RESUMO
ConspectusMetalloenzymes, which are proteins containing earth-abundant transition-metal ions as cofactors in the active site, generate various metal-oxygen intermediates via activating a dioxygen molecule (O2) to mediate vital metabolic functions, such as the oxidative metabolism of xenobiotics and the biotransformation of naturally occurring molecules. By replicating the active sites of metalloenzymes, many bioinorganic chemists have studied the geometric and electronic properties and reactivities of model complexes to understand the nature of enzymatic intermediates and develop bioinspired metal catalysts. Among the reported model complexes, nonporphyrinic macrocyclic ligands are the predominant coordination system widely used in stabilizing and isolating diverse metal-oxygen intermediates, which allows us to extensively investigate the physicochemical characteristics of the analogs of reactive intermediates of metalloenzymes. In particular, it has been reported that the ring size of the macrocyclic ligands, defined by the number of atoms in the macrocyclic ring, drastically affects the identity of the metal-oxygen intermediate. Thus, systematic modification of the macrocyclic ligands has been a great subject being examined in various inorganic fields.In this Account, we describe synthetic advances of a macrocyclic ligand system by introducing pyridine donors into a 12-membered tetraazamacrocyclic ligand (12-TMC) that initially has 4 amine donors. Interestingly, the backbone of the pyridinophane ligand with 2 pyridine and 2 amine donors in a 12-membered ring is shown to be much more folded than in other macrocyclic ligands, thereby allowing the axial and equatorial donors to separately control the electronic structure of metal complexes. Then, we looked over independent electronic and steric effects on metal-oxygen species with thorough physicochemical analysis. The NiIII-peroxo complexes exhibit nucleophilic reactivity dependent on the steric hindrance of the second coordination sphere. Furthermore, the C-H bond strength of the second coordination sphere has also been an important factor in determining the stability of MnIV-bis(hydroxo) intermediates. Electronic tuning on CoIII-hydroperoxo intermediates results in a trend between the electron-donating abilities of para-substituents on pyridine in the pyridinophane ligand and electrophilic reactivities, from which mechanistic insights into the metal-hydroperoxo species have been gained. Importantly, the metal-oxygen intermediates supported by the pyridinophane ligand system have revealed quite challenging chemical reactions, including dioxygenase-like nitrile activation by CoIII-peroxo intermediates and the oxidation of aldehyde and aromatic compounds by manganese-oxygen intermediates. Based on the fine substitution of donors, we have addressed that those novel reactions originated from the unique framework of the pyridinophane system incorporating spin-crossover behavior and high redox potentials of the metal-oxygen intermediates. These results will be valuable for the structure-activity relationship of metal-oxygen intermediates, giving a better understanding on the enzymatic coordination system where amino acid ligands vary for specific chemical reactions.
RESUMO
Recently, transition-metal terminal nonoxo complexes have shown a remarkable ability to activate and functionalize C-H bonds via proton-coupled electron transfer (PCET). Here we report the first example of a mononuclear manganese(IV) bis(fluoro) complex bearing a tetradentate pyridinophane ligand, [MnIV(TBDAP)(F)2]2+ (3), with an X-ray single crystal structure and physicochemical characterization. The manganese(IV) bis(fluoro) complex has a very high reduction potential of 1.61 V vs SCE, thereby enabling the four-electron oxidation of mesitylene to 3,5-dimethylbenzaldehyde. Kinetic studies, including the kinetic isotope effect and employment of other toluene derivatives, reveal the electron transfer (ET)-driven PCET in the C-H bond activation of mesitylene by 3. This novel metal halide intermediate would be prominently valuable for expanding transition-metal halide chemistry.
