Bis-bipyridyl Flavonolate Complexes - ACS Publications - American

Article Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

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Mechanistic Investigations of Photoinduced Oxygenation of Ru(II) Bis-bipyridyl Flavonolate Complexes Xiaozhen Han,†,‡ Murugaeson R. Kumar,† Amanda Hoogerbrugge,† Kevin K. Klausmeyer,† Mukunda M. Ghimire,§,# Lauren M. Harris,§ Mohammad A. Omary,§ and Patrick J. Farmer*,† †

Department Department § Department # Department ‡

of of of of

Chemistry and Biochemistry, Baylor University, Waco, Texas 76798, United States Chemistry and Biochemistry, Stephen F. Austin State University, Nacogdoches, Texas 75962, United States Chemistry, University of North Texas, Denton, Texas 76203, United States Chemistry, Lebanon Valley College, Annville, Pennsylvania 17003, United States

S Supporting Information *

ABSTRACT: We previously reported that a Ru-bound flavonolate model of flavonol dioxygenases, [RuII(bpy)2(3hydroxyfla)][PF6], photochemically reacts with dioxygen in two different manners. Broad-band excitation generates mixtures of products characteristic of 1,3-addition of dioxygen across the central pyrone ring, as is observed in enzymatic reactions. However, low temperature excitation at wavelengths longer than 400 nm generates a unique Ru-bound 2-benzoatophenylglyoxylate product resulting from a 1,2-dioxetane intermediate. Herein, we investigate this reactivity in a series of Ru(II)bisbipyridyl flavonolate complexes [RuII(bpy)2(3-hydroxyflaR)][PF6] (bpy = 2,2′-bipyridine; fla = flavonolate; R = p-OMe (1), pMe (2), p-H (3), p-Cl (4)), and [RuII(bpy)2(5-hydroxyfla)][PF6] (5). The complexes’ structures, photophysical and electrochemical properties, and photochemical reactivity with oxygen were investigated in detail. Two different reaction product mixtures, from 1,2- and 1,3-additions of dioxygen, are observed by illumination into distinct excitation/emission manifolds. By analogy to previous reports of excited state intramolecular proton transfer, the two manifolds are attributed to tautomeric diradicals that predict the observed reactivity patterns.

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INTRODUCTION The flavonols are a broad class of natural products that have been extensively studied for their antioxidant activity in food and health sciences.1−3 These compounds have also been shown to have many other biological and pharmacological activities, including antiviral,4 anti-inflammtory,5−7 antiallergy, and anticancer properties.8−10 In nature, metalloenzyme dioxygenases, such as quercetin dioxygenase (QDO), catalyze oxidative degradation of flavonols, cleaving their central ring via a 1,3-addition pathway with concomitant evolution of carbon monoxide, Scheme 1.11 Many different metal ions have been reported within flavonol dioxygenases from different species, including divalent Fe, Cu, Co, Ni, Zn, and Mn.12,13 Most commonly, single electron transfer (SET) mechanisms are proposed for these enzymes, in which a quercetin-based radical is generated which then reacts rapidly with dioxygen or superoxide.14,15 In such proposals, the metal ion acts as a conduit for an internal electron transfer between the metalbound flavonol and O2, as well to facilitate and orient the radical coupling.16,17 To elucidate the mechanism of these flavonol dioxygenases, a number of flavonolate (fla) complexes with divalent metal ions have been studied, which typically require high temperature (70−80 °C) to undergo dioxygenase-type reactions.18−21 The © XXXX American Chemical Society

Scheme 1

Speier group reported a Cu(II) flavonolate complex, [CuIIL2(fla)], reacts at 70 °C with dioxygen via a 1,3endoperoxide mechanism, with concomitant release of CO, Received: May 31, 2017

