Article pubs.acs.org/IC
Aerobic Oxidation of an Osmium(III) N‑Hydroxyguanidine Complex To Give Nitric Oxide Jing Xiang,†,‡,§ Qian Wang,†,§ Shek-Man Yiu,† Wai-Lun Man,† Hoi-Ki Kwong,† and Tai-Chu Lau*,† †
Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong, Hong Kong College of Chemistry and Environmental Engineering, Yangtze University, Jingzhou, Hubei 434020, People’s Republic of China
‡
S Supporting Information *
ABSTRACT: The aerobic oxidation of the N-hydroxyguanidinum moiety of Nhydroxyarginine to NO is a key step in the biosynthesis of NO by the enzyme nitric oxide synthase (NOS). So far, there is no chemical system that can efficiently carry out similar aerobic oxidation to give NO. We report here the synthesis and X-ray crystal structure of an osmium(III) N-hydroxyguanidine complex, mer[Os I I I {NHC(NH 2 )(NHOH)}(L)(CN) 3 ] − (OsGOH, HL = 2-(2hydroxyphenyl)benzoxazole), which to the best of our knowledge is the first example of a transition metal N-hydroxyguanidine complex. More significantly, this complex readily undergoes aerobic oxidation at ambient conditions to generate NO. The oxidation is pH-dependent; at pH 6.8, fac-[Os(NO)(L)(CN)3]− is formed in which the NO produced is bound to the osmium center. On the other hand, at pH 12, aerobic oxidation of OsGOH results in the formation of the ureato complex [OsIII(NHCONH2)(L)(CN)3]2− and free NO. Mechanisms for this aerobic oxidation at different pH values are proposed.
■
INTRODUCTION Guanidine and related compounds are important molecules in biological systems. In particular, the guanidinium moiety of the amino acid arginine plays an important role in the biosynthesis of nitric oxide, which is an important signaling molecule that regulates various biological processes, including those related to the physiology of mammalian cardiovascular, immune, and nervous systems.1−5 NO is synthesized in our body by the heme enzyme nitric oxide synthase (NOS).6−9 NOS catalyzes the two-step oxidation of arginine to NO and citrulline using O2 and NADPH (Figure 1).10−15 The first step involves the
during the oxidation process. However, a radical-type mechanism that involves initial coordination of NOHA to the Fe(III) heme through the N-hydroxy nitrogen has also been proposed.16 The oxidation of arginine/guanidine and N-hydroxyarginine/ N-hydroxyguanidine derivatives to give NO using various chemical reagents has been studied as models for NOS.17 For example, [Fe(P)Cl] (P = tetrakis(perfluorophenyl)porphyrin),18 K[Ru(Hedta)Cl],19 and K3Fe(CN)620 have been reported to catalyze the oxidation of these substrates to NO using H2O2 as the oxidant. However, metal-mediated oxidation of these substrates using O2 as oxidant has yet to be achieved, although Groves reported that [Fe(OH)P′] (P′ = tetramesityl porphyrin) is able to catalyze the aerobic oxidation of fluorenone oxime, which is used as a model compound of Nhydroxyguanidine.21 We recently reported that an osmium(VI) nitrido complex bearing a tridentate Schiff base ligand reacts with excess cyanide to generate a novel hydrogen cyanamide complex, with the tridentate Schiff base ligand rearranged to a deprotonated bidentate 2-(2-hydroxyphenyl)benzoxazole ligand (L−) (Figure 2).22 We report herein that this osmium(III) hydrogen cyanamide complex readily reacts with NH2OH·HCl to generate an osmium(III) N-hydroxyguanidine complex (OsGOH), which to the best of our knowledge is the first example of a transition metal N-hydroxyguanidine complex. More significantly, we show that this complex readily
Figure 1. Oxidation of L-arginine by NOS.
hydroxylation of the guanidinium moiety of arginine to give Nhydroxyarginine (NOHA), which is then converted to NO and citrulline in the second step. The mechanism of the first step is believed to involve H atom abstraction/O rebound processes that are analogous to cytochrome P450 chemistry. The second step is less certain, but it is generally believed that it involves nucleophilic attack of an iron(III) hydroperoxido species at the N-hydroxyguanidinium moiety of NOHA;14,15 in this mechanism, the NOHA is not coordinated to the Fe(III) heme center © XXXX American Chemical Society
Received: March 16, 2016
A
DOI: 10.1021/acs.inorgchem.6b00652 Inorg. Chem. XXXX, XXX, XXX−XXX
Article
Inorganic Chemistry
Figure 4. X-ray structures of (a) OsGOH, (b) OsNO-a, and (c) OsNHCONH2 anions. Selected bond parameters (Å, deg) of OsGOH: Os1−N4 2.046(2), N4−C17 1.318(4), N6−C17 1.328(4), N7−C17 1.354(4), O1−N7 1.393(3), C17−N4−Os1 131.4(2); OsNO-a: Os1−N4 1.791(7), O1−N4 1.158(9), O1−N4−Os1 172.0(7); OsNHCONH2: Os1−N4 2.011(4), N4−C17 1.336(7), N6−C17 1.365(9), O1−C17 1.251(7), C17−N4−Os1 135.4(4).
