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We report herein the synthesis and application of enantiopure C2 -symmetric primary amine-1,3-bis-thiourea organocatalysts in enantioselective conjugate 1,4-Michael addition of carbonyl containing nucleophiles, to nitroalkenes and N-phenylmaleimide, leading to final products in good enantioselectivities (up to 99%) and yields (up to 99%). We propose supramolecular noncovalent interactions within the organocatalyst's cleft between the substrate and the catalyst, via hydrogen bonding. Supramolecular interaction thus lowers the transition state energy mimicking an enzyme. Mechanism underlying our experimental results is supported by theorical calculations.
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Alcenos , Tioureia , Alcenos/química , Catálise , Nitrocompostos/química , Estereoisomerismo , Tioureia/químicaRESUMO
The pros and cons of using search algorithms alone in identifying new geometries have been discussed by using the Si2C5H2 elemental composition as an example. Within 30 kcal mol-1 at the CCSD(T)/def2-TZVP//PBE0/def2-TZVP level of theory, the coalescence kick and cuckoo methods postulate merely four isomers (1, 3, 6, and 7) for Si2C5H2 (O. Yañez et. al., Chem. Commun., 2017, 53, 12112). On the contrary, chemical intuition yields fourteen (2, 4, 5, and 8-18) new isomers within the same energy range at the B3LYP/6-311++G(2d,2p) level of theory. Based on the relative energies of the first eleven isomers of Si2C5H2 (1, C2v, 0.00; 2, Cs, 21.39; 3, Cs, 21.95; 4, Cs, 22.76; 5, Cs, 24.74; 6, Cs, 25.34; 7, Cs, 25.64; 8, Cs, 25.79; 9, Cs, 27.20; 10, C2v, 28.59; and 11, C2v, 29.16 kcal mol-1) calculated at the CCSD(T)/cc-pVTZ level of theory, it is evident that the search algorithms had missed at least seven isomers in the same energy range. The relative energy gaps of isomers 12-18 fall in the range of 30-40 kcal mol-1 at the latter level of theory. Consequentially, this scenario triggers a speculation going forward with search algorithms alone in the search of all new isomers. While one cannot underestimate the power of these algorithms, the role of chemical intuition may not be completely neglected. Retrospectively, the fourteen new isomers found by chemical intuition may help in writing better search algorithms. All eighteen isomers - including the most stable isomer with a planar tetracoordinate carbon atom 1- remain elusive in the laboratory to date. Thus, structural and spectroscopic parameters have been presented here, which may possibly aid the future experimental studies.
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Eleven isomers of SiC4H2 lying within 50 kcal mol-1 have been theoretically investigated using density functional theory and high-level coupled-cluster methods. Among them, four isomers, 1-ethynyl-3-silacycloprop-1(2)-en-3-ylidene (1), diethynylsilylidene (2), 1-sila-1,2,3,4-pentatetraenylidene (4), and 1,3-butadiynylsilylidene (5), have already been identified in the laboratory. The current investigation reports three low-lying (<1 eV) silylidenes [2-methylenesilabicyclo[1.1.0]but-1(3)-en-4-ylidene (3), 4-sila-2-methylenebicyclo[1.1.0]but-1(3)-en-4-ylidene (6), and 3-ethynyl-1-silapropadienylidene (7)] and three high-lying (>1 eV) silylidenes [2-sila-(didehydrovinylidene)cyclopropene (8), an isomer with a planar tetracoordinate carbon (ptC) atom (10), and 1-ethynyl-1-silapropadienylidene (11)], which remain elusive in the laboratory to date. Isomer 9 also contains a ptC atom, which turned out to be a transition state at all levels. Though all isomers are polar (µ ≠ 0), rotational spectrum is available only for 4. Using matrix isolation, three isomers (1, 2, and 5) have been trapped in the laboratory at 10 K. Considering the astrochemical relevance of silicon-carbide clusters in the interstellar medium, the current theoretical data demand new molecular spectroscopic studies on SiC4H2. Surprisingly, unlike the isovalent C5H2 isomers, where the bent carbenes are yet to be identified in the laboratory, the bent silylidenes (2 and 5) have been trapped in the case of SiC4H2. In both the cases, molecules with transannular C-C and/or Si-C bonds remain elusive, though they lie in the low-lying region. Using suitable precursors, whether these peculiar geometries (especially 3 and 6) would be identified or not in the laboratory needs to be addressed by molecular spectroscopists. The present investigation documents structural and spectroscopic information of SiC4H2 isomers, which may compliment future molecular spectroscopic observations including radioastronomical searches.