RESUMO
The oxidation of aldehyde is one of the fundamental reactions in the biological system. Various synthetic procedures and catalysts have been developed to convert aldehydes into corresponding carboxylic acids efficiently under ambient conditions. In this work, we report the oxidation of aldehydes by a mononuclear manganese(III) iodosylbenzene complex, [MnIII(TBDAP)(OIPh)(OH)]2+ (1), with kinetic and mechanistic studies in detail. The reaction of 1 with aldehydes resulted in the formation of corresponding carboxylic acids via a pre-equilibrium state. Hammett plot and reaction rates of 1 with 1°-, 2°-, and 3°-aldehydes revealed the electrophilicity of 1 in the aldehyde oxidation. A kinetic isotope effect experiment and reactivity of 1 toward cyclohexanecarboxaldehyde (CCA) analogues indicate that the reaction of 1 with aldehyde occurs through the rate-determining C-H bond activation at the formyl group. The reaction rate of 1 with CCA is correlated to the bond dissociation energy of the formyl group plotting a linear correlation with other aliphatic C-H bonds. Density functional theory calculations found that 1 electrostatically interacts with CCA at the pre-equilibrium state in which the C-H bond activation of the formyl group is performed as the most feasible pathway. Surprisingly, the rate-determining step is characterized as hydride transfer from CCA to 1, affording an (oxo)methylium intermediate. At the fundamental level, it is revealed that the hydride transfer is composed of H atom abstraction followed by a fast electron transfer. Catalytic reactions of aldehydes by 1 are also presented with a broad substrate scope. This novel mechanistic study gives better insights into the metal oxygen chemistry and would be prominently valuable for development of transition metal catalysts.
Assuntos
Iodobenzenos , Manganês , Manganês/química , Oxirredução , Transporte de ElétronsRESUMO
Spatial patterning of different cell types is crucial for tissue engineering and is characterized by the formation of sharp boundary between segregated groups of cells of different lineages. The cell-cell boundary layers, depending on the relative adhesion forces, can result in kinks in the border, similar to fingering patterns between two viscous partially miscible fluids which can be characterized by its fractal dimension. This suggests that mathematical models used to analyze the fingering patterns can be applied to cell migration data as a metric for intercellular adhesion forces. In this study, we develop a novel computational analysis method to characterize the interactions between blood endothelial cells (BECs) and lymphatic endothelial cells (LECs), which form segregated vasculature by recognizing each other through podoplanin. We observed indiscriminate mixing with LEC-LEC and BEC-BEC pairs and a sharp boundary between LEC-BEC pair, and fingering-like patterns with pseudo-LEC-BEC pairs. We found that the box counting method yields fractal dimension between 1 for sharp boundaries and 1.3 for indiscriminate mixing, and intermediate values for fingering-like boundaries. We further verify that these results are due to differential affinity by performing random walk simulations with differential attraction to nearby cells and generate similar migration pattern, confirming that higher differential attraction between different cell types result in lower fractal dimensions. We estimate the characteristic velocity and interfacial tension for our simulated and experimental data to show that the fractal dimension negatively correlates with capillary number (Ca), further indicating that the mathematical models used to study viscous fingering pattern can be used to characterize cell-cell mixing. Taken together, these results indicate that the fractal analysis of segregation boundaries can be used as a simple metric to estimate relative cell-cell adhesion forces between different cell types.
Assuntos
Células Endoteliais , Fractais , Movimento CelularRESUMO
A series of cobalt(III)-peroxo complexes, [CoIII(R2-TBDAP)(O2)]+ (1R2; R2 = Cl, H, and OMe), and cobalt(III)-hydroperoxo complexes, [CoIII(R2-TBDAP)(O2H)(CH3CN)]2+ (2R2), bearing electronically tuned tetraazamacrocyclic ligands (R2-TBDAP = N,N'-di-tert-butyl-2,11-diaza[3.3](2,6)-p-R2-pyridinophane) were prepared from their cobalt(II) precursors and characterized by various physicochemical methods. The X-ray diffraction and spectroscopic analyses unambiguously showed that all 1R2 compounds have similar octahedral geometry with a side-on peroxocobalt(III) moiety, but the O-O bond lengths of 1Cl [1.398(3) Å] and 1OMe [1.401(4) Å] were shorter than that of 1H [1.456(3) Å] due to the different spin states. For 2R2, the O-O bond vibration energies of 2Cl and 2OMe were identical at 853 cm-1 (856 cm-1 for 2H), but their Co-O bond vibration frequencies were observed at 572 cm-1 for 2Cl and 550 cm-1 for 2OMe, respectively, by resonance Raman spectroscopy (560 cm-1 for 2H). Interestingly, the redox potentials (E1/2) of 2R2 increased in the order of 2OMe (0.19 V) < 2H (0.24 V) < 2Cl (0.34 V) according to the electron richness of the R2-TBDAP ligands, but the oxygen-atom-transfer reactivities of 2R2 showed a reverse trend (k2: 2Cl < 2H < 2OMe) with a 13-fold rate enhancement at 2OMe over 2Cl in a sulfoxidation reaction with thioanisole. Although the reactivity trend contradicts the general consideration that electron-rich metal-oxygen species with low E1/2 values have sluggish electrophilic reactivity, this could be explained by a weak Co-O bond vibration of 2OMe in the unusual reaction pathway. These results provide considerable insight into the electronic nature-reactivity relationship of metal-oxygen species.
