The apparent Sc3+ adduct of [FeIV(O)-(TMC)]2+ (1, TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane) has been synthesized in amounts sufficient to allow its characterization by various spectroscopic techniques. Contrary to the earlier assignment of a +4 oxidation state for the iron center of 1, we establish that 1 has a high-spin iron(III) center based on its Mössbauer and EPR spectra and its quantitative reduction by 1 equiv of ferrocene to [FeII(TMC)]2+. Thus, 1 is best described as a ScIII–O–FeIII complex, in agreement with previous DFT calculations (Swart, M. Chem. Commun. 2013, 49, 6650.). These results shed light on the interaction of Lewis acids with high-valent metal-oxo species.

Fe(II)(TMC)(OTf)2 reacts with 2-(t)BuSO2-C6H4IO to afford an oxoiron(IV) product, 2, distinct from the previously reported [Fe(IV)(Oanti)(TMC)(NCMe)](2+). In MeCN, 2 has a blue-shifted near-IR band, a higher ν(Fe═O), a larger Mössbauer quadrupole splitting, and quite a distinct (1)H NMR spectrum. Structural analysis of crystals grown from CH2Cl2 reveals a complex with the formulation of [Fe(IV)(Osyn)(TMC)(OTf)](OTf) and the shortest Fe(IV)═O bond [1.625(4) Å] found to date.

We report herein the first example of an oxoiron(IV) complex of an ethylene-bridged dialkylcyclam ligand, [Fe(IV)(O)(Me2EBC)(NCMe)](2+) (2; Me2EBC = 4,11-dimethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane). Complex 2 has been characterized by UV-vis, (1)H NMR, resonance Raman, Mössbauer, and X-ray absorption spectroscopy as well as electrospray ionization mass spectrometry, and its properties have been compared with those of the closely related [Fe(IV)(O)(TMC)(NCMe)](2+) (3; TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane), the intensively studied prototypical oxoiron(IV) complex of the macrocyclic tetramethylcyclam ligand. Me2EBC has an N4 donor set nearly identical with that of TMC but possesses an ethylene bridge in place of the 1- and 8-methyl groups of TMC. As a consequence, Me2EBC is forced to deviate from the trans-I configuration typically found for Fe(IV)(O)(TMC) complexes and instead adopts a folded cis-V stereochemistry that requires the MeCN ligand to coordinate cis to the Fe(IV)═O unit in 2 rather than in the trans arrangement found in 3. However, switching from the trans geometry of 3 to the cis geometry of 2 did not significantly affect their ground-state electronic structures, although a decrease in ν(Fe═O) was observed for 2. Remarkably, despite having comparable Fe(IV/III) reduction potentials, 2 was found to be significantly more reactive than 3 in both oxygen-atom-transfer (OAT) and hydrogen-atom-transfer (HAT) reactions. A careful analysis of density functional theory calculations on the HAT reactivity of 2 and 3 revealed the root cause to be the higher oxyl character of 2, leading to a stronger O---H bond specifically in the quintet transition state.

X-linked inhibitor of apoptosis protein, XIAP, inhibits the initiation and execution phases of the apoptotic pathway. XIAP is the most potent member of the inhibitor of apoptosis protein (IAP) family of the endogenous caspase inhibitors. Therefore, targeting XIAP may be a promising strategy for the treatment of apoptosis-resistant malignancies. In this study we systematically studied the relationships of chemical structures of several novel ligands to their zinc-binding ability, molecular target XIAP, and tumor cell death-inducing activity. We show that treatment of PC-3 prostate cancer and MDA-MB-231 breast cancer cells with these membrane-permeable zinc-chelators with different zinc affinities results in varying degrees of XIAP depletion. Following decreased level of XIAP expression, we also show apoptosis-related caspase activation and cellular morphological changes upon treatment with strong zinc-chelators N4Py and BnTPEN. Addition of zinc has a full protective effect on the cells treated with these chelators, while iron addition has only partial protection that, however, can be further increased to a comparable level of protection as zinc by inhibition of ROS generation, indicating that cell death effects mediated by iron- but not zinc-complexes involve redox cycling. These findings suggest that strong zinc-chelating agents may be useful in the treatment of apoptosis-resistant human cancers.

