Lisa M. Berreau

Synthesis, characterization, and ligand exchange reactivity of a series of first row divalent metal 3-hydroxyflavonolate complexes.

A series of divalent metal flavonolate complexes of the general formula [(6-Ph(2)TPA)M(3-Hfl)]X (1-5-X; X = OTf(-) or ClO(4)(-); 6-Ph(2)TPA = N,N-bis((6-phenyl-2-pyridyl)methyl)-N-((2-pyridyl)methyl)amine; M = Mn(II), Co(II), Ni(II), Cu(II), Zn(II); 3-Hfl = 3-hydroxyflavonolate) were prepared and characterized by X-ray crystallography, elemental analysis, FTIR, UV-vis, (1)H NMR or EPR, and cyclic voltammetry. All of the complexes have a bidentate coordinated flavonolate ligand. The difference in M-O distances (Delta(M-O)) involving this ligand varies through the series, with the asymmetry of flavonolate coordination increasing in the order Mn(II) approximately Ni(II) < Cu(II) < Zn(II) < Co(II). The hypsochromic shift of the absorption band I (pi-->pi*) of the coordinated flavonolate ligand in 1-5-OTf (relative to that in free anion) increases in the order Ni(II) < Mn(II) < Cu(II) < Zn(II), Co(II). Previously reported 3-Hfl complexes of divalent metals fit well with this ordering. (1)H NMR studies indicate that the 3-Hfl complexes of Co(II), Ni(II), and Zn(II) exhibit a pseudo-octahedral geometry in solution. EPR studies suggest that the Mn(II) complex 1-OTf may form binuclear structures in solution. The mononuclear Cu(II) complex 4-OTf has a distorted square pyramidal geometry. The oxidation potential of the flavonolate ligand depends on the metal ion present and/or the solution structure of the complex, with the Mn(II) complex 1-OTf exhibiting the lowest potential, followed by the pseudo-octahedral Ni(II) and Zn(II) 3-Hfl complexes, and the distorted square pyramidal Cu(II) complex 4-OTf. The Mn(II) complex [(6-Ph(2)TPA)Mn(3-Hfl)]OTf (1-OTf) is unique in the series in undergoing ligand exchange reactions in the presence of M(ClO(4))(2).6H(2)O (M = Co, Ni, Zn) in CD(3)CN to produce [(6-Ph(2)TPA)M(CD(3)CN)(n)](X)(2), [Mn(3-Hfl)(2).0.5H(2)O], and MnX(2) (X = OTf(-) or ClO(4)(-)). Under similar conditions, the 3-Hfl complexes of Co(II), Ni(II), and Cu(II) undergo flavonolate ligand exchange to produce [(6-Ph(2)TPA)M(CD(3)CN)(n)](X)(2) (M = Co, Ni, Cu; n = 1 or 2) and [Zn(3-Hfl)(2).2H(2)O]. An Fe(II) complex of 3-Hfl, [(6-Ph(2)TPA)Fe(3-Hfl)]ClO(4) (8), was isolated and characterized by elemental analysis, FTIR, UV-vis, (1)H NMR, cyclic voltammetry, and a magnetic moment measurement. This complex reacts with O(2) to produce the diiron(III) mu-oxo compound [(6-Ph(2)TPAFe(3Hfl))(2)(mu-O)](ClO(4))(2) (6).

Mechanistic Studies of the O2-Dependent Aliphatic Carbon−Carbon Bond Cleavage Reaction of a Nickel Enolate Complex