Figure 2. Reaction of an osmium(VI) nitrido complex with excess KCN.
undergoes pH-dependent aerobic oxidation under ambient conditions to generate nitric oxide.
■
RESULTS AND DISCUSSION Synthesis and Characterization of Osmium Complexes. The synthesis of OsGOH and its aerobic oxidation in CH3OH/H2O at pH 6.8 and 12 to give various products are summarized in Figure 3. Reaction of [OsIII(NHCN)(L)-
(1.354(4) Å), suggesting that there is extensive delocalization of the π electrons in the ligand. The three N−C−N intra-angles in the guanidine ligand are 122.9(3), 120.4(3), and 116.6(3)°, respectively with ΣNCN = 360°, indicating its coplanar character. Inter- and intramolecular H-bonding are observed in the complex (Figure S4). OsGOH undergoes aerobic oxidation when dissolved in CH3OH, with a half-life of around 70 h under 1 atm O2 at 23 °C ([OsGOH] = 0.3 mM). The reaction is faster when water is added; in CH3OH/H2O (1:4 v/v) at pH 6.8, the half-life is around 15 h under 1 atm O2. Aerobic oxidation of OsGOH results in the formation of fac-[Os(NO)(L)(CN)3]− (OsNO) as the predominant product, which could be isolated in 62% yield. The oxidation of OsGOH can also be achieved using other oxidants such as H2O2. OsNO crystallizes from CH2Cl2/Et2O as a mixture of two conformational isomers (OsNO-a and OsNO-b), as reviewed by X-ray crystallography, as a result of the two aromatic rings of ligand L− adopting two different conformations (up, down and down, up). The two isomers could be separated due to their different crystal shapes. OsNO-a and OsNO-b have different solid-state IR spectra, but their UV/vis and 1H NMR spectra in solution are identical, suggesting they have the same structure in solution. OsNO is diamagnetic, as evidenced by the sharp resonances in the normal range in the 1H NMR spectra, consistent with its formulation as the {OsNO}6 species.23 In the IR spectrum (KBr), there is a strong ν(NO) band at 1804 cm−1 for OsNO-a (1816 cm−1 for OsNO-b), which is shifted to the expected wavenumber of 1764 cm−1 for ν(15N O) (Figure S5). The ESI/MS (−ve mode) of OsNO-a and OsNO-b in CH3OH exhibits a predominant peak at m/z 510, which is assigned to the parent ion [M]− (Figure S6). Figure 4b shows the X-ray structure of OsNO-a (Figure S7 for OsNO-b). Notably, the three cyanide ligands have rearranged from meridional in OsGOH to facial configuration, with the NO ligand trans to a cyanide ligand. The N−O bond distance is 1.158(9) Å, and the Os−N1−O1 bond angle is 172.0(7)°. When aerobic oxidation of OsGOH was carried out at pH 12, a mixture of two complexes, [OsIII(NHCN)(L)(CN)3]2− (OsNHCN, 75% yield) and [OsIII(NHCONH2)(L)(CN)3]2− (OsNHCONH2, 15% yield), were isolated instead, and only a trace amount of OsNO was detected by ESI/MS. OsNHCONH2 is paramagnetic with a room temperature magnetic moment of μeff ∼ 1.7 μB, indicating that the +III oxidation state of osmium is retained. The IR spectrum shows strong ν(C N) bands at 2076 and 2108 cm−1, ν(N−H) bands at 3248 and 3167 cm−1, and a ν(CO) band at 1611 cm−1. The ESI/MS of OsNHCONH2 in CH3OH (−ve mode) shows two major
Figure 3. Synthesis and aerobic oxidation of OsGOH to give various products.
