Nucleophilic Attack Of H2O Research Articles

Cobalt-catalyzed direct functionalization of indoles with isocyanides

Non-noble cobalt catalysts have been employed in various CH bond activation and functionalization in recent years. Herein, we report a cobalt-catalyzed CH activation and isocyanide insertion of 1H-indole-3-carboxamides for the divergent synthesis of two types of indole-containing molecules. Notably, the reaction with MgSO4 as the additive produces 1H-indole-2,3-dicarboxamides, while PivOK promotes the formation of 3-imino-3,4-dihydropyrrolo[3,4-b]indol-1(2H)-ones in moderate to high yields. Control experiments reveal that 3-imino-3,4-dihydropyrrolo[3,4-b]indol-1(2H)-ones is likely to be transformed to 1H-indole-2,3-dicarboxamides via the nucleophilic attack of H2O in the reaction system.

A Mononuclear Non-Heme Manganese(III)–Aqua Complex in Oxygen Atom Transfer Reactions via Electron Transfer

Metal-oxygen complexes, such as metal-oxo [M(O2-)], -hydroxo [M(OH-)], -peroxo [M(O22-)], -hydroperoxo [M(OOH-)], and -superoxo [M(O2•-)] species, are capable of conducting oxygen atom transfer (OAT) reactions with organic substrates, such as thioanisole (PhSMe) and triphenylphosphine (Ph3P). However, OAT of metal-aqua complexes, [M(OH2)]n+, has yet to be reported. We report herein OAT of a mononuclear non-heme Mn(III)-aqua complex, [(dpaq)MnIII(OH2)]2+ (1, dpaq = 2-[bis(pyridin-2-ylmethyl)]amino-N-quinolin-8-yl-acetamidate), to PhSMe and Ph3P derivatives for the first time; it is noted that no OAT occurs from the corresponding Mn(III)-hydroxo complex, [(dpaq)MnIII(OH)]+ (2), to the substrates. Mechanistic studies reveal that OAT reaction of 1 occurs via electron transfer from 4-methoxythioanisole to 1 to produce the 4-methoxythioanisole radical cation and [(dpaq)MnII(OH2)]+, followed by nucleophilic attack of H2O in [(dpaq)MnII(OH2)]+ to the 4-methoxythioanisole radical cation to produce an OH adduct radical, 2,4-(MeO)2C6H3S•(OH)Me, which disproportionates or undergoes electron transfer to 1 to yield methyl 4-methoxyphenyl sulfoxide. Formation of the thioanisole radical cation derivatives is detected by the stopped-flow transient absorption measurements in OAT from 1 to 2,4-dimethoxythioanisole and 3,4-dimethoxythioanisole, being compared with that in the photoinduced electron transfer oxidation of PhSMe derivatives, which are detected by laser-induced transient absorption measurements. Similarly, OAT from 1 to Ph3P occurs via electron transfer from Ph3P to 1, and the proton effect on the reaction rate has been discussed. The rate constants of electron transfer from electron donors, including PhSMe and Ph3P derivatives, to 1 are fitted well by the electron transfer driving force dependence of the rate constants predicted by the Marcus theory of outer-sphere electron transfer.

Facile Construction of an α-(1-Cyclopentenyl)ketone Core by Ruthenium-catalyzed Hydrative Cyclization of 1,6-Allenyne: Total Synthesis of (+)-Myomontanone

Ruthenium-catalyzed hydrative cyclization of 1,6-allenyne in the presence of H2O was demonstrated. The reaction proceeded via nucleophilic attack of H2O to a ruthenacyclopentene intermediate, givin...

A paradigm shift in rate determining step from single electron transfer between phenylsulfinylacetic acids and iron(III) polypyridyl complexes to nucleophilic attack of water to the produced sulfoxide radical cation: a non‐linear Hammett

Mechanism of oxidative decarboxylation of phenylsulfinylacetic acids (PSAAs) by iron(III) polypyridyl complexes in aqueous acetonitrile medium has been investigated spectrophotometrically. An initial intermediate formation between PSAA and [Fe(NN)3]3+ is confirmed from the observed Michaelis–Menten kinetics and fractional order dependence on PSAA. Significant rate retardation with concentration of [Fe(NN)3]3+ is rationalized on the basis of coordination of a water molecule at the carbon atom adjacent to the ring nitrogen of the metal polypyridyl complexes by nucleophilic attack at higher concentrations. Electron‐withdrawing and electron‐releasing substituents in PSAA facilitate the reaction and Hammett correlation gives an upward ‘V’ shaped curve. The apparent upward curvature is rationalized based on the change in the rate determining step from electron transfer to nucleophilic attack, by changing the substituents from electron‐releasing to electron‐withdrawing groups. Electron‐releasing substituents in PSAA accelerate the electron transfer from PSAA to the complex and also stabilize the intermediate through resonance interaction leading to negative reaction constants (ρ). Conversely, electron‐withdrawing groups, while retarding the electron transfer exert an accelerating effect on the nucleophilic attack of H2O which leading to low magnitude of ρ+ compared to high ρ− values of electron‐releasing groups. Marcus theory is applied, and a fair agreement is seen with the experimental values. Copyright © 2016 John Wiley & Sons, Ltd.