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A gas-phase approach to form Zn coordination sites on metal-organic frameworks (MOFs) by vapor-phase infiltration (VPI) was developed. Compared to Zn sites synthesized by the solution-phase method, VPI samples revealed approximately 2.8 % internal strain. Faradaic efficiency towards conversion of CO2 to CO was enhanced by up to a factor of four, and the initial potential was positively shifted by 200-300â mV. Using element-specific X-ray absorption spectroscopy, the local coordination environment of the Zn center was determined to have square-pyramidal geometry with four Zn-N bonds in the equatorial plane and one Zn-OH2 bond in the axial plane. The fine-tuned internal strain was further supported by monitoring changes in XRD and UV/Visible absorption spectra across a range of infiltration cycles. The ability to use internal strain to increase catalytic activity of MOFs suggests that applying this strategy will enhance intrinsic catalytic capabilities of a variety of porous materials.
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The rational design of fluorescent nucleoside analogues is greatly hampered by the lack of a general method to predict their photophysics, a problem that is especially acute when base pairing and stacking change fluorescence. To better understand these effects, a series of tricyclic cytidine (tC and tCO ) analogues ranging from electron-rich to electron-deficient was designed and synthesized. They were then incorporated into oligonucleotides, and photophysical responses to base pairing and stacking were studied. When inserted into double-stranded DNA oligonucleotides, electron-rich analogues exhibit a fluorescence turn-on effect, in contrast with the electron-deficient compounds, which show diminished fluorescence. The magnitude of these fluorescence changes is correlated with the oxidation potential of nearest neighbor nucleobases. Moreover, matched base pairing enhances fluorescence turn-on for the electron-rich compounds, and it causes a fluorescence decrease for the electron-deficient compounds. For the tCO compounds, the emergence of vibrational fine structure in the fluorescence spectra in response to base pairing and stacking was observed, offering a potential new tool for studying nucleic acid structure and dynamics. These results, supported by DFT calculations, help to rationalize fluorescence changes in the base stack and will be useful for selecting the best fluorescent nucleoside analogues for a desired application.
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A novel synthetic procedure was set up to gain access to platinum coordination cages Pt2L4, which are less investigated compared to their palladium counterparts. This Pt2L4 nanocage exhibits an adequate cavity for guest encapsulation. Indeed, the Au(III) metal complex [Au(bdt)2]- (bdt = benzene-1,2-dithiolate) was successfully captured inside the cavity, in contrast to the analogous palladium cage which failed to host the gold complex. This result represents a rare example where a metal complex with thio-ligands can be encapsulated in a coordination cage. Moreover, it highlights the role of the metal center and the robustness of the platinum cage for host-guest chemistry. This discovery will inspire researchers in this area to pay more attention to Pt-cages. The host-guest system was fully characterized by NMR techniques and X-ray crystallographic analysis. Moreover, the nature of the host-guest interaction in this unique example was investigated and rationalized by DFT computational studies.
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A unique class of enantiopure N-heterocyclic carbene half-sandwich iridium complexes is reported. These compounds display stable configurations at the metal center, as demonstrated by their chiroptical properties. Remarkably, because of the nature of the naphthalimide molecule, two regioisomers containing five-membered [( R)-2a and ( S)-2a] and six-membered [( R)-2b and ( S)-2b] iridacycles were obtained. Density functional theory calculations are advanced to rationalize their relative stability.
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Herein, we report the synthesis of C2 -symmetric sulfonamides as homogeneous and heterogeneous organocatalysts and their application in the enantioselective conjugate 1,4-Michael addition of carbonylic nucleophiles to ß-nitrostyrene. Organocatalysts hydrogen bond to ß-nitrostyrene and enamine in the transition state, mimicking an enzyme leading to final products in high yields (up to 98%) and good enantioselectivities (up to 96%). In addition, these results were supported by density functional calculations.
