Probing the Mechanism for 2,4'-Dihydroxyacetophenone Dioxygenase Using Biomimetic Iron Complexes.

In this study, we report the synthesis and characterization of [Fe(T1Et4iPrIP)(2-OH-AP)(OTf)](OTf) (2), [Fe(T1Et4iPrIP)(2-O-AP)](OTf) (3), and [Fe(T1Et4iPrIP)(DMF)3](OTf)3 (4) (T1Et4iPrIP = tris(1-ethyl-4-isopropyl-imidazolyl)phosphine; 2-OH-AP = 2-hydroxyacetophenone, and 2-O-AP- = monodeprotonated 2-hydroxyacetophenone). Both 2 and 3 serve as model complexes for the enzyme-substrate adduct for the nonheme enzyme 2,4'-dihydroacetophenone (DHAP) dioxygenase or DAD, while 4 serves as a model for the ferric form of DAD. Complexes 2-4 have been characterized by X-ray crystallography which reveals T1Et4iPrIP to bind iron in a tridentate fashion. Complex 2 additionally contains a bidentate 2-OH-AP ligand and a monodentate triflate ligand yielding distorted octahedral geometry, while 3 possesses a bidentate 2-O-AP- ligand and exhibits distorted trigonal bipyramidal geometry (τ = 0.56). Complex 4 displays distorted octahedral geometry with 3 DMF ligands completing the ligand set. The UV-vis spectrum of 2 matches more closely to the DAD-substrate spectrum than 3, and therefore, it is believed that the substrate for DAD is bound in the protonated form. TD-DFT studies indicate that visible absorption bands for 2 and 3 are due to MLCT bands. Complexes 2 and 3 are capable of oxidizing the coordinated substrate mimics in a stoichiometric and catalytic fashion in the presence of O2. Complex 4 does not convert 2-OH-AP to products under the same catalytic conditions; however, it becomes anaerobically reduced in the presence of 2 equiv 2-OH-AP to 2.

Synthesis, Structure, and Characterization of Tris(1-ethyl-4-isopropyl-imidazolyl-κN)phosphine Nickel(II) Complexes.

In this work we report the synthesis of five new nickel(II) complexes all coordinated to the tripodal ligand tris(1-ethyl-4- i Pr-imidazolyl)phosphine (TlEt4iPrIP). They are [Ni(T1Et4iPrIP)(CH3CN)2(OTf)](OTf) (1), [Ni(T1Et4iPrIP)(OTf)2] (2), [Ni(T1Et4iPrIP)(H2O)(OTf)](OTf) (3), [Ni(T1Et4iPrIP)Cl](OTf) (4), and [Ni(T1Et4iPrIP)Cl2] (5). The complexes serve as bioinorganic structural model complexes for histidine-coordinated nickel proteins. The X-ray structures have been determine for all complexes which feature coordination numbers 4-6. We investigated the spectroscopic interconversions for these compound in dichloromethane solution and demonstrate interconversion between 1-3 and conversion of 2 to 4. Complex 5 can be spectroscopically converted to the cation of 4 by dissolving it in dichloromethane. Fits of variable temperature magnetic susceptibility data yielded the following parameters: g = 1.944, D = -0.327 cm-1, E/D = 3.706 for 1; g = 2.280, D = -0.365 cm-1, E/D = 22.178 for 2; g = 2.000, D = -7.402 cm-1, E/D = -0.272 for 3; g = 2.176, D = -0.128 cm-1, E/D = -0.783 for 4; g = 2.258, D = 14.288 cm-1, E/D = 0.095 for 5. DFT structure optimizations afforded HOMO and LUMO energies indicating that complex 1 is the most stable.

Structural, Spectroscopic, Electrochemical, and Magnetic Properties for Manganese(II) Triazamacrocyclic Complexes.