Mechanism for the decomposition of 5-aza-2′-deoxycytidine: a theoretical study using Monte Carlo simulation plus local microhydration model

The decomposition mechanism of 5-aza-2′-deoxycytidine (decitabine) has been investigated using the Monte Carlo simulation with free energy perturbation technique based on the local microhydration model. The irreversible deformylation process (process 2) was firstly evaluated. Four possible pathways, two stepwise (paths 1 and 3) and two concerted (paths 2 and 4) were examined. In two stepwise pathways, a tetrahedral intermediate is given by the addition of H2O to the C(1)=O(2) bond, followed by the proton shift to the N(3) atom leading to the final products. In two concerted pathways, the nucleophilic attack of H2O at the C(1) atom and the simultaneous movement of hydroxyl H to the N(3) atom induce the cleavage of the C(1)–N(3) single bond. The potential energy profiles along the minimum energy path for four pathways in the gas phase and in water were obtained. Our computed results exhibit that two stepwise mechanisms (paths 1 and 3) are more favorable than two concerted mechanisms (paths 2 and 4) when the solvent effects of bulk water are taken into account. Then, in collaboration with the previous study (Gao et al. in Theor Chem Acc 131:1108–1123, 2012), the whole decomposition processes of decitabine were discussed. Two possible pathways were considered: pathway t1 be made up of B-path 2 (in process 1) and path 1 as well as pathway t2 be composed of B-path 3 (in process 1) and path 3. The results clearly manifest that pathway t2 is more favorable than pathway t1 in the decomposition reaction of decitabine, which leads to IM-dR2 and GuaUre-dR2 as ring-opening-formylated intermediate and decomposition product, respectively. The third step is the rate-controlling step with the free energy barrier height of 29.8 kcal/mol, which is in agreement with the experimentally determined activation free energy (25.4 kcal/mol).

Coordinated nitroxyl anion is produced and released as nitrous oxide by the decomposition of iridium-coordinated nitrosothiols

The aqueous decomposition of the iridium coordinated nitrosothiols (RSNOs) trans-K[IrCl4(CH3CN)NOSPh] (1), and K2[IrCl5(NOECyS)] (2, ECyS=cysteine ethyl ester), was studied by MS analysis of the gaseous products, ESI-MS, NMR, and UV–Vis spectroscopy. Bent NO (NO−, nitroxyl anion), sulfenic acids and nitrite were observed as coordinated products in solution, while nitrous oxide (N2O) and nitrogen were detected in the gas phase. The formation of coordinated NO− and N2O, a nitroxyl dimerization product, allows us to propose the formation of free nitroxyl (HNO) as an intermediate. Complex 1 decomposes 300 times slower than free PhSNO does. In both cases (1 and 2) kinetic results show a first order decomposition behavior and a very negative ΔS≠, which strongly indicates an associative rate-determining step. A proposed decomposition mechanism, supported by the experimental data and DFT calculations, involves, as the first step, nucleophilic attack of H2O on to the sulfur atom of the coordinated RSNO, producing an NO− complex and free sulfenic acid, followed by two competing reactions: a ligand exchange reaction of this NO− with the sulfenic acid or, to a minor extent, coordination of N2O to produce an NO−/N2O complex which finally renders free N2 and coordinated NO2−. Some of the produced NO− is likely to be released from the metal center producing nitroxyl by protonation and finally N2O by dimerization and loss of H2O. In conclusion, the decomposition of these coordinated RSNOs occurs through a different mechanism than for the decomposition of free RSNOs. It involves the formation of sulfenic acids and coordinated NO−, which is released from the complexes and protonated at the reaction pH producing nitroxyl (HNO), and ultimately N2O.

ChemInform Abstract: Unexpected Hydrolysis of 5-Aminoisoxazolbenzoylamide Herbicide Isoxaben into 5-Isoxazolinone.

