Lipoxygenases are mononuclear non-heme iron enzymes that regio- and stereospecifcally convert 1,4-pentadiene subunit-containing fatty acids into alkyl peroxides. The rate-determining step is generally accepted to be hydrogen atom abstraction from the pentadiene subunit of the substrate by an active ferric hydroxide species to give a ferrous water species and an organic radical. Reported here are the synthesis and characterization of a ferric model complex, [Fe(III)(PY5)(OMe)](OTf)(2), that reacts with organic substrates in a manner similar to the proposed enzymatic mechanism. The ligand PY5 (2,6-bis(bis(2-pyridyl)methoxymethane)pyridine) was developed to simulate the histidine-dominated coordination sphere of mammalian lipoxygenases. The overall monoanionic coordination provided by the endogenous ligands of lipoxygenase confers a strong Lewis acidic character to the active ferric site with an accordingly positive reduction potential. Incorporation of ferrous iron into PY5 and subsequent oxidation yields a stable ferric methoxide species that structurally and chemically resembles the proposed enzymatic ferric hydroxide species. Reactivity with a number of hydrocarbons possessing weak C-H bonds, including a derivative of the enzymatic substrate linoleic acid, scales best with the substrates' bond dissociation energies, rather than pK(a)'s, suggesting a hydrogen atom abstraction mechanism. Thermodynamic analysis of [Fe(III)(PY5)(OMe)](OTf)(2) and the ferrous end-product [Fe(II)(PY5)(MeOH)](OTf)(2) estimates the strength of the O-H bond in the metal bound methanol in the latter to be 83.5 +/- 2.0 kcal mol(-1). The attenuation of this bond relative to free methanol is largely due to the high reduction potential of the ferric site, suggesting that the analogously high reduction potential of the ferric site in LO is what allows the enzyme to perform its unique oxidation chemistry. Comparison of [Fe(III)(PY5)(OMe)](OTf)(2) to other coordination complexes capable of hydrogen atom abstraction shows that, although a strong correlation exists between the thermodynamic driving force of reaction and the rate of reaction, other factors appear to further modulate the reactivity.

Lipoxygenases (LOs) are mononuclear, non-heme iron enzymes found in both plants and animals that catalyze the oxidative conversion of 1,4-diene-containing fatty acids to alkyl hydroperoxides. 1,2 The rate-determining step (RDS) of the mechanism is generally accepted to be a hydrogen atom abstraction (HA) of the weak, substrate C-H bond (∼77 kcal/ mol) 3 to generate a substrate-radical which is subsequently trapped by dioxygen. 4,5 The species postulated to be responsible for the HA is a ferric-hydroxide complex, which is subsequently reduced by the H-atom to a ferrous-water complex (eq 1). 6 The reactivity of LOs under anaerobic conditions are consistent with this mechanism as substrate reduces the active ferric site and generates alkyl-radicals. 7,8 However, this mechanism contrasts with traditional biological mechanisms which are generally thought to proceed through a high-valent ironoxo or ferric-peroxy species. 9,10 Presented here is an example of C-H bond HA by a ferric-methoxide complex providing chemical precedent for the proposed RDS of LOs. Additionally, the properties of the substrates and products predict that this reaction is thermodynamically favorable. The chemical similarities of this model complex to the iron-sites in LOs strongly support a HA by a ferric-hydroxide species.The iron coordination environment in LOs generates an iron center with a very positive Fe(III)/Fe(II) reduction potential (∼0.6 V vs SHE). 11 X-ray structural analysis and spectroscopy suggest that 6-coordinate ferrous and ferric forms of soybean-1 LO have a single exogenous water and hydroxide ligand, respectively. 12-16 Of the remaining five endogenous ligands, only one is anionic, which is consistent with the positive redox potential. A short iron-ligand bond distance observed in the ferric form is attributed to a hydroxide ligand. 15 Reduction of this species results in little change in the coordination environment beyond lengthening a single iron-ligand bond distance.A new ligand has been designed and synthesized (Scheme 1) to mimic specific attributes of the iron coordination site in LOs, namely a 5-coordinate environment which can accommodate a sixth exogenous solvent ligand. The ligand, 2,6-bis-((2-pyridyl)methoxymethane)pyridine (PY5), is composed of five pyridine subunits and accommodates a single metal in a nearly idealized square pyramidal coordination. A 6-coordinate ferrous complex is isolated directly from a 1:1 mixture of Fe-(OTf) 2 and PY5 as a methanol solvate: [Fe(PY5)(MeOH)]-(OTf) 2 (1). 17 As in the resting state forms of the various plant and animal LOs, 18,19 the complex is air-stable and high-spin. 20 The structure of 1‚MeOH 21,22 reveals a 6-coordinate ferrous cation bound to all five of the pyridyl subunits and an exogenous methanol ligand. The Fe-O bond length of 2.04 Å is notably short for methanol bound to a divalent metal. The oxidation potential of +0.930 V (in methanol vs SHE), 21 is similar to other ferrous complexes composed of neutral nitrogen atom ligands. 23,24 Oxidation of 1 with 0.5 e...