RESUMO
The strong C-H bond activation of hydrocarbons is a difficult reaction in environmental and biological chemistry. Herein, a high-valent manganese(IV)-hydroxo complex, [MnIV(CHDAP-O)(OH)]2+ (2), was synthesized and characterized by various physicochemical measurements, such as ultraviolet-visible (UV-vis), electrospray ionization-mass spectrometry (ESI-MS), electron paramagnetic resonance (EPR), and helium-tagging infrared photodissociation (IRPD) methods. The one-electron reduction potential (Ered) of 2 was determined to be 0.93 V vs SCE by redox titration. 2 is formed via a transient green species assigned to a manganese(IV)-bis(hydroxo) complex, [MnIV(CHDAP)(OH)2]2+ (2'), which performs intramolecular aliphatic C-H bond activation. The kinetic isotope effect (KIE) value of 4.8 in the intramolecular oxidation was observed, which indicates that the C-H bond activation occurs via rate-determining hydrogen atom abstraction. Further, complex 2 can activate the C-H bonds of aromatic compounds, anthracene and its derivatives, under mild conditions. The KIE value of 1.0 was obtained in the oxidation of anthracene. The rate constant (ket) of electron transfer (ET) from N,N'-dimethylaniline derivatives to 2 is fitted by Marcus theory of electron transfer to afford the reorganization energy of ET (λ = 1.59 eV). The driving force dependence of log ket for oxidation of anthracene derivatives by 2 is well evaluated by Marcus theory of electron transfer. Detailed kinetic studies, including the KIE value and Marcus theory of outer-sphere electron transfer, imply that the mechanism of aromatic C-H bond hydroxylation by 2 proceeds via the rate-determining electron-transfer pathway.
Assuntos
Hidrogênio , Manganês , Manganês/química , Cinética , Oxirredução , Hidrogênio/química , AntracenosRESUMO
Metal iodosylarene species have received interest because of their potential oxidative power as a catalyst. We present the first example of hydride-transfer reactions to a mononuclear manganese(III) iodosylbenzene complex, [MnIII(TBDAP)(OIPh)(OH)]2+ (1; TBDAP = N,N-di-tert-butyl-2,11-diaza[3.3](2,6)pyridinophane), with dihydronicotinamide adenine dinucleotide (NADH) analogues. Kinetic studies show that hydride-transfer from the NADH analogues to 1 occurs via a proton-coupled electron transfer, followed by a rapid electron transfer.
RESUMO
Cells use gaseous molecules such as nitric oxide (NO) to transmit both intracellular and intercellular signals. In principle, the endogenous small molecules regulate physiological changes, but it is unclear how randomly diffusive molecules trigger and discriminate signaling programs. Herein, it is shown that gasotransmitters use time-dependent dynamics to discriminate the endogenous and exogenous inputs. For a real-time stimulation of cell signaling, we synthesized a photo-cleavable metal-nitrosyl complex, [CoIII (MDAP)(NO)(CH3 CN)]2+ (MDAP=N,N'-dimethyl-2,11-diaza[3,3](2,6)pyridinophane), which can stably deliver and selectively release NO with fine temporal resolution in the cytosol, and used this to study the extracellular signal-regulated kinases (ERKs), revealing how cells use both exogenous and endogenous NO to disentangle cellular responses. This technique can be to understand how diverse cellular signaling networks are dynamically interconnected and also to control drug delivery systems.