A

DOI: 10.1021/acs.inorgchem.7b01384 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry but the analogous bis-flavonolate complex [CuII(L)(fla)2] underwent oxygenation through a 1,2 pathway, proven by the observation of chemiluminescence that accompanies the decomposition of a putative dioxetane intermediate, shown in Scheme 1.22 Several groups have reported photochemical oxygenation reactions using flavonolate metal complexes. The Berreau group has reported that flavnonolate complexes of group 12 metal (Zn(II), Cd(II), and Hg(II)) undergo 1,3-addition, with CO release, when irradiated with UV light.19b In 2013, they also described the photochemical reactivity of RuII (η6-p-cymene) flavonolate compound and found the photoinduced loss of the p-cymene ligand initiated oxygenation of the flavonolate ligand and release of carbon monoxide, as in the native dioxygenase activity, upon irradiation of UV or visible light.23 However, the mechanisms of these photoinduced oxygenations have not been elucidated. Photooxygenations may be initiated by way of three fundamental pathways: by direct addition of dioxygen with excited state radicals, or indirectly by energy or electron transfer forming singlet oxygen or superoxide, respectively.24,25 In the energy transfer pathways, singlet oxygen is generated either by the substrate itself or a surrogate, and this high-energy species performs the oxygenation. Photosensitized oxygenations of the 3-hydroxyflavonols yield products of both 1,2- and 1,3additions but only in the presence of sensitizers such as Rose Bengal which is consistent with the intermediacy of singlet oxygen.26 In the electron transfer pathways, a long-lived excited state of the substrate or surrogate undergoes an electron transfer reaction with dioxygen to form superoxide, which subsequently engenders the oxygenation. Often times, [RuII(bpy)2L]2+ complexes are utilized to initiate such photochemical redox reactions due to well-characterized electron transfer reactivity from long-lived luminescent states.27 The general family of low spin d6 [RuII(bpy)2L]2+ complexes is also quite inert, which allows characterization of unusual ligand-based reactivity; we have used such complexes to characterize products of O atom exchange and S atom extrusion reactions of Ru-bound dithiocarbamates,28 as well as oxidative and photoinduced C− H activation of Ru-bound heterocycles.29,30 We recently reported that photooxygenation of a Ru(II) flavonolate complex, using excitation at longer wavelengths than 400 nm, generates a unique Ru-bound 2-benzoatophenylglyoxylate (Ru-bpg) complex resulting from a 1,2 addition pathway, shown in Scheme 2, whereas broad-band excitation yields product mixtures derived from 1,3-addition and loss of CO.31 In this report, we investigate the possible mechanistic pathways of this reactivity using a series of analogous Ru(II) bis-bipyridyl flavonolate complexes, [RuII(bpy)2(3-hydroxyflaR)] [PF6] (R = p-OMe (1), p-Me (2), p-H (3), p-Cl (4)) as well as a structurally different analogue [RuII(bpy)2(5-

hydroxyfla)] [PF6] (5) in Scheme 3. Complexes 1−4 react with dioxygen under analogous conditions to form Ru-bpg products, Scheme 3

complexes 1b−4b; analogue complex 5 does not undergo photooxygenation. Importantly, two excitation/emission manifolds for compounds 1−4 are characterized, which distinctly lead to products of 1,2- or 1,3-addition of dioxygen.

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RESULTS Synthesis and Characterization of Complexes. The syntheses of the Ru(II) bis-bipyridyl flavonolate complexes follow a methodology that has been previously described.29−31 The complexes were prepared by mixing 1 equiv of RuII(bpy)2Cl2 with 1.2 equiv of ligand flavonol and 2.0 equiv of trimethylamine in ethanol. The reaction was refluxed and stirred under N2 for 14 h. The resulting complexes were isolated as purple diamagnetic PF6− salts. While complexes 1−5 are relatively stable under air in the solid state, all but complex 5 react with O2 in solution. The complexes have all been characterized by 1H NMR, UV−vis-NIR electronic absorption, photoluminescence, and infrared spectroscopies, cyclic voltammetry, mass spectrometry, and complex 5 by X-ray crystallography, as shown in Supporting Information (SI 1). Electrochemical Measurements. The redox properties of complexes 1−5 were examined by cyclic voltammetry (SI 2), with results summarized in Table 1. Electrochemically reversible Ru(III/II) couples are observed for all complexes, with ΔEp equal to ca. 65 mV and ipa/ipc close to unity. The reduction potentials increase in the order of 1 to 5. The plot of E1/2 vs Hammett constant σ is linear, as shown in Figure 1, indicating that the potentials are directly affected by the Table 1. Electrochemical Data for Complexes 1−5a

Scheme 2

complex

E1/2 (V)