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We have calculated the temperature-dependent rate coefficients of the addition reactions of butadien-2-yl (C4H5) and acroylyl (C3H3O) radicals with ethene (C2H4), carbon monoxide (CO), formaldehyde (H2CO), hydrogen cyanide (HCN), and ketene (H2CCO), in order to explore the balance between kinetic and thermodynamic control in these combustion-related reactions. For the C4H5 radical, the 1,3-diene form of the addition products is more stable than the 1,2-diene, but the 1,2-diene form of the radical intermediate is stabilized by an allylic delocalization, which may influence the relative activation energies. For the reactions combining C3H3O with C2H4, CO, and HCN, the opposite is true: the 1,2-enone form of the addition products is more stable than the 1,3-enone, whereas the 1,3-enone is the slightly more stable radical species. Optimized geometries and vibrational modes were computed with the QCISD/aug-cc-pVDZ level and basis, followed by single-point CCSD(T)-F12a/cc-pVDZ-F12 energy calculations. Our findings indicate that the kinetics in all cases favor reaction along the 1,3 pathway for both the C4H5 and C3H3O systems. The Rice-Ramsperger-Kassel-Marcus (RRKM) microcanonical rate coefficients and subsequent solution of the chemical master equation were used to predict the time-evolution of our system under conditions from 500 K to 2000 K and from 10-5 bar to 10 bars. Despite the 1,3 reaction pathway being more favorable for the C4H5 system, our results predict branching ratios of the 1,2 to 1,3 product as high as 0.48 at 1 bar. Similar results hold for the acroylyl system under these combustion conditions, suggesting that under kinetic control the branching of these reactions may be much more significant than the thermodynamics would suggest. This effect may be partly attributed to the low energy difference between 1,2 and 1,3 forms of the radical intermediate. No substantial pressure-dependence is found for the overall forward reaction rates until pressures decrease below 0.1 bar.
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A novel class of chiral luminescent square-planar platinum complexes with a π-bonded chiral thioquinonoid ligand is described. Remarkably the presence of this chiral organometallic ligand controls the aggregation of this square planar luminophor and imposes a homo- or hetero-chiral arrangement at the supramolecular level, displaying non-covalent Pt-Pt and π-π interactions. Interestingly these complexes are highly luminescent in the crystalline state and their photophysical properties can be traced to their aggregation in the solid state. A TD-DFT calculation is obtained to rationalize this unique behavior.
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A novel palladium-based metallacage was self-assembled. This nanocage displayed two complementary effects that operate in synergy for guest encapsulation. Indeed, a metal complex, [Pt(NO2)4](2-), was hosted inside the cavity, as demonstrated by solution NMR studies. Single-crystal X-ray diffraction shows that the guest adopts two different orientations, depending on the nature of the host-guest interactions involved. A density functional theory computational study is included to rationalize this type of host-guest interaction. These studies pave the way to a better comprehension of chemical interaction and transformation within confined nanospaces.
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Mutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant uniquely preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employed static and dynamic structural methods and found that, compared to R132H, the R132Q active site adopted a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling revealed a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity.
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Mutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant uniquely preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employed static and dynamic structural methods and found that, compared to R132H, the R132Q active site adopted a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling revealed a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity.
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Mutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant unusually preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employ static and dynamic structural methods and observe that, compared to R132H, the R132Q active site adopts a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling reveals a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity.
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Domínio Catalítico , Isocitrato Desidrogenase , Mutação , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Humanos , Cinética , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores Enzimáticos/farmacologiaRESUMO
The electrochemistry of several p-phenylenediamine derivatives, in which one of the amino groups is part of an urea functional group, has been investigated in methylene chloride and acetonitrile. The ureas are abbreviated U(R)R', where R' indicates the substituent on the N that is part of the phenylenediamine redox couple and R indicates the substituent on the other urea N. Cyclic voltammetry and UV-vis spectroelectrochemical studies indicate that U(Me)H and U(H)H undergo an apparent 1e(-) oxidation that actually corresponds to 2e(-) oxidation of half the ureas to a quinoidal-diimine cation, U(R)(+). This is accompanied by proton transfer to the other half of the ureas to make the electroinactive cation HU(R)H(+). This explains the observed irreversibility of the oxidation of U(Me)H in both solvents and U(H)H in acetonitrile. However, the oxidation of U(H)H in methylene chloride is reversible at higher concentrations and slower scan rates. Several lines of evidence suggest that the most likely reason for this is the accessibility of a H-bond complex between U(H)(+) and HU(H)H(+) in methylene chloride. Reduction of the H-bond complex occurs at a less negative potential than that of U(H)(+), leading to reversible behavior. This conclusion is strongly supported by the appearance of a more negative reduction peak at lower concentrations and faster scan rates, conditions in which the H-bond complex is less favored. The overall reaction mechanism is conveniently described by a "wedge scheme", which is a more general version of the square scheme typically used to describe redox processes in which proton transfer accompanies electron transfer.
