Models for Nonheme Iron Intermediates:  Structural Basis for Tuning the Spin States of Fe(TPA) Complexes

Abstract

Our efforts to model the oxygen activation chemistry of nonheme iron enzymes have yielded transient intermediates with novel properties. These properties can be dramatically affected by the introduction of a 6-methyl substituent on the pendant pyridines of the tetradentate ligand TPA (TPA = tris(2-pyridylmethyl)amine). A series of Fe(TPA) complexes has thus been synthesized and characterized to provide the structural basis for these dramatic effects. The following complexes have been obtained: [Fe(L)(CH3CN)2](ClO4)2 (1, L = TPA; 2, L = 6-MeTPA; 3, L = 6-Me2TPA; 4, L = 6-Me3TPA) and [Fe(L)(acac)](ClO4)2 (5, L = TPA; 6, L = 5-Me3TPA; 7, L = 6-MeTPA). As indicated by 1H NMR and/or EPR, 1, 5, and 6 with no 6-methyl substituent are low spin, while complexes 2, 3, 4, and 7 with at least one 6-methyl substituent are all high spin, with higher redox potentials than their low-spin counterparts. The ligands with 6-methyl substituents thus favor a metal center with a larger ionic radius, i.e., FeII over FeIII and high spin over low spin. Careful scrutiny of the crystal structures of 1, 4, 6, and 7 reveals that one hydrogen of the 6-methyl group is only 2.7 Å away from the metal center in the high-spin complexes. Its presence thus prevents the pyridine nitrogen from forming an Fe−N bond shorter than 2.1 Å as required for an iron center to adopt a low-spin configuration. This steric effect of the 6-methyl substituent serves as a simple but very useful ligand design tool to tune the electronic properties of the metastable alkylperoxoiron(III) species derived from the reactions of 1−4 with tert-butyl hydroperoxide. These intermediates serve as models for low-spin and high-spin peroxoiron(III) species in the reaction cycles of the antitumor drug bleomycin and lipoxygenase, respectively. Similar principles apply in the design of nonheme diiron(II) complexes that reversibly bind dioxygen and of high-valent bis(μ-oxo)diiron complexes that model the high-valent intermediates in the redox cycles of nonheme diiron enzymes such as methane monooxygenase and ribonucleotide reductase.

Electronic Structure and Spectro-Structural Correlations of FeIIIZnII Biomimetics for Purple Acid Phosphatases: Relevance to DNA Cleavage and Cytotoxic Activity

“…As demonstrated above, an electron-withdrawing group such as -NO 2 or -Br decreases the basicity of the Fe III -bound OH -group while a hydrogen or a methyl group, by an inductive effect, increases the basicity of the hydroxo group, which acts as the initiating nucleophile in the hydrolysis of phosphate diester bonds (Scheme 1). Interestingly, a linear correlation was found between the Hammett parameter σ p and the IC 50 values for complexes 1-4 (Figure 9f). Nevertheless, on the basis of the experimental results presented in this study, at present we were unable to establish a clear relationship between DNA in vitro cleavage and tumor cell death.…”

“…The in vitro cytotoxic activities of complexes 1-4 were evaluated against K562 and GLC4 tumor cell lines. The concentrations of complexes necessary to inhibit 50% of cell growth, IC 50 , are shown in Table 6. By comparing the activity of the complexes, one observes that the effectiveness increases in the order 4 < 3 < 2 < 1.…”

“…Cell number was determined by Coulter counter analysis. The sensitivity to the drug was evaluated by the concentration required to inhibit cell growth by 50%, the IC 50 . The mean IC 50 ( SD was determined in three independent experiments each performed in duplicate.…”

An Fe IV O complex of a tetradentate tripodal nonheme ligand

“…This reaction course differs from that observed for the reactions of 1 with other peroxides such as H 2 O 2 or ROOH, which require at least 1.5 equiv. In these cases, either an Fe III OOOH or Fe III OOOR intermediate is observed instead (24,27,45).…”

“…The data were obtained in fluorescence mode [A exp (C f ͞C 0 )] at 13(1) K. Our XAS data analysis protocol has been described (26). (24). Intermediate 2 is stable for several days at Ϫ40°C, but it decays on warming to a stable species 3, whose visible spectrum strongly resembles that of [Fe III 2 ( -O)( -OAc)(TPA) 2 ] 3ϩ ( Fig.…”