ΔEp (V)

ipa/ipc

σb

1 2 3 4 5

0.63 0.65 0.67 0.71 0.72

0.061 0.070 0.067 0.063 0.064

0.93 0.88 0.78 0.91 0.72

−0.27 −0.17 0.00 0.23

a

All potentials measured with Ag/AgCl reference electrode, Pt disc working electrode, and Pt wire counter electrode. Measured potentials were corrected using a ferrocene standard, with the Fc/Fc+ couple set to 400 mV NHE and all potentials adjusted vs NHE. Data obtained at a scan rate of 100 mV/s in CH3CN, 0.1 M TBAPF6. bHammett constants σ for substituents (OCH3, CH3, H, and Cl) are from ref 32. B


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Inorganic Chemistry

Likewise, the second-order rate constants for oxygenation of complexes 1−4 correlate directly with the E1/2 of the complexes, as shown in the plot of k2 vs E1/2 (RuIII/II) in Figure 2b. Photophysical Characterizations. All of the complexes exhibit similar absorption spectra, with maxima as noted in Table 3. The normalized UV−vis absorption spectra of

electron-donating or -withdrawing nature of the substituent groups.32

Table 3. Photophysical Data for Complexes 1−5 complex

λmax (nm)

ext. coef. (M−1 cm−1)

ex. λmax (nm)

em. λmax (nm)

1

380 529 376 527 370 526 364 523 426

9680 6260 10600 6900 11230 7710 13800 8680 4970

350 419 340 425 340 420 340 425 426

535 472 535 475 535 485 535 475 572

2

Figure 1. Plot of E1/2 of the RuII/III of complexes 1−4 vs the Hammett constant σ.

3 4

Oxygenation Kinetics. The rates of oxygenation of complexes 1−4 at different temperatures under comparable conditions were monitored by the decrease of the complex absorption peak (e.g., 530 nm for complex 1) during continuous broadband excitation within the spectrometer. The conditional rate constants and activation parameters derived from variable temperature kinetic experiments are given in the Supporting Information (SI 3). The determined rates exhibit a linear relationship with respect to the initial concentrations of both the complex and oxygen (see SI 3). Therefore, a rate law was modeled as d[RuII(bpy)2flaR]+/dt = k[RuII(bpy)2flaR]+[O2]. Using these comparative data, the oxygenation reactivity for complexes 1−4 decreases in the order 1 > 2 > 3 > 4. A Hammett plot (log k2R/k2H vs σ) for this dependence is linear (ρ = −0.65), as depicted in Figure 2a.

5

complex 3, oxygenation product complex 3b, and [RuII(bpy)3]2+ in CH3CN are shown in Figure 3. Complexes

Figure 3. Electronic absorption spectra of anaerobic 30 μM solutions of complex 3 (solid), complex 3b (short dash), and [RuII(bpy)3]2+ (long dash) in CH3CN.

1−5 of this study show significantly broadened absorption bands in the metal ligand charge transfer (MLCT) region between 400 and 700 nm comparable to that observed in spectra of [RuII(bpy)3]2+, suggesting that the lower-lying π* orbitals of the flavonolate ligand have extensive π back-bonding interactions with the Ru(II) center.33 As previously reported for complex 3, excitations of complexes 1−4 within the putative MLCT absorptions at wavelengths above 450 nm give no observable emission. However, excitations close to the flavonolate absorption generates two distinct emission manifolds, as illustrated by the luminescence action spectra of complex 3 in Figure 4. The low-energy inner manifold for complex 3 has excitation and emission maxima at 420 and 485 nm, respectively, with a welldefined (0,0) transition of ca. 450 nm. The high-energy outer manifold exhibits excitation and emission maxima at 340 and 535 nm, respectively, corresponding to a Stokes shift of ca. 10,700 cm−1, much large than the corresponding 3190 cm−1 Stokes shift for the low-energy inner manifold. For comparison, only a single manifold is observed for nonreactive complex 5, Figure 4; excitation of this complex at 426 nm generates a corresponding emission with a maximum at 572 nm, with a (0,0) transition at ca. 480 nm. The excitation and emission peak maxima derived from the action spectra for complexes 1−

Figure 2. (a) Hammett plot of log kR/kH vs σ. (b) Correlation of comparative second-order rate constants vs E1/2. C


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Inorganic Chemistry

Figure 5. Mass spectrum of the product mixture after photooxygenation of complex 2 (m/z 665) for 10 min in an ice bath using excitation through a 400 nm high-pass optical filter, producing complex 2b (m/z 697) in ca. 70% yield.

