexes to cleave the P−O bond of Paraoxon.
In addition to P−O bond cleavage, complexes 4, 8 and 9 were investigated to cleave the C−N bond of the β-lactam antibiotic Penicillin G. As 9 bears long side chains, this complex was expected to be the most active. It was thus surprising that none of these complexes showed any activity to cleave the β-lactam ring of Penicillin G. The reason for this was investigated by binding studies of the β-lactam substrates Penicillin G, Ampicillin, 6-aminopenicillanic acid, Cephalotin and Sulbactam to 2. It was demonstrated by ESI-MS, NMR and IR spectroscopy that all substrates coordinated to the zinc atoms of the complex in a µ1,3-binding fashion of the carboxylate group that is present in all substrates. In addition, X-ray analysis confirmed these studies as suitable single crystals were obtained in a reaction with the substrate Sulbactam (17). This complex is the first example of a β-lactam antibiotic drug, which coordinates to a complex, and is analysed by X-ray diffraction. The µ1,3-binding fashion of the carboxylate groups of the substrates thus explains the inactivity of the complexes to cleave Penicillin G.
To design complexes that might be active, the Zn···Zn separations can be increased, so that the zinc atoms cannot be bridged by the carboxylate moiety. This might result in a vacant position for the nucleophile and thus in the activity to cleave the substrates.
Another possibility is to design ligands, which bear less donor functions. This would result in a complex that can even be active if the substrate coordinates to the zinc atoms as it was demonstrated. A further vacant position for the nucleophile would thus be available and might increase the activity of the complexes.