(CN)3]2− (OsNHCN) with excess NH2OH·HCl in CH3OH affords mer-[Os III (NHC(NH 2 )(NHOH))(L)(CN) 3 ] − (OsGOH) in 45% yield. The formation of OsGOH probably involves initial protonation of Os−NHCN to give the Os− NCNH2, followed by nucleophilic attack of NH2OH at the carbon atom, since OsNHCN does not react with NH2OH under similar conditions. In the IR spectrum, there are strong ν(CN) bands around 1630 cm−1 and ν(N−H) bands at 3450, 3343, and 3319 cm−1, which are due to the GOH ligand. Strong ν(CN) bands are also found at 2080−2120 cm−1 (Figure S1). The electrospray ionization mass spectrum (ESI/ MS) of OsGOH in CH3OH shows a predominant peak at m/z 555 (−ve mode), which is assigned to its parent anion [M]− (Figure S2). OsGOH has a room temperature magnetic moment of μeff = 1.8 μB, which is consistent with low-spin d5 configuration of osmium(III). The cyclic voltammogram (CV) of OsGOH shows a reversible OsIV/III couple at E1/2 = 0.09 V (vs Cp2Fe+/0) and an irreversible reduction wave at Epc = −1.26 V (Figure S3). The structure of OsGOH has been determined by X-ray crystallography (Figure 4a). The osmium center is octahedrally coordinated by a bidentate L− ligand, a N-bonded parent Nhydroxyguanidine ligand (GOH), and three cyanides in mer configuration. In the N-hydroxyguanidine ligand, the C17−N4 (1.318(4) Å) and C17−N6 (1.328(4) Å) bond distances are similar and are slightly shorter than the C17−N7 distance B
DOI: 10.1021/acs.inorgchem.6b00652 Inorg. Chem. XXXX, XXX, XXX−XXX
Article
Inorganic Chemistry peaks at m/z 539 and 878, which are assigned to [M]− and [M + PPh4]−, respectively (Figure S8). The CV displays a quasireversible/irreversible wave at ca. 0.02 V, which is tentatively assigned to the OsIV/III couple; there is also an irreversible reduction wave at −0.52 V (vs Cp2Fe+/0) (Figure S9). Unlike OsNO, the X-ray crystal structure of OsNHCONH2 shows that the mer configuration of three cyanide ligands in OsNHCONH2 is retained, with the ureato ligand trans to the phenolato oxygen O2 (Figure 4c). The Os1−N4 bond distance is 2.011(4) Å, which is comparable with that of Os−N(HCN) (2.020(4) Å) in OsNHCN,22 consistent with the ureato ligand bearing a negative charge. We have previously reported the Xray crystal structure of OsNHCN, which shows that the three cyanides also have a mer configuration.22 Mechanistic Studies. The oxidation of OsGOH at pH 6.8 and 12 was monitored by ESI/MS. The mass spectra of the various ions observed are depicted in Figure 5. The MS of
Figure 6. ESI/MS of OsGOH in CH3OH/H2O (1:4 v/v) under O2 (1 atm) at 23 °C at various time intervals at (a) pH 6.8 and (b) pH 12.
The oxidation of OsGOH under neutral conditions was also carried out using H2O2 (Figure S12). The reaction with H2O2 is faster than with O2, and the half-life is around 3 h at 23 °C for the reaction of 0.11 mM of OsGOH with 80 equiv of H2O2 in CH3OH (10 mL) under argon. The reaction is less clean than aerobic oxidation, but OsNO is still the predominant product. However, additional intermediate peaks at m/z 554 and 553 were observed, which are absent in aerobic oxidation. The m/z 554 peak is assigned to [OsIII(NHCNH2(NHO))(L)(CN)3]− that is formed by the loss of a H atom from the hydroxyl group of OsGOH. Iminoxy radical species (−NHO•) have been proposed as intermediates in the oxidation of N-hydroxyguanidines by chemical reagents24−26 and by NOS.17 In this case, the iminoxy species is probably stabilized via coordination to the osmium center. The peak at m/z 553 is assigned to the nitrosoamidine species [OsIII(NHCNH2(NO))(L)(CN)3]− that is formed by further loss of a H atom from [OsIII(NHCNH2(NHO))(L)(CN)3]−. Similar nitroso species have also been proposed as intermediates in the chemical and biological oxidation of N-hydroxyguanidines.20,27−29 The m/z 554 and 553 peaks are not observed in aerobic oxidations, presumably because in aerobic oxidation these intermediates are formed more slowly than their subsequent reactions. The oxidation of OsGOH by 1 atm O2 at pH 12 was also monitored by ESI/MS (Figure 6b). After 1 h, a major peak at m/z 554 (one m/z unit less than the parent ion of OsGOH) was found together with three less intense peaks at m/z 539 (OsNHCONH2), 521 (OsNHCN), and 480 (Os). The relative intensity of the m/z 554 peak decreased with time, while those at m/z 521 and 480 increased. After 24 h, the latter two peaks became predominant. The half-life of this reaction is around 10 h at 23 °C. In contrast to aerobic oxidation at pH 6.8, at pH 12, only a trace amount of OsNO (m/z 510) was detected at the end of the reaction. However, peaks at m/z 46 and 62 could be observed in the MS, which are assigned to NO2− and NO3−, respectively (Figure S13). NO2− and NO3− were also analyzed by ion chromatography, which showed the presence of 50.2% of NO2− and 24.8% of NO3− (Figure S14). These results suggest that free NO is formed in aerobic oxidation at pH 12, which is converted to NO2− and NO3− via the reactions shown in eqs 1−4). The NO2−/NO3− ratio depends on the relative rates of reactions 2 and 4.