and related [RuII(bpy)2L]+ complexes are known to be sensitizers.34 Likewise, there is much precedence for the generation of dioxetanes via reactivity of singlet oxygen.35 However, broad-band excitation of complexes 1−4 in oxygenated solutions generates no emission ca. 1270 nm as is characteristic of singlet oxygen generation. Likewise, addition of the specific singlet oxygen quenchers 9,10-dimethyl anthracene or NaN3 did not block the low-energy manifold reaction of complexes 1−4 with oxygen nor decrease the reaction rate under broadband excitation (SI 8).36

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DISCUSSION As previously noted, photooxygenations may occur by several distinct mechanisms: direct reactions, initial activation of substrate or oxygen (e.g., energy or electron transfer between reagents), or external activation (e.g., generation of singlet oxygen by sensitizer).37,38 Both spectral and reactivity experiments strongly argue against singlet oxygen as an intermediate in these reactions. Electron transfer activation, or SET, is commonly proposed for both enzymatic and nonenzymatic oxygenations of flavonols. Indeed, the electrochemical and broad-band oxygenation rate data for complexes 1−4 show a correlation of reactivity with electron density. Evidence against SET comes from characterizations of the analogue complex 5, which has an oxidation potential close to that of reacting complex 4 but shows a single emission/excitation manifold and does not undergo photooxygenation. For complexes 1−4, two wavelength dependent reactivity pathways are observed, Scheme 5, corresponding to excitation into distinct excitation/emission manifolds. A generalized potential energy surface (PES) diagram for this photophysical behavior is illustrated in Scheme 6. Low energy excitation from the ground state (GS) configuration generates ES1, the lowest energy state with a similar nuclear configuration to that of the GS. This state exhibits a typical emission that overlaps with the excitation band. Higher energy excitation via direct excitation (vis-à-vis intersystem crossing) paradoxically leads to a much lower energy emitting state, ES2. The relatively large Stokes shift observed for the higher energy excitation, >10,000 cm−1 or

Figure 4. (top) Action spectra of complex 3 in CH3CN showing two excitation/emission manifolds, described in the text as the low-energy inner manifold (dotted lines) and high-energy outer manifolds. (bottom) Action spectra of complex 5 in CH3CN showing a single excitation/emission manifold.

5 are listed in Table 3, and full action spectra are available in SI 4. Wavelength Dependent Oxygenations. Low temperature photooxygenations through a 400 nm high pass optical filter of complexes 1−4 generate the corresponding Ru-bpg complexes 1b−4b in high yield; experimental detail are given in SI 5. For example, a 5 min excitation of complex 2 generates ca. 70% of complex 2b, as determined by ESI-MS, Figure 5. Likewise, the products of these reactions engender a chemiluminescence, confirming the intermediacy of 1,2dioxetanes (SI 6).22 Analogous low temperature photooxygenations of complexes 1−4 illuminated through a 310 nm (±5 nm) notch-pass optical filter, which corresponds to excitation into the high-energy manifold, yield mixtures of products typical of the 1,3-addition reactivity, as identified in ESI-MS of the reaction mixtures, illustrated in Scheme 4 for the photooxidation of compound 3 (SI 7). Similar mixtures of products were observed in initial photooxygenations in the absence of filters.31 Intermediacy of 1O2. The generation of Ru-bpg products upon selective photooxidation of complexes 1−4 was initially assumed to involve singlet oxygen, as the parent [RuII(bpy)3]2+ D


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Inorganic Chemistry Scheme 4

Scheme 5

to a proton shift within the alfa-hydroxy ketone moiety leading to two different emitting tautomeric states, and thus are classic examples of excited state intramolecular proton transfer (ESIPT).42−45 For metal-flavonolate chelate complexes, no such proton transfers are possible, as both oxygen atoms are bound to the metal ion; most previous studies of metalflavonolate luminescence report single emission manifolds.19,22 In the ESIPT literature, a variety of structures have been proposed for the excited state tautomers, typically invoking delocalized π systems;46 a recent computational effort investigated such configurations in terms of global aromaticity.47 However, a simplistic view of localized diradicals resulting from an excited state proton shift directly predicts the dioxygenation reactivity observed, as illustrated in Scheme 7.