We report the synthesis of [Mn(tacud)2](OTf)2 (1) (tacud = 1,4,8-triazacycloundecane), [Mn(tacd)2](OTf)2 (2) (tacd = 1,4,7-triazacyclodecane), and [Mn(tacn)2](OTf)2 (3) (tacn = 1,4,7-triazacyclononane). Electrochemical measurements on the MnIII/II redox couple show that complex 1 has the largest anodic potential of the set (E 1/2 = 1.16 V vs NHE, ΔE p = 106 mV) compared to 2 (E 1/2 = 0.95 V, ΔE p = 108 mV) and 3 (E 1/2 = 0.93 V, ΔE p = 96 mV). This is due to the fact that 1 has the fewest 5-membered chelate rings and thus is least stabilized. Magnetic studies of 1-3 revealed that all complexes remain high spin throughout the temperature range investigated (2 - 300 K). X-band EPR investigations in methanol glass indicated that the manganese(II) centers for 2 and 3 resided in a more distorted octahedral geometric configuration compared to 1. To ease spectral interpretation and extract ZFS parameters, we performed high-frequency high-field EPR (HFEPR) at frequencies above 200 GHz and a field of 7.5 T. Simulation of the spectral data yielded g = 2.0013 and D = -0.031 cm-1 for 1, g = 2.0008, D = -0.0824 cm-1, |E/D| = 0.12 for 2, and g = 2.00028, D = -0.0884 cm-1 for 3. These results are consistent with 3 possessing the most distorted geometry. Calculations (PBE0/6-31G(d)) were performed on 1-3. Results show that 1 has the largest HOMO-LUMO gap energy (6.37 eV) compared to 2 (6.12 eV) and 3 (6.26 eV). Complex 1 also has the lowest HOMO energies indicating higher stability.

A Structural Model for the Iron-Nitrosyl Adduct of Gentisate Dioxygenase.

We present the synthesis, properties, and characterization of [Fe(T1Et4iPrIP)(NO)(H2O)2](OTf)2 (1) (T1Et4iPrIP = Tris(1-ethyl-4-isopropyl-imidazolyl)phosphine) as a model for the nitrosyl adduct of gentisate 1,2-dioxygenase (GDO). The further characterization of [Fe(T1Et4iPrIP)(THF)(NO)(OTf)](OTf) (2) which was previously communicated (Inorg. Chem. 2014, 53, 5414) is also presented. The weighted average Fe-N-O angle of 162° for 1 is very close to linear (≥ 165°) for these types of complexes. The coordinated water ligands participate in hydrogen bonding interactions. The spectral properties (EPR, UV-vis, FTIR) for 1 are compared with 2 and found to be quite comparable. Complex 1 closely follows the relationship between the Fe-N-O angle and NO vibrational frequency which was previously identified for 6-coordinate {FeNO}7 complexes. Liquid FTIR studies on 2 indicate that the ν(NO) vibration position is sensitive to solvent shifting to lower energy (relative to the solid) in donor solvent THF and shifting to higher energy in dichloromethane. The basis for this behavior is discussed. The K eq for NO binding in 2 was calculated in THF and found to be 470 M-1. Density functional theory (DFT) studies on 1 indicate donation of electron density to the iron center from the π* orbitals of formally NO-. Such a donation accounts for the near linearity of the Fe-N-O bond and the large ν(NO) value of 1791 cm-1.

Self-assembly of multiferroic core-shell composites using DNA functionalized nanoparticles.

Ferrite-ferroelectric core-shell nanoparticles were prepared by deoxyribonucleic acid (DNA) assisted self-assembly and the strained mediated magneto-electric (ME) interactions between the ferroic phases were studied. The nanoparticle type and size were varied and the DNA linker sequence was also varied. Two kinds of particles, one with 600 nm barium titanate (BTO) core and 200 nm nickel ferrite (NFO) shell and another with 200 nm BTO core and 50 nm nickel cobalt ferrite (NCFO) shell were prepared. The particles were linked by three different oligomeric DNA containing 19, 18 or 30 base pairs. The core-shell structure was evident from electron microscopy and scanning microwave microscopy images. Films and disks of the core-shell particles were assembled in a magnetic field and used for measurements of low frequency ME voltage coefficient (MEVC) and magnet-dielectric effect. The MEVC data on films indicate that particles assembled with DNA with 30 base pairs exhibit the strongest ME coupling suggesting a more fully integrated heterogenous nanocomposite and the weakest interaction for DNA with 18 base pairs. These results indicate that the longer linker region in DNA is the key factor for forming better composites. This result may be due to the irregular shape of the nanoparticles. Longer DNA strands would be able to bridge better generating more linkages. Shorter strands would not able to bridge the irregularly shaped particles as well and therefore result in linkages and less heterogeneity in the composites.

Thermally Induced Oxidation of [FeII(tacn)2](OTf)2 (tacn = 1,4,7-triazacyclononane).