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This report entails a multifaceted approach to benzodiazepine (BZ) action, involving electron affinity, receptors, cell signaling and other aspects. Computations of the electron affinities (EAs) of different BZs have been carried out to establish the effect of various substituents on their EA. These computations were undertaken to serve as a first step in determining what role electron transfer (ET) plays in BZ activity. The calculations were conducted on the premise that the nature of the substituent will either decrease or increase the electron density of the benzene ring, thus altering the ability of the molecule to accept an electron. Investigations were performed on the effect of drug protonation on EA. Similarities involving substituent effects in prior electrochemical studies are also discussed. As part of the multifaceted approach, EA is linked to ET, which appears to play a role in therapeutic activity and toxicity. There is extensive literature dealing with the role of receptors in BZ activity. Significant information on receptor involvement was reported more than 40 years ago. Gamma-aminobutyric acid (GABA) is known to be importantly involved. GABA is a probable mediator of BZ effects. BZ and GABA receptors, although not identical, are physiologically linked. Cell signaling is known to play a part in the biochemistry of BZ action. Various factors participated, such as gene expression, allosteric influence, toxic effects and therapeutic action. Evidence points to involvement of EA and ET in the mode of action in cell signaling. Oxidative stress and antioxidant effects are also addressed.
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Benzodiazepinas/metabolismo , Encéfalo/metabolismo , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/metabolismo , Benzodiazepinas/química , Sítios de Ligação , Transporte de Elétrons , Humanos , Receptores de GABA-A/fisiologia , Transdução de Sinais/genética , Ácido gama-Aminobutírico/fisiologiaRESUMO
The synthesis and X-ray molecular structure of the first metal-stabilized o-dithiobenzoquinone [Cp*Ir-o-(η(4)-C(6)H(4)S(2))] (2) are described. The presence of the metal stabilizes this elusive intermediate by π coordination and increases the nucleophilic character of the sulfur atoms. Indeed, the π-bonded dithiolene complex 2 was found to react with the organometallic solvated species [Cp*M(acetone)(3)][OTf](2) (M = Rh, Ir) to give a unique class of binuclear dithiolene compounds [Cp*Ir(C(6)H(4)S(2))MCp*][OTf](2) [M = Rh (3), Ir (4)] in which the elusive dithiolene η-C(6)H(4)S(2) acts as a bridging ligand toward the two Cp*M moieties. The electrochemical behavior of all complexes was investigated and provided us with valuable information about their redox properties. Density functional theory (DFT) calculations on the π-bonded dithiobenzoquinone ligand and related bimetallic systems show that the presence of Cp*M at the arene system of the dithiolene ligand increases the stability compared to the known monomeric species [Cp*Ir-o-(C(6)H(4)S(2)-κ(2)-S,S)] and enables these complexes Cp*Ir(C(6)H(4)S(2))MCp*][OTf](2) (3 and 4) to act as electron reservoirs. Time-dependent DFT calculations also predict the qualitative trends in the experimental UV-vis spectra and indicate that the strongest transitions arise from ligand-metal charge transfer involving primarily the HOMO-1 and LUMO. All of these compounds were fully characterized and identified by single-crystal X-ray crystallography. These results illustrate the first examples describing the coordination chemistry of the elusive o-dithiobenzoquinone to yield bimetallic complexes with an o-benzodithiolene ligand. These compounds might have important applications in the area of molecular materials.