The mononuclear nickel(II) enolate complex [(6-Ph(2)TPA)Ni(PhC(O)C(OH)C(O)Ph]ClO(4) (I) was the first reactive model complex for the enzyme/substrate (ES) adduct in nickel(II)-containing acireductone dioxygenases (ARDs) to be reported. In this contribution, the mechanism of its O(2)-dependent aliphatic carbon-carbon bond cleavage reactivity was further investigated. Stopped-flow kinetic studies revealed that the reaction of I with O(2) is second-order overall and is ∼80 times slower at 25 °C than the reaction involving the enolate salt [Me(4)N][PhC(O)C(OH)C(O)Ph]. Computational studies of the reaction of the anion [PhC(O)C(OH)C(O)Ph](-) with O(2) support a hydroperoxide mechanism wherein the first step is a redox process that results in the formation of 1,3-diphenylpropanetrione and HOO(-). Independent experiments indicate that the reaction between 1,3-diphenylpropanetrione and HOO(-) results in oxidative aliphatic carbon-carbon bond cleavage and the formation of benzoic acid, benzoate, and CO:CO(2) (∼12:1). Experiments in the presence of a nickel(II) complex gave a similar product distribution, albeit benzil [PhC(O)C(O)Ph] is also formed, and the CO:CO(2) ratio is ∼1.5:1. The results for the nickel(II)-containing reaction match those found for the reaction of I with O(2) and provide support for a trione/HOO(-) pathway for aliphatic carbon-carbon bond cleavage. Overall, I is a reasonable structural model for the ES adduct formed in the active site of Ni(II)ARD. However, the presence of phenyl appendages at both C(1) and C(3) in the [PhC(O)C(OH)C(O)Ph](-) anion results in a reaction pathway for O(2)-dependent aliphatic carbon-carbon bond cleavage (via a trione intermediate) that differs from that accessible to C(1)-H acireductone species. This study, as the first detailed investigation of the O(2) reactivity of a nickel(II) enolate complex of relevance to Ni(II)ARD, provides insight toward understanding the chemical factors involved in the O(2) reactivity of metal acireductone species.

A cadmium hydroxide complex of a N3S-donor ligand containing two hydrogen bond donors: synthesis, characterization, and CO2 reactivity

Treatment of the ebnpa (N-2-(ethylthio)ethyl-N,N-bis((6-neopentylamino-2-pyridyl)methyl)amine) ligand with a molar equivalent amount of Cd(ClO(4))(2).5H(2)O in CH(3)CN followed by the addition of [Me(4)N]OH.5H(2)O yielded the cadmium hydroxide complex [(ebnpaCd)(2)(mu-OH)(2)](ClO(4))(2) (1). Complex 1 has a binuclear cation in the solid-state with secondary hydrogen-bonding and CH/pi interactions involving the ebnpa ligand. In acetonitrile, 1 forms a binuclear/mononuclear equilibrium mixture. The formation of a mononuclear species has been confirmed by conductance measurements of 1 at low concentrations. Variable temperature studies of the binuclear/mononuclear equilibrium provided the standard enthalpy and entropy associated with the formation of the monomer as DeltaH degrees = +31(2) kJ mol(-1) and DeltaS degrees = +108(8) J mol(-1) K(-1), respectively. Enhanced secondary hydrogen-bonding interactions involving the terminal Cd-OH moiety may help to stabilize the mononuclear complex. Treatment of 1 with CO(2) in acetonitrile results in the formation of a binuclear cadmium carbonate complex, [(ebnpaCd)(2)(mu-CO(3))](ClO(4))(2) (2).

A Structurally-Tunable 3-Hydroxyflavone Motif for Visible Light-Induced Carbon Monoxide-Releasing Molecules (CORMs).

Molecules that can be used to deliver a controlled amount of carbon monoxide (CO) have the potential to facilitate investigations into the roles of this gaseous molecule in biology and advance therapeutic treatments. This has led to the development of light-induced CO-releasing molecules (photoCORMs). A goal in this field of research is the development of molecules that exhibit a combination of controlled CO release, favorable biological properties (e.g., low toxicity and trackability in cells), and structural tunability to affect CO release. Herein, we report a new biologically-inspired organic photoCORM motif that exhibits several features that are desirable in a next-generation photoCORM. We show that 3-hydroxyflavone-based compounds are easily synthesized and modified to impart changes in absorption features and quantum yield for CO release, exhibit low toxicity, are trackable in cells, and can exhibit both O2-dependent and -independent CO release reactivity.

Halide-promoted dioxygenolysis of a carbon-carbon bond by a copper(II) diketonate complex.

A mononuclear Cu(II) chlorodiketonate complex was prepared, characterized, and found to undergo oxidative aliphatic carbon-carbon bond cleavage within the diketonate unit upon exposure to O2 at ambient temperature. Mechanistic studies provide evidence for a dioxygenase-type C-C bond cleavage reaction pathway involving trione and hypochlorite intermediates. Significantly, the presence of a catalytic amount of chloride ion accelerates the oxygen activation step via the formation of a Cu-Cl species, which facilitates monodentate diketonate formation and lowers the barrier for O2 activation. The observed reactivity and chloride catalysis is relevant to Cu(II) halide-catalyzed reactions in which diketonates are oxidatively cleaved using O2 as the terminal oxidant. The results of this study suggest that anion coordination can play a significant role in influencing copper-mediated oxygen activation in such systems.