We previously reported the spin-crossover (SC) properties of [FeII(tacn)2](OTf)2 (1) (tacn = 1,4,7-triazacyclononane) [Eur. J. Inorg. Chem. 2013, 2115]. Upon heating under dynamic vacuum, 1 undergoes oxidation to generate a low spin iron(III) complex. The oxidation of the iron center was found to be facilitated by initial oxidation of the ligand via loss of an H atom. The resulting complex was hypothesized to have the formulation [FeIII(tacn)(tacn-H)](OTf)2 (2) where tacn-H is N-deprotonated tacn. The formulation was confirmed by ESI-MS. The powder EPR spectrum of the oxidized product at 77 K reveals the formation of a low-spin iron(III) species with rhombic spectrum (g = 1.98, 2.10, 2.19). We have indirectly detected H2 formation during the heating of 1 by reacting the headspace with HgO. Formation of water (1HNMR in anhydrous d6-DMSO) and elemental mercury were observed. To further support this claim, we independently synthesized [FeIII(tacn)2](OTf)3 (3) and treated it with one equiv base yielding 2. The structures of 3 was characterized by X-ray crystallography. Compound 2 also exhibits a low spin iron(III) rhombic signal (g = 1.97, 2.11, 2.23) in DMF at 77 K. Variable temperature magnetic susceptibility measurements indicate that 3 undergoes gradual spin increase from 2 to 400 K. DFT studies indicate that the deprotonated nitrogen in 2 forms a bond to iron(III) exhibiting double bond character (Fe-N, 1.807 Å).

Assembly of a mononuclear ferrous site using a bulky aldehyde-imidazole ligand.

A new iron(II) complex has been prepared and characterized. [Fe(TrImA)2(OTf)2] (1, TrImA = 1-Tritylimidazole-4-carboxaldehyde). The solid state structure of 1 has been determined by X-ray crystallography. Compound 1 crystallizes in monoclinic space group P21/c, with a = 10.8323(18) Å, b = 8.1606(13) Å and c = 24.818(4) Å. The iron center is coordinated to two imidazole groups, two pendant aldehyde-derived carbonyl oxygens and two triflate oxygens. The complex is high spin between 300 and 20 K as indicated by variable field variable temperature magnetic measurements. A fit of the magnetic data yielded g = 2.17 and D = 4.05 cm-1. A large HOMO-LUMO gap energy (4.49 eV) exists for 1 indicating high stability.

Highest recorded N-O stretching frequency for 6-coordinate {Fe-NO}7 complexes: an iron nitrosyl model for His3 active sites.

We report the synthesis, structure, and reactivity of [Fe(T1Et4iPrIP)(OTf)2] [1; T1Et4iPrIP = tris(1-ethyl-4-isopropylimidazolyl)phosphine]. Compound 1 reacts reversibly with nitric oxide to afford [Fe(T1Et4iPrIP)(NO)(THF)(OTf)](OTf) (2), which is the first example of a 6-coordinate {FeNO}(7) S = 3/2 complex containing a linear Fe-N-O group. 2 exhibits the highest ν(NO) for compounds in this class. Density functional theory studies reveal an enhanced degree of ß-electron transfer from π*(NO) to the Fe d orbitals accounting for the large stretching frequency.

A structural and functional model for alkene dioxygenases.

In this article, we report sterically-controlled iron sites based on non-chelating bulky imidazole ligands. Adding 6 equiv. of 1,2-dimethylimidazole (1,2-Me2Im) to Fe(OTf)2⋅2CH3CN affords the first example of a 5-coordinate imidazole­iron complex ([Fe(1,2-Me2Im)5](OTf)2, 1). The structure is distorted square pyramidal (τ5 = 0.41). When an iPr group is substituted for the methyl group at the 2-position on the imidazole (2-iPr-1-MeIm), the 14-electron complex ([Fe(2-iPr-1-MeIm)4](OTf)2, 2) is obtained. This complex exhibits slightly distorted tetrahedral geometry (τ'4 = 0.93) with four N-donors and serves as a 4-His iron structural model complex for carotenoid cleavage dioxygenases (CCD). The electronic structure of 1 and 2 were characterized by Mössbauer spectroscopy. Reactions of 1 and 2 with model olefin substrates (1-R-4-(1-methoxyprop-1-en-2-yl)benzene; R = Me or Br) in the presence of oxygen result in olefin cleavage yielding ketone and aldehyde products, although 2 yields more products than 1. Support for a proposed reaction mechanism for 2 is offered from Density Functional Theory (DFT) calculations.

Synthesis and Determination of Anticancer Activity of Dicobalt Hexacarbonyl 2'-Deoxy-5-alkynylfuropyrimidines.