Tetramethylcyclam (TMC, 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane) exhibits two faces in supporting an oxoiron(IV) moiety, as exemplified by the prototypical [(TMC)-FeIV(Oanti)(NCCH3)](OTf)2, where anti indicates that the O atom is located on the face opposite all four methyl groups, and the recently reported syn isomer [(TMC)FeIV(Osyn)(OTf)](OTf). The ability to access two isomers of [(TMC)FeIV(Oanti/syn)] raises the fundamental question of how ligand topology can affect the properties of the metal center. Previously, we have reported the formation of [(CH3CN)-(TMC)FeIII−Oanti−CrIII(OTf)4(NCCH3)] (1) by inner-sphere electron transfer between Cr(OTf)2 and [(TMC)FeIV(Oanti)(NCCH3)]-(OTf)2. Herein we demonstrate that a new species 2 is generated from the reaction between Cr(OTf)2 and [(TMC)FeIV(Osyn)(NCCH3)]-(OTf)2, which is formulated as [(TMC)FeIII−Osyn−CrIII(OTf)4(NCCH3)] based on its characterization by UV−vis, resonance Raman, Mössbauer, and X-ray absorption spectroscopic methods, as well as electrospray mass spectrometry. Its pre-edge area (30 units) and Fe−O distance (1.77 Å) determined by X-ray absorption spectroscopy are distinctly different from those of 1 (11-unit pre-edge area and 1.81 Å Fe−O distance) but more closely resemble the values reported for [(TMC)FeIII−Osyn−ScIII(OTf)4(NCCH3)] (3, 32-unit pre-edge area and 1.75 Å Fe−O distance). This comparison suggests that 2 has a square pyramidal iron center like 3, rather than the six-coordinate center deduced for 1. Density functional theory calculations further validate the structures for 1 and 2. The influence of the distinct TMC topologies on the coordination geometries is further confirmed by the crystal structures of [(Cl)(TMC)FeIII−Oanti−FeIIICl3] (4Cl) and [(TMC)FeIII−Osyn−FeIIICl3](OTf) (5). Complexes 1–5 thus constitute a set of complexes that shed light on ligand topology effects on the coordination chemistry of the oxoiron moiety.

The syn and anti isomers of [Fe IV (O)(TMC)] 2+ (TMC=tetramethylcyclam) represent the first isolated pair of synthetic non‐heme oxoiron(IV) complexes with identical ligand topology, differing only in the position of the oxo unit bound to the iron center. Both isomers have previously been characterized. Reported here is that the syn isomer [Fe IV (O syn )(TMC)(NCMe)] 2+ ( 2 ) converts into its anti form [Fe IV (O anti )(TMC)(NCMe)] 2+ ( 1 ) in MeCN, an isomerization facilitated by water and monitored most readily by 1 H NMR and Raman spectroscopy. Indeed, when H 2 18 O is introduced to 2 , the nascent 1 becomes 18 O‐labeled. These results provide compelling evidence for a mechanism involving direct binding of a water molecule trans to the oxo atom in 2 with subsequent oxo–hydroxo tautomerism for its incorporation as the oxo atom of 1 . The nonplanar nature of the TMC supporting ligand makes this isomerization an irreversible transformation, unlike for their planar heme counterparts.

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In this study, a methyl group on the classic tetramethylcyclam (TMC) ligand framework is replaced with a benzylic group to form the metastable [FeIV(Osyn)(Bn3MC)]2+ (2‐syn; Bn3MC=1‐benzyl‐4,8,11‐trimethyl‐1,4,8,11‐tetraazacyclotetradecane) species at −40 °C. The decay of 2‐syn with time at 25 °C allows the unprecedented monitoring of the steps involved in the intramolecular hydroxylation of the ligand phenyl ring to form the major FeIII−OAr product 3. At the same time, the FeII(Bn3MC)2+ (1) precursor to 2‐syn is re‐generated in a 1:2 molar ratio relative to 3, accounting for the first time for all the electrons involved and all the Fe species derived from 2‐syn as shown in the following balanced equation: 3 [FeIV(O)(LPh)]2+ (2‐syn)→2 [FeIII(LOAr)]2+ (3)+[FeII(LPh)]2+ (1)+H2O. This system thus serves as a paradigm for aryl hydroxylation by FeIV=O oxidants described thus far. It is also observed that 2‐syn can be intercepted by certain hydrocarbon substrates, thereby providing a means to assess the relative energetics of aliphatic and aromatic C−H hydroxylation in this system.