Figure 5. Mass spectra of various complex ions observed by ESI/MS. Although OsNHCONH2 and OsNHCN have a 2− charge, the 1− ions can be readily observed in the MS due to loss of an electron during the electrospraying process. The 2− ions can also be observed at m/z = 269.5 and 260.5, respectively (Figure S11).
OsGOH (0.28 mM) in CH3OH/H2O (1:4 v/v) at pH 6.8 shows the parent peak at m/z 555. Upon exposure to 1 atm O2 at 23 °C, the relative intensity of this peak gradually decreased, and a peak at m/z 510 due to OsNO gradually appeared. There are also minor peaks at m/z 539 (OsNHCONH2), 521 (OsNHCN), 494 (OsN), and 480 (Os) in the MS. The Os peak most likely came from in-source fragmentation of OsN. The relative intensity of OsNO increased with time, and after 48 h, it became the predominant species (Figure 6a). In the positive region, a peak at m/z 43 (+ve mode) was also observed, which can be assigned to [NH2CN + H]+ (Figure S10); this species should arise from the oxidative cleavage of the GOH ligand (NHC(NH2)NHOH), which would give NO and NH2CN.
2NO + O2 → 2NO2
(1)
NO + NO2 → N2O3
(2) −
N2O3 + H 2O → 2NO2 + 2H C
+
(3) DOI: 10.1021/acs.inorgchem.6b00652 Inorg. Chem. XXXX, XXX, XXX−XXX
Article
Inorganic Chemistry 2NO2 + H 2O → NO3− + NO2− + 2H+
nm (Figure S16), presumably due to the formation of an osmium(IV) species. This observation further supports the conclusion that the oxidation of OsGOH by O2 or H2O2 at neutral conditions did not go through an osmium(IV) intermediate. On the other hand, the aerobic oxidation of OsGOH at pH 12 resulted in the rapid appearance of an intense peak at 538 nm in the UV/vis spectrum, with isosbestic points at 317, 359, and 613 nm, and a pseudo-first-order rate constant of 7.6 × 10−3 s−1 at 25.0 °C (Figure 9). A similar spectral change also
(4)
In order to probe the origin of NO formed from the aerobic oxidation of OsGOH, various 15N and 18O-labeled OsGOH complexes were prepared and their oxidation products were monitored by ESI/MS. Results are summarized in Figure 7 and
Figure 7. Preparation and oxidation of compounds.
15
N- and
18
O-labeled Figure 9. Spectral changes at 50 s intervals for the oxidation of OsGOH (5.00 × 10−5 M) by O2 in CH3OH/H2O/NaOH (pH 12) at 298.0 K.
Figures S2 and S6. When Os−NHC(NH2)(15NHOH) is oxidized, Os−15NO is produced, while oxidation of Os−NH C(NH2) (NH18OH) gives Os−N18O. These results together with control experiments demonstrate unambiguously that the N and O atoms in OsNO arise exclusively from the −NHOH moiety of the N-hydroxyguanidine ligand. This finding is similar to arginine oxidation by NOS, where the NO product is shown to originate exclusively from the N-hydroxy group of Nhydroxyarginine.30 The oxidation of OsGOH was also monitored by UV/vis spectrophotometry. The oxidation of OsGOH by H2O2 at pH 6.8 showed only slight changes in the UV/vis spectrum in the first 30 min (Figure 8a); however, during this period, ESI/MS
occurred when OsGOH was treated with Na2IrCl6 at pH 12 (Figure 10).31 These results suggest that, at pH 12, aerobic oxidation goes through an osmium(IV) intermediate, which corresponds to the peak at m/z 554 observed in the MS.