Dicobalt hexacarbonyl 5-alkynyl furopyrimidine nucleoside analogs, with 4-methylphenyl (p-tolyl) and 4-pentylphenyl substituents attached at the C-6 base position, designed in the form of ribose acetyl esters, were synthesized (42-96%). Attached at the C-5 position were propargyl alcohol, its methyl ether and acetate derivatives, butynol, and the 4-methylphenyl- (p-tolyl) and 4-pentylphenyl-substituted alkynyl groups, which were coordinated to a dicobalt hexacarbonyl unit. The structure of 5-(3-acetoxyprop-1-yn-1-yl)-6-p-tolyl-2'-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-one was determined by X-ray crystallography. Density functional theory calculations performed on the corresponding derivative yielded geometric parameters for the dicobalt hexacarbonyl adduct of this ligand. The cytotoxic activity of each of dicobalt modified nucleosides on cancer cells of different phenotypes was determined in vitro. The investigated compounds showed antiproliferative effects with median inhibitory concentration (IC50) values in the ranges of 14-90 and 9-50 µM for HeLa and K562 cells, respectively. The formation of reactive oxygen species in the presence of modified nucleosides was determined in K562 cells. The results indicate that the mechanism of action for the studied compounds may be related to the induction of oxidative stress.

A Biomimetic System for Studying Salicylate Dioxygenase.

We report the characterization of [Fe(T1Et4iPrIP)(sal)] (2) (T1Et4iPrIP = tris(1-ethyl-4-isopropyl-imidazolyl)phosphine; sal2- = salicylate dianion), which serves as a model for substrate-bound salicylate dioxygenase (SDO). Complex 2 crystallizes in the monoclinic space group P21/n with a = 10.7853(12) Å, b = 16.5060(19) Å, c = 21.217(2) Å, ß = 94.489(2)°, and V = 3765.5(7) Å3. The structure consists of FeII bonded in distorted square pyramidal geometry (τ = 0.32) with two salicylate oxygens and two T1Et4iPrIP nitrogens serving as the base and the apical position occupied by the other ligand nitrogen. [Fe(T1Et4iPrIP)(OTf)2] (1), the precursor for 2, catalyzes the cleavage of 1,4-dihydroxy-2-naphthoate in the presence of O2. Complex 1 is also capable of cleaving the salicylate aromatic ring in the presence of H2O2. The progression of this reaction toward product formation involves an FeIII-phenoxide species.

Organometallic Nucleosides: Synthesis and Biological Evaluation of Substituted Dicobalt Hexacarbonyl 2'-Deoxy-5-oxopropynyluridines.

Reactions of dicobalt octacarbonyl [Co2(CO)8] with 2'-deoxy-5-oxopropynyluridines and related compounds gave dicobalt hexacarbonyl nucleoside complexes (83-31 %). The synthetic outcomes were confirmed by X-ray structure determination of dicobalt hexacarbonyl 2'-deoxy-5-(4-hydroxybut-1-yn-1-yl)uridine, which exhibits intermolecular hydrogen bonding between a modified base and ribose. The electronic structure of this compound was characterized by the DFT calculations. The growth inhibition of HeLa and K562 cancer cell lines by organometallic nucleosides was examined and compared to that by alkynyl nucleoside precursors. Coordination of the dicobalt carbonyl moiety to the 2'-deoxy-5-alkynyluridines led to a significant increase in the cytotoxic potency. The cobalt compounds displayed antiproliferative activities with median inhibitory values (IC50) in the range of 20 to 80 µm for the HeLa cell line and 18 to 30 µm for the K562 cell line. Coordination of an acetyl-substituted cobalt nucleoside was expanded by using the 1,1-bis(diphenylphosphino)methane (dppm) ligand, which exhibited cytotoxicity at comparable levels. The formation of reactive oxygen species in the presence of cobalt compounds was determined in K562 cells. The results indicate that the mechanism of action for most antiproliferative cobalt compounds may be related to the induction of oxidative stress.

Synthesis and reactivity of a 4His enzyme model complex.