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Técnicas Eletroquímicas , Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Teoria Quântica , Compostos de Sulfidrila/química , Cristalografia por Raios X , Irídio/química , Modelos Moleculares , Estrutura Molecular , Rutênio/químicaRESUMO
A series of chiral cyclometalated iridium complexes of the type [Ir(C^N)2(C^C:)], {(C^N) = ppy (2); dfppy (3)} featuring a naphthalimide N-heterocyclic carbene ligand (C^C:) = (Naphthalimide-NHC) are described and fully characterized. The racemic complexes rac-2 and rac-3 were resolved via chiral column chromatography techniques into their corresponding enantiopure species Δ-2, Λ-2, Δ-3, Λ-3 as confirmed by their CD curves. This unique class of molecules containing organic and inorganic chromophores might be used as a platform to probe the stereochemical effect on the photophysical properties. Vibrational circular dichroism (VCD) was used as an important tool to assign successfully the stereochemistry of the enantiomers. TD-DFT calculations are also advanced to support the experimental studies and to rationalize the observed results.
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Hydrogen bonding phenomena are explored using a combination of X-ray diffraction, NMR and IR spectroscopy, and DFT calculations. Three imidazolylphosphines R(2)PImH (ImH = imidazol-2-yl, R = t-butyl, i-propyl, phenyl, 1a-1c) and control phosphine (i-Pr)(2)PhP (1d) lacking an imidazole were used to make a series of complexes of the form Cp*Ir(L(1))(L(2))(phosphine). In addition, in order to suppress intermolecular interactions with either imidazole nitrogen, 1e, a di(isopropyl)imidazolyl analogue of 1b was made along with its doubly (15)N-labeled isotopomer to explore bonding interactions at each imidazole nitrogen. A modest enhancement of transfer hydrogenation rate was seen when an imidazolylphosphine ligand 1b was used. Dichloro complexes (L(1) = L(2) = Cl, 2a-2c,2e) showed intramolecular hydrogen bonding as revealed by four X-ray structures and various NMR and IR data. Significantly, hydride chloride complexes [L(1) = H, L(2) = Cl, 3a-3c and 3e-((15)N)(2)] showed stronger hydrogen bonding to chloride than hydride, though the solid-state structure of 3b evinced intramolecular Ir-H...H-N bonding reinforced by intermolecular N...H-N bonding between unhindered imidazoles. These results are compared to literature examples, which show variations in preferred hydrogen bonding to hydride, halide, CO, and NO ligands. Surprising differences were seen between the dichloro complex 2b with isopropyl groups on phosphorus, which appeared to exist as a mixture of two conformers, and related complex 2a with tert-butyl groups on phosphorus, which exists in chlorinated solvents as a mixture of conformer 2a-endo and chelate 5a-Cl, the product of ionization of one chloride ligand. This difference became apparent only through a series of experiments, especially (15)N chemical shift data from 2D (1)H-(15)N correlation. The results highlight the difficulty of characterizing hemilabile, bifunctional complexes and the importance of innocent ligand substituents in determining structure and dynamics.
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Diacetyl, a butter-flavoring component, has recently attracted scientific and media attention because it has been implicated as an agent that induces popcorn lung disease in exposed plant workers. This disease, officially referred to as bronchiolitis obliterans, entails exposure-induced compromise to the lung's epithelial barrier function. In this review, we present a novel molecular mechanism (electron transfer, ET) designed to explain how diacetyl and its imine derivatives might interact to produce lung damage. We relate the fact that diacetyl and related compounds possess reduction potentials amenable to electron transfer (ET) in vivo. The electrochemical nature of these toxicants can potentially disrupt normal ET processes, generate reactive oxygen species (ROS), and participate in cell signaling events. Condensation of diacetyl with protein may also play a role in the toxicity caused by this compound. ET is a common feature of toxic substances, usually involving their metabolites which can operate per se or through reactions that generate ROS and oxidative stress (OS). Examples of agents capable of ET are quinone and metal compounds, aromatic nitro compounds, and iminium salts. Among compounds that generate ET, the alpha-dicarbonyl ET class, of which diacetyl is a member, is much less studied. This review emphasizes diacetyl as an agent that acts through oxidative processes to cause its effects. However, we also treat related substances that appear to act by a similar mechanism. This mechanism forms a theoretical framework capable of describing the mechanism by which diacetyl may induce its effects and is in accord with various physiological activities displayed by other alpha-dicarbonyl substances. Examples of substances that may act by mechanisms similar to that displayed by diacetyl include cyclohexane-1,2-dione, marinopyrroles, reactive carbonyl species, the bacterial signaling agent DPD, and advanced glycation end products.