Scheme 6

1.2 eV for all reacting complexes, implies that a substantial structural change in nuclear configuration accompanies the ES2 exciton. It should be noted that excitation profiles in Figure 4 suggest that the ES1 exciton can easily feed the ES2 state and sensitize the formation of its exciton and subsequent photoproduct in Scheme 6. Observations of distinct inner and outer excitation/emission manifolds that lead to distinct reactivity are well precedented in photochemistry. For example, (halo)(isonitrile)gold(I) complexes exhibit similar dual photophysical behavior,39a−d which was subsequently exploited in the photochemical generation of gold nanoparticles.39e Likewise, organic excimers and exciplexes of polynuclear aromatic molecules undergo photoinduced cycloaddition and other photochemical reactions generating photoproducts that exhibit large Stokes shifted emissions.40 Bimodal emissions have also been observed for free flavonols, but typically both are observed concurrently in steady state measurements.41 These bimodal emissions have been attributed

Scheme 7

E


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Inorganic Chemistry

Thermo Electron Linear Trap Quadropole Orbitrap Discovery mass spectrometer. NMR spectra were recorded on a Varian 500 NMR system in deuterated acetonitrile (CD3CN); spectra of synthesized complexes are given in SI 10. Elemental analyses were performed by Atlantic Microlabs Inc., Norcross, GA. The desired temperatures in kinetic studies were achieved by a Hakke F3 circulating bath. Steadystate excitation and emission spectra for dilute acetonitrile solutions of complexes 1−5 were collected using a Photon Technology International (PTI) Quanta Master Model QM-4 scanning spectrofluorometer equipped with a 75 W xenon arc lamp, emission and excitation monochromators, excitation correction unit, and a photomultiplier tube (PMT). Synthesis of Complexes. General procedure for synthesis of complexes 1−5: Ru(bpy)2Cl2 (0.95 mmol) and flavonol (1.00 mmol) and trimethylamine (2 mmol) were placed in a three-neck flask with 10 mL of ethanol. A three-neck flask was fitted with a condenser, and an inert atmosphere, established using standard Schlenk techniques. The reaction solution was brought to reflux and stirred under N2 for 14 h. The mixture was cooled and then poured into 200 mL of deionized H2O, with addition of excess KPF6. The resulting purple precipitate was collected on a Buchner funnel under vacuum filtration. The crude product was purified on a basic alumina column with CH2Cl2/CH3CN as the eluent. Typical yields of over 80% were obtained following chromatography. [Ru(bpy)2(3-hydroxyflaOCH3)][PF6], Complex 1. Yield: 619 mg, 74%. Found: C, 52.31; H, 3.35; N, 6.73; Calcd for C36H27F6N4O4RuP: C, 52.37; H, 3.30; N, 6.79. FT-IR (KBr, cm−1): 1602 (νC=O). ESI MS: m/z (pos.) 681.19. 