Figure 10. Spectral changes for the reaction of OsGOH (5.00 × 10−5 M) with Na2IrCl6 (5.00 × 10−5 M) in CH3OH/H2O/NaOH (pH 12) at 298.0 K under argon.
Figure 8. (a) Spectral changes at 300 s intervals for the first phase of the reaction of OsGOH (1.40 × 10−4 M) with H2O2 (2.80 × 10−3 M) in MeOH/H2O (1:4 v/v, pH 6.8) at 298.0 K. Inset shows the expanded spectrum from 450 to 750 nm. (b) Spectral changes at 6000 s intervals for the second phase of the reaction.
Based on our experimental results, the proposed mechanisms for the aerobic oxidation of OsGOH at pH 6.8 and 12 are shown in Figure 11. At pH 6.8, we propose that the Nhydroxyguanidine ligand first transfers a H atom to O2 or O2− to generate an osmium iminoxy intermediate, which then loses another H atom to give a nitrosoamidine. The latter species then undergoes linkage isomerization followed by oxidative cleavage to give OsNO and NH2CN. OsNO and NH3CN+ have been observed in ESI/MS; the complex has also been isolated in 62% yield. Since isotopic labeling experiments demonstrate that NO is derived from the −NHOH moiety of GOH, which is not directly bonded to the Os(III) center in OsGOH, this means that in order to form the OsNO product, a linkage isomerization process has to occur during the
showed the appearance of intermediate peaks at m/z 554 and 553. This suggests that these two intermediates are still osmium(III) species with little change in the coordination environment. After 30 min, the absorption peaks at 540, 357, 325, and 290 nm gradually decreased, and the final spectrum was consistent with OsNO mixed with minor quantities of OsNHCONH2 and OsNHCN (Figures 8b and S15), as also observed in ESI/MS. OsGOH was also reacted with a oneelectron oxidant Na2IrCl6 (E0 = 0.9 V vs NHE) at pH 6.8, and the reaction was followed by UV/vis. In this case, an intense peak appeared at 599 nm, with isosbestic points at 368 and 448 D
DOI: 10.1021/acs.inorgchem.6b00652 Inorg. Chem. XXXX, XXX, XXX−XXX
Article
Inorganic Chemistry
an O-alkylated N-hydroxyguanidine ligand have been reported.32 However, these complexes are not known to undergo aerobic oxidation to give nitric oxide. O-Alkylated hydroxyguanidine is also a very poor substrate of nitric oxide synthase (with very little NO production).33 On the other hand, we demonstrate that N-hydroxyguanidine bound to an osmium(III) center readily undergoes aerobic oxidation at ambient conditions to give NO. The oxidation is found to be pHdependent. At neutral pH, the NO is bound to the osmium center and free NH2CN is formed; however, at high pH, free NO is generated. Our results also suggest that a new class of NO-releasing agents may be designed based on metal Nhydroxyguanidine precursors.
■
EXPERIMENTAL SECTION
Materials. (PPh4)2[OsIII(NHCN)(L)(CN)3] (OsNHCN) was synthesized according to a literature method.22 [nBu4N]PF6 (Aldrich) for electrochemistry was recrystallized three times from ethanol and dried under vacuum at 120 °C for 24 h. Acetonitrile (Aldrich) for electrochemistry was distilled over calcium hydride. All other chemicals were of reagent grade and used without further purification. Physical Measurements. IR spectra were obtained as KBr discs using a Nicolet 360 FTIR spectrophotometer. UV/vis spectra were recorded using a PerkinElmer Lambda 19 spectrophotometer in 1 cm quartz cuvettes. Elemental analysis was done using an Elementar Vario EL analyzer. Magnetic measurements were carried out at room temperature using a Sherwood magnetic balance (Mark II). Electrospray ionization mass spectrometry was performed using a PE-SCIEX API 365 triple quadruple mass spectrometer. 