The benzoylamide derivative of 5-aminoisoxazol, i.e. the herbicide isoxaben 1 (N-[3-(1-ethyl-1-methylpropyl)isoxazol-5-yl]-2,6-dimethoxybenzamide) was transformed by aqueous acid hydrolysis into the unexpected 5-isoxazolinone 3 (3-(1-ethyl-1-methylpropyl)isoxazolin-5-one) plus mainly 2,6-dimethoxybenzamide 4. The expected 5-aminoisoxazol 7 (5-amino-3-(1--ethyl-1-methylpropyl)isoxazol) was not generated, except in very low amounts when high acid concentrations were used. In separate hydrolysis trials made in similar aqueous acid conditions, it was observed that the 5-aminoisoxazol 7 and 5-isoxazolinone 3 were not transformed. The 5-isoxazolinone 3 formed by isoxaben 1 acid hydrolysis thus was the first generated product, and was not formed by the consecutive nucleophilic substitution of 5-amino-isoxazol 7 which would have been formed in a first step. This unexpected 5-amino C-N bond cleavage by nucleophilic attack of H2O at the 5-C of the isoxazol ring of isoxaben 1 -instead of the usual amide CO-N bond cleavage- probably is due to the positive charge existing at the 5-C atom of the isoxazol ring. The acid hydrolysis pathway observed for isoxaben 1 also is the main soil metabolism pathway. The absence of formation of an aromatic amino compound by chemical hydrolysis reduces the concern as to their potential tranformation into carcinogenic nitroso or azo compounds in soil. On the other hand, isoxaben 1 was not hydrolyzed in aqueous dilute alkali.

Formation and Fate of a Sulfenic Acid Intermediate in the Metabolic Activation of the Antithrombotic Prodrug Prasugrel

Metabolic activation of the tetrahydro-thienopyridine antithrombotic prodrug, prasugrel, involves two steps: an esterase-dependent hydrolysis of its acetate function leading to thiolactone 6 and a cytochrome P450 (P450)-catalyzed oxidative cleavage of this thiolactone. This article shows that this second step involves the intermediate formation of a sulfenic acid 9 that has been trapped by dimedone during the metabolism of prasugrel by rat and human liver microsomes. The dimedone adduct has been characterized by mass spectrometry (MS) and (1)H and (13)C NMR spectroscopy. This article also describes the fate of the sulfenic acid intermediate in liver microsomes in the presence of various nucleophiles. Its reaction with a water-soluble phosphine cleanly leads to the corresponding thiol 7, which has been reported as the pharmacologically active metabolite of prasugrel. Its reaction with glutathione (GSH) leads to mixed disulfide 11, which may further react with GSH in excess to provide thiol 7. Experiments using microsomal incubations in the presence of (18)O(2) and (18)OH(2) have provided the first data on the mechanism of the P450-catalyzed oxidative cleavage of thiolactones such as 6. They indicate that sulfenic acid 9 is derived from a nucleophilic attack of H(2)O either directly on the electrophilic keto group of intermediate keto-sulfoxide 12, which is formed by P450-dependent S-oxidation of 6, or on the keto group of a cyclic sulfenic ester 13, which could derive from the rearrangement of 12. These data provide a first detailed mechanism for the metabolic activation of prasugrel to its pharmacologically active metabolites such as thiol 7.

Molecular Mechanism of Water Oxidation Reaction at Photo-Irradiated TiO<sub>2</sub> and Related Metal Oxide Surfaces

Recent studies on the molecular mechanism of water photooxidation (or oxygen photoevolution) reaction on TiO2 and related metal oxides or oxynitrides are reviewed. It is shown that a lot of experimental and theoretical studies give definite support to our recently proposed new mechanism, called “nucleophilic attack of H2O” or “Lewis acid-base” mechanism. The new mechanism has the prominent features that it possesses energetic and kinetics different from the conventional electron-transfer mechanism and can explain water photooxidation reaction on visible-light responsive metal oxides or oxynitrides, contrary to the conventional one. The result indicates that the new mechanism is useful for searching for new efficient visible-light responsive materials for solar water splitting.