O2-dependent aliphatic carbon-carbon bond cleavage reactivity in a Ni(II) enolate complex having a hydrogen bond donor microenvironment; comparison with a hydrophobic analogue.

A mononuclear Ni(II) complex having an acireductone type ligand, and supported by the bnpapa (N,N-bis((6-neopentylamino-2-pyridyl)methyl)-N-((2-pyridyl)methyl)amine) ligand, [(bnpapa)Ni(PhC(O)C(OH)C(O)Ph)]ClO(4) (14), has been prepared and characterized by elemental analysis, (1)H NMR, FTIR, and UV-vis. To gain insight into the (1)H NMR features of 14, the air stable analogue complexes [(bnpapa)Ni(CH(3)C(O)CHC(O)CH(3))]ClO(4) (16) and [(bnpapa)Ni(ONHC(O)CH(3))]ClO(4) (17) were prepared and characterized by X-ray crystallography, (1)H NMR, FTIR, UV-vis, mass spectrometry, and solution conductivity measurements. Compounds 16 and 17 are 1:1 electrolyte species in CH(3)CN. (1)H and (2)H NMR studies of 14, 16, and 17 and deuterated analogues revealed that the complexes having six-membered chelate rings for the exogenous ligand (14 and 16) do not have a plane of symmetry within the solvated cation and thus exhibit more complicated (1)H NMR spectra. Compound 17, as well as other simple Ni(II) complexes of the bnpapa ligand (e.g., [(bnpapa)Ni(ClO(4))(CH(3)CN)]ClO(4) (18) and [(bnpapaNi)(2)(mu-Cl)(2)](ClO(4))(2) (19)), exhibit (1)H NMR spectra consistent with the presence of a plane of symmetry within the cation. Treatment of [(bnpapa)Ni(PhC(O)C(OH)C(O)Ph)]ClO(4) (14) with O(2) results in aliphatic carbon-carbon bond cleavage within the acireductone-type ligand and the formation of [(bnpapa)Ni(O(2)CPh)]ClO(4) (9), benzoic acid, benzil, and CO. Use of (18)O(2) in the reaction gives high levels of incorporation (>80%) of one labeled oxygen atom into 9 and benzoic acid. The product mixture and level of (18)O incorporation in this reaction is different than that exhibited by the analogue supported the hydrophobic 6-Ph(2)TPA ligand, [(6-Ph(2)TPA)Ni(PhC(O)C(OH)C(O)Ph)]ClO(4) (2). We propose that this difference is due to variations in the reactivity of bnpapa- and 6-Ph(2)TPA-ligated Ni(II) complexes with triketone and/or peroxide species produced in the reaction pathway.

Kinetic and mechanistic studies of the reactivity of Zn–OHn (n=1 or 2) species in small molecule analogs of zinc-containing metalloenzymes

Abstract Reactive Zn–OH n (n=1 or 2) species are proposed in the catalytic cycles of several zinc-containing enzymes. In order to gauge the chemical factors that influence the formation and reactivity of Zn–OH n species, synthetic model complexes have been prepared and systematically examined for biologically relevant stoichiometric and catalytic reactivity. Systems that promote the hydration of CO 2 , the activation and oxidation of alcohols, and amide and phosphate ester cleavage reactions are discussed.

Heterocyclic donor influences on the binding and activation of CO, NO, and O2 by copper complexes of hybrid triazacyclononane–pyridyl ligands