1H NMR spectra were recorded on a Bruker AV400 (400 MHz) FT-NMR spectrometer. Chemical shifts (ppm) were reported relative to tetramethylsilane (Me4Si). Cyclic voltammetry was performed using a PAR model 273 potentiostat with a glassy carbon working electrode, a Ag/AgNO3 (0.1 M in CH3CN) reference electrode, and a Pt wire counter electrode. Ferrocene (Cp2Fe) was used as an internal standard. X-ray Crystallography. Details of the intensity data collection and crystal data are given in Table S1. The X-ray diffraction data were collected on an Oxford Diffraction Gemini S Ultra X-ray single-crystal diffractometer using graphite-monochromatized Cu Kα radiation (λ = 1.54178 Å). The structure was solved by direct methods employing the SHELXL-97 program. Full-matrix least-squares refinement on F2 was used in the structure refinement. The positions of H atoms were calculated based on the riding mode with thermal parameters equal to 1.2 times those of the associated C atoms and participated in the calculation of the final R indices.34 In the final stage of least-squares refinement, all non-hydrogen atoms were refined anisotropically. Preparation of (PPh 4 )[Os III {NHC(NH 2 )(NHOH)}(L)(CN) 3 ] (OsGOH). NH2OH·HCl (139 mg, 2.0 mmol) was added to a red solution of (PPh4)2[OsIII(NHCN)(L)(CN)3] (239.8 mg, 0.20 mmol) in methanol, and the resulting solution was stirred at room temperature for 5 h under argon. The solvent was then removed, and the resulting purple solid was washed with H2O (3 × 5 mL) and then air-dried. Yield: 83.2 mg, 45%. Crystals suitable for X-ray crystallography were obtained by slow diffusion of diethyl ether into a methanolic solution of the compound. Anal. Calcd for C41H33N7O3OsP·CH3OH·2H2O: C, 52.49; H, 4.30; N, 10.20. Found: C, 52.38; H, 4.03; N, 10.40. IR (KBr, cm−1): ν(N−H) 3450, 3343, 3319; ν(O−H) 2819; ν(CN) 2081, 2120; ν(C = N) 1627, 1608. UV/vis (CH3CN): λmax[nm] (ε [mol−1 dm3 cm−1]) 272 (14200), 291 (12200), 338 (11800), 516 (2530). ESI/MS: m/z 555 [M]−. The 98% 15N-labeled (PPh4)[OsIII{15NHCNH2(NHOH)}(L)(CN)3] was prepared by the same method except 98% 15N-labeled [OsVI(15N)(L)(Cl)(H2O)] was used as the starting material. IR (KBr, cm−1): ν(N−H) 3449, 3332, 3321. ESI-MS: m/z 556 [M]−. The 98% 15 N-labeled (PPh4)[OsIII{NHCNH2(15NHOH)}(L)(CN)3] was obtained by a similar procedure using 98% 15N-labeled NH2OH·HCl. IR (KBr, cm−1): ν(N−H) 3449, 3342, 3310. ESI-MS: m/z 556 [M]−. The 10% 18O-labeled (PPh4)[OsIII{NHCNH2(NH18OH)}(L)(CN)3] was
Figure 11. Proposed mechanism for aerobic oxidation of OsGOH at (a) pH 6.8 and (b) pH 12.
oxidation process. This is supported by the observed change in configuration of the three cyanide ligands from meridional in OsGOH to facial in OsNO. At pH 12, a species in the MS (m/z 554), which has one mass unit less than the parent ion, is also observed. We propose that this species is an Os(IV) intermediate bearing a deprotonated N-hydroxyguanidine ligand rather than an iminoxyl complex. This species is formed by the loss of 1H+/ 1e from OsGOH. This assignment is supported by UV/vis spectrophotometry. At high pH, it is reasonable to assume that deprotonation of Os−NH− occurs and the resulting species should be more easily oxidized by O2 to generate OsIV. The resulting OsIV−N bond order should be higher than the starting OsIII−NH and hence linkage isomerization, which would involve breaking of the Os−N bond, does not occur in this case. The Os(IV) intermediate is then oxidized by two electrons to give an Os(IV) nitrosoamidine species, which then undergoes parallel oxidative cleavage to give OsHNCN and its hydrated form, OsNHCONH2. The meridional configurations of the three cyanides are retained in these two products, which is evidence that linkage isomerization has not occurred, and hence free NO is produced as a result. Oxidation of NO followed by dimerization and hydrolysis gives a mixture of NO2− and NO3−, which can be detected by ESI/MS and ion chromatography.