1H NMR (500 MHz, CD3CN): δ 9.03 (d, 1H), 8.84 (d, 1H), 8.48 (m, 4H), 8.42 (d, 1H), 8.39 (d, 1H), 8.06 (d, 1H), 8.02 (d, 1H), 7.93 (d, 1H), 7.85 (d, 1H), 7.80 (m, 2H), 7.75 (d, 1H), 7.70 (m, 2H), 7.60 (t, 1H) 7.52 (t, 1H), 7.36 (m, 1H), 7.18 (t, 1H), 7.16 (t, 1H), 6.94 (d, 2H), 3.82 (s, 3H). [Ru(bpy)2(3-hydroxyflaCH3)][PF6], Complex 2. Yield: 713 mg, 88%. Found: C, 53.47; H, 3.34; N, 7.03; Calcd for C36H27F6N4O3RuP: C, 53.40; H, 3.36; N, 6.92. FT-IR (KBr, cm−1): 1609 (νC=O). ESI MS: m/z (pos.) 665.12. 1H NMR (500 MHz, CD3CN): δ 9.03 (d, 1H), 8.83 (d, 1H), 8.50 (m, 4H), 8.42 (t, 2H), 8.37 (d, 2H), 8.06 (t, 1H), 8.02 (t, 1H), 7.82 (t, 2H), 7.75 (d, 1H), 7.72 (m, 2H), 7.60 (t, 1H) 7.53 (t, 1H), 7.37 (m, 1H), 7.22 (d, 2H), 7.18 (t, 1H), 7.16 (t, 1H), 2.35 (s, 3H). [Ru(bpy)2(3-hydroxyflaCl)][PF6], Complex 4. Yield: 681 mg, 83%. Found: C, 50.38; H, 2.90; N, 6.75; Calcd for C35H24F6N4O3ClRuP: C, 50.64; H, 2.91; N, 6.75. FT-IR (KBr, cm−1): 1612 (νC=O). ESI MS: m/z (pos.) 685.06. 1H NMR (500 MHz, CD3CN): δ 9.00 (d, 1H), 8.82 (d, 1H), 8.50 (m, 4H), 8.42 (d, 1H), 8.39 (d, 1H), 8.05 (t, 1H), 8.02 (t, 1H), 7.95 (d, 1H), 7.82 (m, 3H), 7.73 (m, 3H), 7.60 (t, 1H), 7.53 (t, 1H), 7.38 (m, 3H), 7.18 (t, 1H), 7.16 (t, 1H). [Ru(bpy)2(5-hydroxyfla)][PF6], Complex 5. Yield: 677 mg, 85%. Found: C, 52.85; H, 3.12; N, 6.97; Calcd for C35H25F6N4O3RuP: C, 52.84; H, 3.17; N, 7.04. ESI MS: m/z (pos.) 651.10. 1H NMR (500 MHz, CD3CN): δ 9.06 (d, 1H), 8.98 (d, 1H), 8.78 (d, 1H), 8.74 (d, 1H), 8.69 (d, 1H), 8.63 (d, 1H), 8.21 (t, 1H), 8.15 (t, 1H), 8.05 (m, 3H), 7.96 (t, 1H), 7.91 (t, 2H), 7.77 (t, 1H), 7.67 (t, 1H) 7.59 (m, 1H), 7.55 (m, 2H), 7.34 (t, 1H), 7.28 (m, 2H), 6.82 (s, 1H), 6.62 (d, 1H), 6.52 (d, 1H). Complex 6 was crystallized in CHCl3/hexane, forming purple cubic crystals suitable for X-ray diffraction. Wavelength Dependent Photoreactions. As previously described, wavelength selective photoreactions were performed using O2 saturated solutions of complexes 1−5 cooled in an ice bath in the absence of light; reaction was initiated by illumination in the beam path of an Oriel Apex Quartz source with a 150 W Xe arc lamp with selective wavelength filters placed in the beam path. Optical filters used include an absorptive neutral density filter from Thor Laboratories (NE205B) and a 310 nm (±5 nm) notch-pass optical filter from Aulluxa Optics. The lamp transmission profiles and other details of these photochemical setups are given in SI 5. Kinetic Measurements. Time and temperature dependence measurements of the reactions of complexes 1−4 with oxygen were carried out in a screw-capped UV cuvette with broadband excitation in