Abstract Copper(I) complexes of 1,4-diisopropyl-7-R″-1,4,7-triazacyclononane (R″=2-pyridylmethyl, LPy; 6-methyl-2-pyridylmethyl, L6MePy; 5-methyl-2-pyridylmethyl, L5MePy; 6-phenyl-2-pyridylmethyl, L6PhPy; 2-quinolylmethyl, LQuin) were prepared and characterized by CHN analysis, NMR and FTIR spectroscopy, cyclic voltammetry, and mass spectrometry. An X-ray crystal structure of [L6PhPyCu]SbF6 was determined and compared to that previously reported for [LPyCu]O3SCF3; similar distorted trigonal bipyramidal geometries are adopted with the ligands coordinated in η4 fashion. The complexes [LCu]+ (L=LPy or LQuin) form adducts with CO(g) in which the heterocyclic appendage is displaced. With NO(g), [LPyCu]O3SCF3 reacts in a disproportionation process to yield N2O and [LPyCu(ONO)]O3SCF3, which was structurally defined by X-ray crystallography. Upon reaction with O2(g) at −75°C the Cu(I) complexes of LPy and L5MePy yield trans-1,2-peroxo species [LCuOOCuL]2+ as determined by UV–Vis and resonance Raman spectroscopy. In contrast, spectroscopy indicates that low temperature oxygenation of [L6PhPyCu]SbF6 yields a bis(μ-oxo)dicopper core, postulated to be capped by η3-L6PhPy (pyridyl appendage not coordinated). Decomposition of the trans-1,2-peroxo compounds results in hydroxylation of the ligand at the benzylic position of the heterocyclic appendage, but the bis(μ-oxo) complexes decay to give products resulting from N-dealkylation of the heterocycle arm. The different fates of the Cu(I) complexes of LPy and L5MePy versus that of L6PhPy upon oxygenation may be traced to the coordination of the heterocycle; in the former cases, the pyridyl unit remains coordinated, favoring trans-1,2-peroxo generation, whereas pyridyl dissociation facilitated by the sterically bulky 6-phenyl group on L6PhPy yields a [η3-L6PhPyCu]+ fragment amenable to bis(μ-oxo) core formation. The steric properties of the heterocyclic components of the ligands used in this study thus are important determinants of the reactivity of their Cu(I) complexes with small molecules.

Hexanickel Enediolate Cluster Generated in an Acireductone Dioxygenase Model Reaction

A nickel(II) enediolate cluster (2) forms upon treatment of [(6-Ph(2)TPA)Ni(PhC(O)C(OH)C(O)Ph)]ClO(4) (1) with Me(4)NOH x 5 H(2)O in CH(3)CN. Crystallographic studies of 2 revealed a hexanuclear structure of S(6) symmetry with a formula of {[Ni(PhC(O)C(O)C(O)Ph)(CH(3)OH)] x 1.33 CH(3)OH}(6). Because isolation of bulk amounts of 2 from the reaction involving 1 proved impossible, a solvation analogue of 2 (labeled 5) was generated from admixture of Ni(ClO(4))(2) x 6 H(2)O, 2-hydroxy-1,3-diphenylpropane-1,3-dione, and Me(4)NOH x 5 H(2)O in CH(3)OH/CH(3)CN. Complex 5 is formulated as {[Ni(PhC(O)C(O)C(O)Ph)(H(2)O)] x H(2)O x 0.25 CH(3)CN}(6) based on elemental analysis, a molecular weight determination, UV-vis, and a magnetic moment measurement. Treatment of 5 with O(2) and 6-Ph(2)TPA (6 equiv) results in the formation of CO and [(6-Ph(2)TPA)Ni(O(2)CPh)(2)(H(2)O)] (3), the latter of which was isolated in 69% yield. The level of (18)O incorporation in this reaction matches that for a reaction wherein 2 is generated from 1. These results provide evidence that a nickel(II) enediolate cluster is the O(2) reactive species in a previously reported model reaction for nickel(II)-containing acireductone dioxygenase.

COORDINATION AND BIOINORGANIC CHEMISTRY OF ARYL-APPENDED TRIS(2-PYRIDYLMETHYL)AMINE LIGANDS

Aryl-appended tris(2-pyridylmethyl)amine ligands are a relatively new class of chelate ligands in coordination and synthetic bioinorganic chemistry. As outlined herein, to date, coordination complexes of such ligands have been prepared and characterized for first row metal ions from groups 7–12. These studies revealed key coordination properties for this family of ligands. Aryl-appended tris(2-pyridylmethyl)amine ligands have been recently employed in synthetic, biologically relevant metal complexes that exhibit: 1) arene hydroxylation reactivity relevant to non-heme iron-containing containing enzymes that hydroxylate aromatic amino acids; and 2) structural and reactivity properties relevant to Ni(II)-containing acireductone dioxygenase, urease, and glyoxalase I enzymes.