■
CONCLUSIONS In conclusion, we have reported the synthesis and structure of an osmium(III) N-hydroxyguanidine complex, mer[OsIII{NHC(NH2)(NHOH)}(L)(CN)3]− (HL = 2-(2hydroxyphenyl)benzoxazole), which to the best of our knowledge is the first example of a transition metal Nhydroxyguanidine complex. Platinum(II) complexes containing E
DOI: 10.1021/acs.inorgchem.6b00652 Inorg. Chem. XXXX, XXX, XXX−XXX
Article
Inorganic Chemistry obtained using 10% 18O-labeled NH218OH·HCl.35 ESI-MS: m/z 555 [M]−. Preparation of fac-(PPh4)[OsII(NO)(L)(CN)3] (OsNO-a and OsNO-b). OsGOH (20 mg, 0.022 mmol) was dissolved in CH3OH/H2O (1:4 v/v, 50 mL), and the solution was stirred at room temperature under O2 for 1 week. During this period, the red solution gradually turned gray. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using acetone/CH2 Cl2 (1:4 v/v) as eluent. Recrystallization by slow diffusion of diethyl ether into a CH2Cl2 solution of the residue in the dark afforded light yellow single crystals suitable for X-ray diffraction analysis. Yield: 11.5 mg, 62%. Anal. Calcd for C40H28N5O3OsP: C, 56.66; H, 3.33; N, 8.26. Found: C, 56.46; H, 3.53; N, 8.03. 1H NMR (400 MHz, CDCl3): δ 8.70−8.73 (m, 1H, Ar− H), 7.96 (dd, J = 8.2, 1.8 Hz, 1H, Ar−H), 7.86−7.93 (m, 4H, Ar−H), 7.76−7.83 (m, 8H, Ar−H), 7.65−7.72 (m, 8H, Ar−H), 7.54−7.59 (m, 1H, Ar−H), 7.37−7.47 (m, 2H, Ar−H), 7.31 (ddd, J = 8.7, 6.9, 1.9 Hz, 1H, Ar−H), 7.07−7.12 (m, 1H, Ar−H), 6.69 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H, Ar−H); IR (KBr, cm−1): ν(CN) 2151, 2135; ν(NO) 1803. UV/vis (CH3CN): λmax [nm] (ε [mol−1 dm3 cm−1]) 296 (11700), 367 (6860). ESI-MS: (m/z) 510 [M] − . For (PPh 4 )[Os II (L)(CN)3(15NO)]: IR (KBr, cm−1): ν(15NO) 1764. ESI-MS: (m/z) 511 [M]−; In solution, OsNO-a and OsNO-b have the same UV and 1 H NMR data. Preparation of (PPh4)2[OsIII(NHCONH2)(L)(CN)3] (OsNHCONH2). OsGOH (30 mg, 0.034 mmol) and PPh4Cl (12.5 mg, 0.034 mmol) were dissolved in methanol (15 mL) in the presence of Et3N (500 μL), and the solution was stirred at room temperature for 24 h. Slow diffusion of diethyl ether into resulting solution gave dark red block crystals. Yield: 6.20 mg, 15%. Anal. Calcd for C65H51N6O3OsP2·3H2O: C, 61.24; H, 4.70; N, 6.37. Found: C, 61.45; H, 4.52; N, 6.62. IR (KBr, cm−1): ν(CN) 2076, 2108; ν(C = O) 1611. UV/vis (CH3CN): λmax [nm] (ε [mol−1 dm3 cm−1]) 291 (26290), 375sh (12000), 341 (20680), 508 (3939). ESI-MS: (m/z) 539 [M]−, 878 [M + PPh4]−.
■
(2) Moncada, S.; Palmer, R. M., Jr.; Higgs, E. A. Pharmacol. Rev. 1991, 43, 109−142. (3) Murad, F. Angew. Chem., Int. Ed. 1999, 38, 1856−1868. (4) Furchgott, R. F. Angew. Chem., Int. Ed. 1999, 38, 1870−1880. (5) Ignarro, L. J. Angew. Chem., Int. Ed. 1999, 38, 1882−1892. (6) Xie, W. W.; Cho, H.; Kashiwabara, Y.; Baum, M.; Weidner, J. R.; Elliston, K.; Mumford, R.; Nathan, C. J. Biol. Chem. 1994, 269, 28500− 28505. (7) Bredt, D. S.; Snyder, S. H. Proc. Natl. Acad. Sci. U. S. A. 1990, 87, 682−685. (8) Moncada, S.; Palmer, R. M.; Higgs, E. A. Biochem. Pharmacol. 