A series of transition metal complexes derived from the pentadentate ligand PY5, 2,6-(bis-(bis-2-pyridyl)methoxymethane)pyridine, illustrates the intrinsic propensity of this ligand to complex metal ions. X-ray structural data are provided for six complexes (1-6) with cations of the general formula [M(II)(PY5)(Cl)](+), where M = Mn, Fe, Co, Ni, Cu, Zn. In complexes 1-4 and 6, the metal ions are coordinated in a distorted-octahedral fashion; the four terminal pyridines of PY5 occupy the equatorial sites while the axial positions are occupied by the bridging pyridine of PY5 and a chloride anion. Major distortions from an ideal octahedral geometry arise from displacement of the metal atom from the equatorial plane toward the chloride ligand and from differences in pyridine-metal-pyridine bond angles. The series of complexes shows that M(II) ions are consistently accommodated in the ligand by displacement of the metal ion from the PY5 pocket, a tilting of the axial pyridine subunit, and nonsymmetrical pyridine subunit ligation in the equatorial plane. The displacement from the ligand pocket increases with the ionic radius of M(II). The axial pyridine tilt, however, is approximately the same for all complexes and appears to be independent of the electronic ground state of M(II). In complex 5, the Cu(II) ion is coordinated by only four of the five pyridine subunits of the ligand, resulting in a square-pyramidal complex. The overall structural similarity of 5 with the other complexes reflects the strong tendency of PY5 to enforce a distorted-octahedral coordination geometry. Complexes 1-6 are further characterized in terms of solution magnetic susceptibility, electrochemical behavior, and optical properties. These show the high-spin nature of the complexes and the anticipated stabilization of the divalent oxidation state.

A series of ferrous complexes with the pentadentate ligand 2,6-(bis-(bis-2-pyridyl)methoxymethane)pyridine (PY5) was prepared and examined. PY5 binds ferrous iron in a square-pyramidal geometry, leaving a single coordination site accessible for complexation of a wide range of monodentate exogenous ligands: [Fe(II)(PY5)(X)](n+), X = MeOH, H(2)O, MeCN, pyridine, Cl-, OBz-, N(3)-, MeO-, PhO-, and CN-. The spin-states of these ferrous complexes are extremely sensitive to the nature of the single exogenous ligand; the spectroscopic and structural properties correlate with their high-spin (hs) or low-spin (ls) electronic ground state. Systematic metrical trends within six crystallographic structures clearly indicate a preferred conformational binding mode of the PY5 ligand. The relative binding affinities of the exogenous ligands in MeOH indicate that exogenous ligand charge is the primary determinant of the binding affinity; the [Fe(II)(PY5)](2+) unit preferentially binds anionic ligands over neutral ligands. At parity of charge, strong-field ligands are preferentially bound over weak-field ligands. In MeOH, the pK(a) of the exogenously ligated MeOH in [Fe(PY5)(MeOH)](2+) (9.1) limits the scope of exogenous ligands, as strongly basic ligands preferentially deprotonate [Fe(PY5)(MeOH)](2+) to yield [Fe(PY5)(OMe)](1+) rather than ligate to the ferrous center. Exogenous ligation by a strongly basic ligand, however, can be achieved in polar aprotic solvents.

An efficient modular protocol for synthesizing a series of facial-capping tris-pyridyl ligands, based on the tris(2-pyridyl)methoxymethane backbone, has been developed which allows for systematic variations of the steric demands at the periphery of the ligand. The coordination chemistry of one such family of ligands that positions 0-->3 methoxy groups at the periphery with Cu(I) and Cu(II) is presented. The ligands are tris(2-pyridyl)methoxymethane (L(0)()), bis(2-pyridyl)(2-(6-methoxy)pyridyl)methoxymethane (L(1)()), bis(2-(6-methoxy)pyridyl)(2-pyridyl)methoxymethane (L(2)()), and tris(2-(6-methoxy)pyridyl)methoxymethane (L(3)()). The ligand exchange behavior and, to a lesser extent, the structures of the these complexes vary dramatically given the small perturbation of introducing methoxy substituents. Two distinct coordination modes are observed for the Cu(I) complexes, both in solution and the solid state. One is a pseudo-tetrahedral coordination comprised of the facial-capping, tris-pyridyl ligand and a monodentate ligand such as CH(3)CN, CO, or PPh(3). The other structural type is also a pseudo-tetrahedral Cu(I) monomer formed by two tris-pyridyl ligands coordinated in a bidentate manner with preferable binding by the nonmethoxy pyridyl subunits. With the exception of the most sterically hindered ligand, L(3)(), which only displays monoligation to Cu(I), all ligands form both types of Cu(I) complexes, and the formation is controlled by stoichiometry. Both competitive ligand binding experiments and ligand substitution with CO(g) show that the [(L(0)())(2)Cu](+) and [(L(1)())(2)Cu](+) complexes have nearly equivalent stability in aprotic solvent, and greater stability than the [(L(2)())(2)Cu](+) complex due to inclusion of bulky methoxypyridines into the Cu(I) coordination sphere. The Cu(II) complexes of the ligand series generate "bis-tris", [(L(0)()(-->)(3)())(2)Cu](2+), complexes, with the Cu(II) ligated in a tetragonally distorted octahedral coordination environment. The degree of bulk at the ligand periphery dictates the Cu(II)-ligand bond lengths both in solution and the solid state. In these complexes, the bulky pyridyl ring prefers to bind in the axial position. For the most sterically encumbered ligand, L(3)(), the bisligated Cu(II) complex is moisture sensitive, reacting to give a monoligated, tris-aqua species, [L(3)()Cu(H(2)O)(3)](2+).