A new iron(II) complex has been prepared and characterized. [Fe(TrIm)4(OTf)2] (1, TrIm = 1-Tritylimidazole). The solid state structure of 1 has been determined by X-ray crystallography. Compound 1 crystallizes in triclinic space group P1̄, with a = 13.342(7) Å, b = 13.5131(7) Å and c = 13.7025(7) Å. The iron center resides in distorted octahedral geometry coordinated to four equatorial imidazole groups and two axial triflate oxygens groups. The complex is high spin between 20 K and 300 K as indicated by variable field variable temperature magnetic measurements. A fit of the magnetic data yielded g = 2.24 and D = -0.80 cm-1. A large HOMO-LUMO gap energy (3.89 eV) exists for 1 indicating high stability. Addition of H2O2 or t BuOOH to 1 results in formation of an oxygenated intermediate which upon decomposition results in oxidation of the trityl substituent on the imidazole ligand.

New binuclear Mn(II) and Fe(II) complexes supported by 1,4,8-triazacycloundecane.

Two new binuclear metal complexes supported by 1,4,8-triazacycloundecane (tacud) are reported. [Fe(2)(tacud)(2)(µ-Cl)(2)Cl(2)] (1) and [Mn(2)(tacud)(2)(µ-Cl)(2)Cl(2)] (2) are isomorphs consisting of bis(µ-chloro) bridged metal centers along with terminal chloro groups and tacud ligands. Both compounds 1 and 2 crystallize in the P1 space group. For 1, a = 7.7321(12) Å, b = 7.8896(12) Å, c = 11.4945(17) Å, α = 107.832(2)°, ß = 107.827(2)°, γ = 92.642(2)°, V = 627.85(17) Å(3) and Z = 1. For 2, a = 7.7607(12) Å, b = 7.9068(12) Å, c = 11.6111(18) Å, α = 108.201(2)°, ß = 108.041(2)°, γ = 92.118(3)°, V = 636.47(17) Å(3) and Z = 1. Variable-temperature and variable-field magnetic susceptibility studies on 1 indicate the presence of weak ferromagnetic interactions between the high-spin iron(ii) centers in the dimer (J = + 1.6 cm(-1)) and the crystalline field anisotropy of the ferrous ion (D = - 2.8, E = - 0.1 cm(-1)). Variable temperature magnetic susceptometry studies on 2 indicate that weak antiferromagnetic coupling exists between the manganese(ii) centers (J = - 1.8 cm(-1)). Compounds 1 and 2 retain their dinuclearity in weakly coordinating or low polarity solvents, while both become mononuclear in solvents such as methanol.

N,N'-dimethylformamide-derived products from catalytic oxidation of 3-hydroxyflavone.

The biomimetic conversion of 3-hydroxyflavone in the presence of a copper(II) catalyst, dioxygen, and N,N'-dimethylformamide to oxidation products as well as two previously unreported solvent-derived products is seen. The two solvent-derived products were characterized, and their crystal structures were determined.

Mechanistic studies on the formation and reactivity of dioxygen adducts of diiron complexes supported by sterically hindered carboxylates.

Dioxygen activation by enzymes such as methane monooxygenase, ribonucleotide reductase, and fatty acid desaturases occurs at a nonheme diiron active site supported by two histidines and four carboxylates, typically involving a (peroxo)diiron(III,III) intermediate in an early step of the catalytic cycle. Biomimetic tetracarboxylatodiiron(II,II) complexes with the familiar "paddlewheel" topology comprising sterically bulky o-dixylylbenzoate ligands with pyridine, 1-methylimidazole, or THF at apical sites readily react with O(2) to afford thermally labile peroxo intermediates that can be trapped and characterized spectroscopically at low temperatures (193 K). Cryogenic stopped-flow kinetic analysis of O(2) adduct formation carried out for the three complexes reveals that dioxygen binds to the diiron(II,II) center with concentration dependences and activation parameters indicative of a direct associative pathway. The pyridine and 1-methylimidazole intermediates decay by self-decomposition. However, the THF intermediate decays much faster by oxygen transfer to added PPh(3), the kinetics of which has been studied with double mixing experiments in a cryogenic stopped-flow apparatus. The results show that the decay of the THF intermediate is kinetically controlled by the dissociation of a THF ligand, a conclusion supported by the observation of saturation kinetic behavior with respect to PPh(3), inhibition by added THF, and invariant saturation rate constants for the oxidation of various phosphines. It is proposed that the proximity of the reducing substrate to the peroxide ligand on the diiron coordination sphere facilitates the oxygen-atom transfer. This unique investigation of the reaction of an O(2) adduct of a biomimetic tetracarboxylatodiiron(II,II) complex provides a synthetic precedent for understanding the electrophilic reactivity of like adducts in the active sties of nonheme diiron enzymes.