Assuntos
Cobalto/química , Fotólise , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Sistemas de Liberação de Medicamentos , Modelos MolecularesRESUMO
Transition metal-iodosylarene complexes have been proposed to be key intermediates in the catalytic cycles of metal catalysts with iodosylarene. We report the first X-ray crystal structure and spectroscopic characterization of a mononuclear nonheme manganese(III)-iodosylarene complex with a tetradentate macrocyclic ligand, [MnIII(TBDAP)(OIPh)(OH)]2+ (2). The manganese(III)-iodosylarene complex is capable of conducting various oxidation reactions with organic substrates, such as C-H bond activation, sulfoxidation and epoxidation. Kinetic studies including isotope labeling experiments and Hammett correlation demonstrate the electrophilic character on the Mn-iodosylarene adduct. This novel intermediate would be prominently valuable for expanding the chemistry of transition metal catalysts.
RESUMO
Naphthalene oxidation with metal-oxygen intermediates is a difficult reaction in environmental and biological chemistry. Herein, we report that a MnIV bis(hydroxo) complex, which was fully characterized by various physicochemical methods, such as ESI-MS, UV/Vis, and EPR analysis, X-ray diffraction, and XAS, can be employed for the oxidation of naphthalene in the presence of acid to afford 1,4-naphthoquinone. Redox titration of the MnIV bis(hydroxo) complex gave a one-electron reduction potential of 1.09â V, which is the most positive potential for all reported nonheme MnIV bis(hydroxo) species as well as MnIV oxo analogues. Kinetic studies, including kinetic isotope effect analysis, suggest that the naphthalene oxidation occurs through a rate-determining electron transfer process.
Assuntos
Complexos de Coordenação/química , Compostos de Manganês/química , Naftalenos/química , Elétrons , Cinética , Modelos Moleculares , Naftoquinonas/síntese química , Oxirredução , Análise Espectral/métodos , Difração de Raios XRESUMO
A mononuclear side-on peroxocobalt(III) complex with a tetradentate macrocyclic ligand, [CoIII(TBDAP)(O2)]+ (1), shows a novel and facile mode of dioxygenase-like reactivity with nitriles (R-C≡N; R = Me, Et, and Ph) to produce the corresponding mononuclear hydroximatocobalt(III) complexes, [CoIII(TBDAP)(R-C(âNO)O)]+, in which the nitrile moiety is oxidized by two oxygen atoms of the peroxo group. The overall reaction proceeds in one-pot under ambient conditions (ca. 1 h, 40 °C). 18O-Labeling experiments confirm that both oxygen atoms are derived from the peroxo ligand. The structures of all products, hydroximatocobalt(III) complexes, were confirmed by X-ray crystallography and various spectroscopic techniques. Kinetic studies including the Hammett analysis and isotope labeling experiments suggest that the mechanistic mode of 1 for activation of nitriles occurs via a concerted mechanism. This novel reaction would be significantly valuable for expanding the chemistry for nitrile activation and utilization.
RESUMO
Dinuclear FeIII and NiII complexes, [(phenO)Fe(N3 )]2 (NO3 )2 (1) and [(phenOH)Ni(N3 )2 ]2 (2), were prepared by treating Fe(NO3 )3 â 9 H2 O and Ni(NO3 )2 â 6 H2 O in methanol, respectively, with phenOH (=N-(2-pyridylmethyl)-N'-(2-hydroxyethyl)ethylenediamine) and NaN3 ; both 1 and 2 were characterized by elemental analysis, IR spectroscopy, X-ray diffraction, and magnetic susceptibility measurements. Two ethoxo-bridged FeIII and two azido-bridged NiII were observed in 1 and 2, respectively; corresponding antiferromagnetic interaction via the bridged ethoxo groups and strong ferromagnetic coupling via the bridged end-on azido ligands within the dimeric unit were observed. Complex 1 did not exhibit any catalytic activity, while 2 exhibited excellent catalytic activities for the epoxidation of aliphatic, aromatic, and terminal olefins.