With the assumption that the diradical excited state is localized within the 4-hydroxypyrone central ring of the flavonolate, the initial 2,3 diradical would react with dioxygen through a dioxetane intermediate, whereas the 2,4 diradical formed after ESIPT would precede an endoperoxide intermediate. Applying similar logic to the role of the metal ion cofactor in the flavonol dioxygenases, perhaps coordination of the flavonol to the metal ion promotes such a tautomeric shift, Scheme 8, which would Scheme 8

facilitate the 1,3-addition pathway and loss of CO by either photoexcitation or SET. Indeed, a recent report describes an extended polyaromatic flavonol with bimodal ESIPT emissions, whose quantum yield for CO release, which is characteristic of the 1,3-addition pathway, increases in the presence of Zn(II).48

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CONCLUSIONS In summary, a series of Ru(II) bis-bipyridyl flavonolate complexes undergo oxidative cleavage of the Ru-bound flavonol dependent on both light and oxygen. The complexes’ structures, photophysical and electrochemical properties, as well as their reactivity with oxygen were investigated in detail. Two distinct reaction product mixtures from 1,2- and 1,3additions of oxygen are produced by illumination into distinct excitation/emission manifolds. The two manifolds are attributed to tautomeric biradicals, which predict the observed reactivity patterns.

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EXPERIMENTAL SECTION

Materials and Methods. The different flavonol ligands used (3hydroxyflavone, 5-hydroxyflavone, 3,7-dihydroxyflavone, 4′-methyl-3hydroxyflavone, 4′-methoxy-3-hydroxyflavone, 4′-choloro-3-hydroxyflavone, and cis-dichloro(2,2′-bipyridine)ruthenium(II)chloride (Ru(bpy)2Cl2)) were obtained from Alfa-Aesar. Other chemicals were purchased from Sigma-Aldrich, and used as received. All air-sensitive manipulations were carried out using Schlenk techniques. Physical Measurements. Electronic adsorption spectra were recorded with an Agilent Technologies diode array spectrophotometer. UV−vis range excitation and emission spectra were recorded on a Hitachi F-4500 fluorescence spectrometer. FI-IR spectra were recorded with a Nicolet 6700 spectrophotometer; spectra of synthesized complexes are given in SI 9. Crystallographic data was collected at 110 K on a Bruker X8 Apex using Mo K radiation (λ = 0.71073 Å). The data were processed using the Bruker AXS SHELXTL software, version 6.10.40. Redox potentials were measured by cyclic voltammetry under anaerobic conditions using a CHI-760B potentiostat in dry-degassed CH3CN with 0.1 M tetrabutylammonium hexafluorophosphate (TBAPF6) as the supporting electrolyte. Measured potentials were corrected using a ferrocene standard, with the Fc/Fc+ couple set to 400 mV NHE. Accurate masses were resolved by an Accela Bundle Liquid Chromatograph (LC) coupled to a F


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Inorganic Chemistry the Agilent spectrometer (spectra taken at 5 s intervals over 4000 s) and monitored by the loss of the substrate absorbance at 530 nm. A Hakke F3 circulating bath was used to keep the reaction at a desired temperature (20−40 °C). In a series of assays, the solution of acetonitrile of complexes 1−4 (30−150 μM) was kept at a desired temperature under N2 for several minutes. Then, oxygen was bubbled into solution to replace N2. For oxygen and substrate dependence studies, samples of complexes 1−4 at various concentrations were kept in dry acetonitrile in a UV cuvette under N2 for several minutes and then different concentrations of oxygen in acetonitrile were added. The concentration of O2saturated acetonitrile stock solution, prepared by bubbling O2 through a solution of dry CH3CN, is 8.0 mM according to the literature.49 Solutions containing lower O2 concentrations were prepared by diluting the saturated O2 solution with N2 saturated acetonitrile solution using a gastight syringe. Likewise, for singlet oxygen reactivity assays, an O2-saturated aliquot was added to a solution of 30 μM complex 3 and varying concentration of quenchers (0.1−1 mM 9,10dimethyl anthracene or NaN3) in dry acetonitrile in a UV cuvette, and monitored by the loss of the substrate absorbance at 530 nm (SI 8).