1989, 38, 1709−1715. (9) Stuehr, D. J.; Nathan, C. F. J. Exp. Med. 1989, 169, 1543−1555. (10) Stuehr, D. J.; Santolini, J.; Wang, Z. Q.; Wei, C. C.; Adak, S. J. Biol. Chem. 2004, 279, 36167−36170. (11) Davydov, R.; Sudhamsu, J.; Lees, N. S.; Crane, B. R.; Hoffman, B. M. J. Am. Chem. Soc. 2009, 131, 14493−14507. (12) Rosen, G. M.; Tsai, P.; Pou, S. Chem. Rev. 2002, 102, 1191− 1199. (13) Wei, C. C.; Crane, B. R.; Stuehr, D. J. Chem. Rev. 2003, 103, 2365−2384. (14) Wei, C. C.; Wang, Z. Q.; Tejero, J.; Yang, Y. P.; Hemann, C.; Hille, R.; Stuehr, D. J. J. Biol. Chem. 2008, 283, 11734−11742. (15) Woodward, J. J.; Chang, M. M.; Martin, N. I.; Marletta, M. A. J. Am. Chem. Soc. 2009, 131, 297−305. (16) Groves, J. T.; Wang, C. C. Y. Curr. Opin. Chem. Biol. 2000, 4, 687−695. (17) Cai, T. B.; Lu, D.; Wang, P. G. Curr. Top. Med. Chem. 2005, 5, 721−736. (18) Keseru, G. M.; Balogh, G. T.; Karancsi, T. Bioorg. Med. Chem. Lett. 2000, 10, 1775−1777. (19) Marmion, C. J.; Murphy, T.; Nolan, K. B. Chem. Commun. 2001, 1870−1871. (20) Fukuto, J. M.; Wallace, G. C.; Hszieh, R.; Chaudhuri, G. Biochem. Pharmacol. 1992, 43, 607−613. (21) Wang, C. C. Y.; Ho, D. M.; Groves, J. T. J. Am. Chem. Soc. 1999, 121, 12094−12103. (22) Xiang, J.; Man, W. L.; Yiu, S. M.; Peng, S. M.; Lau, T. C. Chem. Eur. J. 2011, 17, 13044−13051. (23) Enemark, J. H.; Feltham, R. D. Coord. Chem. Rev. 1974, 13, 339−406. (24) Korth, H. G.; Sustmann, R.; Thater, C.; Butler, A. R.; Ingold, K. U. J. Biol. Chem. 1994, 269, 17776−17779. (25) Maldotti, A.; Molinari, A.; Vitali, I.; Ganzaroli, E.; Battioni, P.; Mathieu, D.; Mansuy, D. Eur. J. Inorg. Chem. 2004, 2004, 3127−3135. (26) Schade, D.; Kotthaus, J.; Klein, N.; Kotthaus, J.; Clement, B. Org. Biomol. Chem. 2011, 9, 5249−5259. (27) Fukuto, J. M.; Stuehr, D. J.; Feldman, P. L.; Bova, M. P.; Wong, P. J. Med. Chem. 1993, 36, 2666−2670. (28) Cho, J. Y.; Dutton, A.; Miller, T.; Houk, K. N.; Fukuto, J. M. Arch. Biochem. Biophys. 2003, 417, 65−76. (29) Cai, T.; Xian, M.; Wang, P. G. Bioorg. Med. Chem. Lett. 2002, 12, 1507−1510. (30) Leone, A. M.; Palmer, R. M. J.; Knowles, R. G.; Francis, P. L.; Ashton, D. S.; Moncada, S. J. Biol. Chem. 1991, 266, 23790−23795. (31) The absorbance at 538 nm is, however, lower than that for aerobic oxidation. One reason may be because the Ir(IV) is also partly oxidizing the coordinated hydroxyguanidine. (32) Ratilla, E. M. A.; Scott, B. K.; Moxness, M. S.; Kostic, N. M. Inorg. Chem. 1990, 29, 918−926. (33) Jousserandot, A.; Boucher, J.-L.; Desseaux, C.; Delaforge, M.; Mansuy, D. Bioorg. Med. Chem. Lett. 1995, 5, 423−426. (34) (a) Sheldrick, G. M. SHELXS-97 and SHELXL-97, Programs for Crystal Structure Solution and Refinement, University of Göttingen, Germany, 1997. (b) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112−122. (35) Taylor, G. A. J. Chem. Soc., Perkin Trans. 1 1985, 1, 1181−1184.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.6b00652. Figures S1−S16 and Tables S1−S4 (PDF) X-ray data for OsGOH (CIF) X-ray data for OsNO-a (CIF) X-ray data for OsNO-b (CIF) X-ray data for OsNHCONH2 (CIF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Author Contributions §
J.X. and Q.W. contributed equally.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work was supported by a GRF grant (CityU 101811), the Hong Kong University Grants Committee Area of Excellence Scheme (AoE/P-03-08), and the Natural Science Foundation of China (21201023).
■
REFERENCES
(1) Kerwin, J. F., Jr.; Lancaster, J. R.; Feldman, P. L. J. Med. Chem. 1995, 38, 4343−4362. F
DOI: 10.1021/acs.inorgchem.6b00652 Inorg. Chem. XXXX, XXX, XXX−XXX