RESUMO
The versatile applications of nitrile have led to the widespread use of nitrile activation in the synthesis of pharmacologically and industrially valuable compounds. We reported the activation of nitriles using mononuclear cobalt(III)-hydroperoxo complexes, [CoIII(Me3-TPADP)(O2H)(RCN)]2+ [R = Me (2) and Ph (2Ph)], to form cobalt(III)-peroxyimidato complexes, [CoIII(Me3-TPADP)(R-C(=NH)O2)]2+ [R = Me (3) and Ph (3Ph)]. The independence of the rate on the nitrile concentration and the positive Hammett value of 3.2(2) indicated that the reactions occur via an intramolecular nucleophilic attack of the hydroperoxide ligand to the coordinated nitrile carbon atom. In contrast, the previously reported cobalt(III)-hydroperoxo complex, [CoIII(TBDAP)(O2H)(CH3CN)]2+ (2TBDAP), exhibited the deficiency of reactivity toward nitrile. The comparison of pKa values and redox potentials of 2 and 2TBDAP showed that Me3-TPADP had a stronger ligand field strength than that of TBDAP. The density functional theory calculations for 2 and 2TBDAP support that the strengthened ligand field in 2 is mainly due to the replacement of two tert-butyl amine donors in TBDAP with methyl groups in Me3-TPADP, resulting in the compression of the Co-Nax bond lengths. These results provide mechanistic evidence of nitrile activation by the cobalt(III)-hydroperoxo complex and indicate that the basicity dependent on the ligand framework contributes to the ability of nitrile activation.
RESUMO
Quercetin 2,4-dioyxgenase (QueD) has been known to catalyze the oxygenative degradation of flavonoids and quercetin. Recent crystallographic study revealed a nickel ion occupies the active site as a co-factor to support O2 activation and catalysis. Herein, we report a nickel(II) flavonolate complex bearing a tridentate macrocyclic ligand, [NiII(Me3-TACN)(Fl)(NO3)](H2O) (1, Me3-TACN = 1,4,7-trimethyl-1,4,7-triazacyclononane, Fl = 3-hydroxyflavone) as a functional model for QueD. The flavonolatonickel(II) complex was characterized by using spectrometric analysis including UV-vis spectroscopy, electrospray ionization mass spectrometer (ESI-MS), infrared spectroscopy (FT-IR) and 1H nuclear magnetic resonance spectroscopy (NMR). The single crystal X-ray structure of 1 shows two isomers with respect to the direction of a flavonolate ligand. Two isomers commonly are in the octahedral geometry with a bidentate of flavonolate and a monodentate of nitrate as well as a tridentate binding of Me3-TACN ligand. The spin state of 1 is determined to be a triplet state based on the Evans' method. Interestingly, electronic configuration of 1 from density functional theory (DFT) calculations revealed that the two singly occupied molecular orbitals (SOMOs) lie energetically lower than the highest (doubly) occupied molecular orbital (HOMO), that is so-called the SOMO-HOMO level inversion (SHI). The HOMO shows an electron density localized in the flavonolate ligand, indicating that flavonolate ligand is oxidized first rather than the nickel center. Thermal degradation of 1 resulted in the formation of benzoic acid and salicylic acid, which is attributed to the oxygenation of flavonolate of 1.
Assuntos
Complexos de Coordenação/química , Dioxigenases/química , Modelos Moleculares , Níquel/química , Quercetina/químicaRESUMO
Introduction: Controlling the formation of blood and lymphatic vasculatures is crucial for engineered tissues. Although the lymphatic vessels originate from embryonic blood vessels, the two retain functional and physiological differences even as they develop in the vicinity of each other. This suggests that there is a previously unknown molecular mechanism by which blood (BECs) and lymphatic endothelial cells (LECs) recognize each other and coordinate to generate distinct capillary networks. Methods: We utilized Matrigel and fibrin assays to determine how cord-like structures (CLS) can be controlled by altering LEC and BEC identity through podoplanin (PDPN) and folliculin (FLCN) expressions. We generated BEC ΔFLCN and LEC ΔPDPN , and observed cell migration to characterize loss lymphatic and blood characteristics due to respective knockouts. Results: We observed that LECs and BECs form distinct CLS in Matrigel and fibrin gels despite being cultured in close proximity with each other. We confirmed that the LECs and BECs do not recognize each other through paracrine signaling, as proliferation and migration of both cells were unaffected by paracrine signals. On the other hand, we found PDPN to be the key surface protein that is responsible for LEC-BEC recognition, and LECs lacking PDPN became pseudo-BECs and vice versa. We also found that FLCN maintains BEC identity through downregulation of PDPN. Conclusions: Overall, these observations reveal a new molecular pathway through which LECs and BECs form distinct CLS through physical contact by PDPN which in turn is regulated by FLCN, which has important implications toward designing functional engineered tissues. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-022-00730-2.