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(4) Cao, G.; Sofic, E.; Prior, E. Antioxidant and Prooxidant Behavior of Flavonoids: Structure-Activity Relationships. Free Radical Biol. Med. 1997, 22, 749−760. (5) Van Hoof, L.; Van den Berghe, D. A.; Hatfield, G. M.; Vlietinck, A. Plant Antiviral Agents; VI.1 3-Methoxyflavones as Potent Inhibitors of Viral-Induced Block of Cell Synthesis. Planta Med. 1984, 50, 513− 517. (6) Villar, A.; Gasco, M. A.; Alcaraz, M. J. Anti-inflammatory and anti-ulcer properties of hypolaetin-8-glucoside, a novel plant flavonoid. J. Pharm. Pharmacol. 1984, 36 (12), 820−823. (7) Wei, B. L.; Lu, C. M.; Tsao, L. T.; Wang, J. P.; Lin, C. N. In Vitro Anti-Inflammatory Effects of Quercetin 3-O-Methyl Ether and Other Constituents from Rhamnus Species. Planta Med. 2001, 67, 745−747. (8) Huang, M.; Ferraro, T. In Phenolic Compounds in Food and their Effect on Health II; Huang, M. T., Ho, C. T., Lee, C. Y., Eds.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992; Chapter 2, p 507. (9) Fischer, M.; Mills, G. D.; Slaga, T. J. Inhibition of Mouse Skin Tumor Promotion by Several Inhibitors of Arachidonic Acid Metabolism. Carcinogenesis 1982, 3, 1243−1245. (10) Huang, M. T.; Wood, A. W.; Newmark, H. L.; Sayer, J. M.; Yagi, H.; Jerina, D. M.; Conney, A. H. Inhibition of the Mutagenicity of Bayregion Diol-epoxides of Polycyclic Aromatic Hydrocarbons by Phenolic Plant Flavonoids. Carcinogenesis 1983, 4, 1631−1637. (11) Wollenweber, E. In Flavonoids: Advances in Research; Harborne, J. B., Mabry, T. J., Eds.; Chapman & Hall: London, 1982. (12) Schaab, M. R.; Barney, B. M.; Francisco, W. A. Kinetic and spectroscopic studies on the quercetin 2, 3-dioxygenase from Bacillus subtilis. Biochemistry 2006, 45, 1009−1016. (13) Nianios, D.; Thierbach, S.; Steimer, L.; Lulchev, P.; Klostermeier, D.; Fetzner, S. Nickel quercetinase, a “promiscuous” metalloenzyme: metal incorporation and metal ligand substitution studies. BMC Biochem. 2015, 16, 10. (14) Bugg, T.; Ramaswamy, S. Non-heme iron-dependent dioxygenases: unraveling catalytic mechanisms for complex enzymatic oxidations. Curr. Opin. Chem. Biol. 2008, 12, 134−140. (15) Fetzner, S. Ring-Cleaving Dioxygenases with a Cupin Fold. Appl. Environ. Microbiol. 2012, 78, 2505−2514. (16) Gopal, B.; Madan, L. L.; Betz, S. F.; Kossiakoff, A. A. The crystal structure of a quercetin 2,3-dioxygenase from Bacillus subtilis suggests modulation of enzyme activity by a change in the metal ion at the active site. Biochemistry 2005, 44, 193−201. (17) Jeoung, J. H.; Nianios, D.; Fetzner, S.; Dobbek, H. Quercetin 2, 4-Dioxygenase Activates Dioxygen in a Side-On O2−Ni Complex. Angew. Chem., Int. Ed. 2016, 55, 3281−3284. (18) (a) Kaizer, J.; Barath, G.; Pap, J. S.; Speier, G. Manganese and Iron Flavonolates as Flavonol 2,4-Dioxygenase Mimics. Chem. Commun. 2007, 5235−5237. (b) Matuz, A.; Giorgi, M.; Speier, G.; Kaizer, J. Structural and Functional Comparison of Manganese-, Iron-, Cobalt-, Nickel-, and Copper-Containing Biomimic Quercetinase Models. Polyhedron 2013, 63, 41−49. (c) Balogh-Hergovich, É.; Kaizer, J.; Speier, G.; Fulop, V.; Parkanyi, L. Quercetin 2,3Dioxygenase Mimicking Ring Cleavage of the Flavonolate Ligand Assisted by Copper. Synthesis and Characterization of Copper(I) Complexes [Cu(PPh3)2(fla)] (fla = Flavonolate) and [Cu(PPh3)2(Obs)] (O-bs = O-Benzoylsalicylate). Inorg. Chem. 1999, 38, 3787−3795. (19) (a) Grubel, K.; Rudzka, K.; Arif, A. M.; Klotz, K. L.; Halfen, J. A.; Berreau, L. M. Synthesis, Characterization, and Ligand Exchange Reactivity of a Series of First Row Divalent Metal 3-Hydroxyflavonolate Complexes. Inorg. Chem. 2010, 49, 82−96. (b) Grubel, K.; Laughlin, B. J.; Maltais, T. R.; Smith, R. C.; Arif, A. M.; Berreau, L. M. Photochemically-induced Dioxygenase-type CO-release Reactivity of Group 12 Metal Flavonolate Complexes. Chem. Commun. 2011, 47, 10431−10433. (20) (a) Barhacs, L.; Kaizer, J.; Speier, G. Kinetics and Mechanism of the Stoichiometric Oxygenation of the Ionic Zinc(II) Flavonolate Complex [Zn(fla)(idpa)]ClO4 (fla = flavonolate; idpa = 3,3′iminobis(N,N-dimethylpropylamine)). J. Mol. Catal. A: Chem. 2001, 172, 117−125. (b) Kaizer, J.; Pap, J.; Speier, G.; Párkányi, L. The

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b01384. Crystallographic data, FT-IR, 1H NMR, ESI-MS, cyclic voltammograms, action spectra, and chemiluminescence spectra (PDF) Accession Codes

CCDC 1553145 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Lauren M. Harris: 0000-0001-8165-3852 Mohammad A. Omary: 0000-0002-3247-3449 Patrick J. Farmer: 0000-0001-9911-999X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS P.J.F. acknowledges support from National Science Foundation (CHE-1057942) and from Baylor University for this project. M.A.O. greatly acknowledges support of his group’s contributions from the Welch Foundation (B-1542) and the National Science Foundation (CHE-1413641). We also thank Dr. Jay Winkler for helpful discussions.

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REFERENCES

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