A Myoglobin Functional Model Composed of a Ferrous Porphyrin and a Cyclodextrin Dimer with an Imidazole Linker

A 1:1 inclusion complex (Fe(II)PImCD) of 5,10,15,20-tetrakis- (4-sulfonatophenyl)porphinatoiron(II) (Fe(II)P) and an O-methylated beta-cyclodextrin dimer with an imidazole linker (ImCD) was found to bind dioxygen in aqueous solution. The half-saturation pressure of dioxygen (P(1/2)O2) is 1.7 torr at 25 degrees C, which is 10 times lower than that for a previous myoglobin functional model (hemoCD) with a pyridine linker. Meanwhile, the half-life of oxygenated Fe(II)PImCD is 3 h, which is 10 times shorter than that of oxygenated hemoCD. The covering of the iron(II) center by a microscopic environment is essential for preventing autoxidation of oxygenated ferrous porphyrin, which is promoted by nucleophilic attack of H2O and/or nucleophiles such as inorganic anions. Due to structural requirements, covering of the Fe(II) center of Fe(II)PImCD is insufficient compared with the case of hemoCD. As a result, water molecules can penetrate more easily the cleft of the O2-Fe(II)PImCD complex and act as an autoxidation inducer. This structure also causes poorer selectivity against carbon monoxide (M = 1040). In contrast, the dioxygen affinity of Fe(II)PImCD is much higher than that of hemoCD because the imidazole moiety is a stronger electron donor than pyridine.

Substituent effect on the photoinduced electron-transfer reaction of para-substituted triphenylphosphines sensitised by 9,10-dicyanoanthracene

The photoinduced electron-transfer reaction of para-substituted triphenylphosphines sensitised by 9,10-dicyanoanthracene (DCA) occurred in acetonitrile containing 2 vol% water to form the corresponding triphenylphosphine oxide. Transient absorption spectral measurements were carried out during 355 nm laser flash photolysis of a mixture of the phosphine and DCA. The electron transfer from the phosphine to singlet excited DCA initiated the reaction. A para substituent on the benzene ring affects the quantum yields of the phosphine radical cation and phosphine oxide. The back electron transfer from the DCA radical anion to the phosphine radical cation governed the quantum yield of the phosphine radical cation. The quantum yield of the phosphine oxide was dependent on the conjugation between the π-electron of the benzene ring and the n-electron of the phosphorus atom in the phosphine radical cation. The phosphine oxide forms through nucleophilic attack of H2O toward the phosphorus atom of the phosphine radical cation, producing the phosphoranyl radical.

Electron-Transfer Oxidation of 9-Alkylanthracenes and the Decay Kinetics of Radical Cations in Acetonitrile

Abstract Transient absorption spectra of radical cations of 9-alkylanthracenes (RAn•+) formed by the electron-transfer oxidation of 9-alkylanthracenes with Fe(ClO4)3·9H2O have been detected by using a stopped flow spectrophotometer. The decay rates of RAn•+ obey the second-order kinetics due to the electron-transfer disproportionation reactions, followed by the nucleophilic attack of H2O on the resulting dications leading to the final ring-oxygenated products.

Unexpected Hydrolysis of 5‐Aminoisoxazolbenzoylamide Herbicide Isoxaben into 5‐Isoxazolinone

AbstractThe benzoylamide derivative of 5‐aminoisoxazol, i.e. the herbicide isoxaben 1 (N‐[3‐(1‐ethyl‐1‐methylpropyl)isoxazol‐5‐yl]‐2,6‐dimethoxybenzamide) was transformed by aqueous acid hydrolysis into the unexpected 5‐isoxazolinone 3 (3‐(1‐ethyl‐1‐methylpropyl)isoxazolin‐5–one) plus mainly 2,6‐dimethoxybenzamide 4. The expected 5‐aminoisoxazol 7 (5‐amino‐3‐(1‐ethyl‐1‐methylpropyl)isoxazol) was not generated, except in very low amounts when high acid concentrations were used. In separate hydrolysis trials made in similar aqueous acid conditions, it was observed that the 5‐aminoisoxazol 7 and 5‐isoxazolinone 3 were not transformed. The 5‐isoxazolinone 3 formed by isoxaben 1 acid hydrolysis thus was the first generated product, and was not formed by the consecutive nucleophilic substitution of 5‐aminoisoxazol 7 which would have been formed in a first step. This unexpected 5‐amino C‐N bond cleavage by nucleophilic attack of H2O at the 5‐C of the isoxazol ring of isoxaben 1 ‐instead of the usual amide CO‐N bond cleavage‐ probably is due to the positive charge existing at the 5‐C atom of the isoxazol ring. The acid hydrolysis pathway observed for isoxaben 1 also is the main soil metabolism pathway. The absence of formation of an aromatic amino compound by chemical hydrolysis reduces the concern as to their potential tranformation into carcinogenic nitroso or azo compounds in soil. On the other hand, isoxaben 1 was not hydrolyzed in aqueous dilute alkali.