RESUMO
A mononuclear cobalt(III)-bis(tert-butylperoxo) adduct (CoIII-(OOtBu)2) bearing a tetraazamacrocyclic ligand was synthesized and characterized using various physicochemical methods, such as X-ray, UV-vis, ESI-MS, EPR, and NMR analyses. The crystal structure of the CoIII-(OOtBu)2 complex clearly showed that two OOtBu ligands bound to the equatorial position of the cobalt(iii) center. Kinetic studies and product analyses indicate that the CoIII-(OOtBu)2 intermediate exhibits nucleophilic oxidative reactivity toward external organic substrates.
Assuntos
Cobalto/química , Complexos de Coordenação/química , Cristalografia por Raios X , Ciclamos/química , Cinética , Ligantes , Conformação MolecularRESUMO
Despite their unique advantages, the full potential of molecular probes for fluorescent monitoring of amyloid-ß (Aß) aggregates has not been fully exploited. This limited utility stems from the lack of knowledge about the hydrophobic interactions between the molecules of Aß probes, as well as those between the probe and the Aß aggregate. Herein, we report the first mechanistic study, which firmly establishes a structure-signaling relationship of fluorescent Aß probes. We synthesized a series of five fluorescent Aß probes based on an archetypal donor-acceptor-donor scaffold (denoted as SN1-SN5). The arylamino donor moieties were systematically varied to identify molecular factors that could influence the interactions between molecules of each probe and that could influence their fluorescence outcomes in conditions mimicking the biological milieu. Our probes displayed different responses to aggregates of Aß, Aß40 and Aß42, two major isoforms found in Alzheimer's disease: SN2, having pyrrolidine donors, showed noticeable ratiometric fluorescence responses (Δν = 797 cm-1) to the Aß40 and Aß42 samples that contained oligomeric species, whereas SN4, having N-methylpiperazine donors, produced significant fluorescence turn-on signaling in response to Aß aggregates, including oligomers, protofibrils, and fibrils (with turn-on ratios of 14 and 10 for Aß42 and Aß40, respectively). Mechanistic investigations were carried out by performing field-emission scanning electron microscopy, X-ray crystallography, UV-vis absorption spectroscopy, and steady-state and transient photoluminescence spectroscopy experiments. The studies revealed that the SN probes underwent preassembly prior to interacting with the Aß species and that the preassembled structures depended profoundly on the subtle differences between the amino moieties of the different probes. Importantly, the studies demonstrated that the mode of fluorescence signaling (i.e., ratiometric response versus turn-on response) was primarily governed by stacking geometries within the probe preassemblies. Specifically, ratiometric fluorescence responses were observed for probes capable of forming J-assembly, whereas fluorescence turn-on responses were obtained for probes incapable of forming J-aggregates. This finding provides an important guideline to follow in future efforts at developing fluorescent probes for Aß aggregation. We also conclude, on the basis of our study, that the rational design of such fluorescent probes should consider interactions between the probe molecules, as well as those between Aß peptides and the probe molecule.
RESUMO
Copper(ii)-alkylperoxo adducts, [Cu(CHDAP)(OOR)]+ (CHDAP = N,N'-dicyclohexyl-2,11-diaza[3,3](2,6)pyridinophane; R = C(CH3)2Ph and tBu), were prepared and characterized using various physicochemical methods. These are the first synthetic Cu(ii)-alkylperoxo complexes that can perform aldehyde deformylation (i.e., nucleophilic reactivity) under the stoichiometric reaction conditions, which was confirmed by kinetic studies.