Acceleration of Nucleophilic CH Activation by Strongly Basic Solvents

(IPI)Ru(II)(OH)_n(H_2O)_m, 2, where IPI is the NNN-pincer ligand, 2,6-diimidizoylpyridine, is shown to catalyze H/D exchange between hydrocarbons and strongly basic solvents at higher rates than in the case of the solvent alone. Significantly, catalysis by 2 is accelerated rather than inhibited by increasing solvent basicity. The evidence is consistent with the reaction proceeding by base modulated nucleophilic CH activation

Mechanism of efficient anti-Markovnikov olefin hydroarylation catalyzed by homogeneous Ir(III) complexes

The mechanism of the hydroarylation reaction between unactivated olefins (ethylene, propylene, and styrene) and benzene catalyzed by [(R)Ir(μ-acac-O,O,C^3)-(acac-O,O)_2]_2 and [R-Ir(acac-O,O)_2(L)] (R = acetylacetonato, CH_3, CH_2CH_3, Ph, or CH_2CH_2Ph, and L = H_2O or pyridine) Ir(III) complexes was studied by experimental methods. The system is selective for generating the anti-Markovnikov product of linear alkylarenes (61 : 39 for benzene + propylene and 98 : 2 for benzene + styrene). The reaction mechanism was found to follow a rate law with first-order dependence on benzene and catalyst, but a non-linear dependence on olefin. ^(13)C-labelling studies with CH_3^(13)CH_2-Ir-Py showed that reversible β-hydride elimination is facile, but unproductive, giving exclusively saturated alkylarene products. The migration of the ^(13)C-label from the α to β-positions was found to be slower than the C–H activation of benzene (and thus formation of ethane and Ph-d_5-Ir-Py). Kinetic analysis under steady state conditions gave a ratio of the rate constants for CH activation and β-hydride elimination (k_(CH): k_β) of 0.5. The comparable magnitude of these rates suggests a common rate determining transition state/intermediate, which has been shown previously with B3LYP density functional theory (DFT) calculations. Overall, the mechanism of hydroarylation proceeds through a series of pre-equilibrium dissociative steps involving rupture of the dinuclear species or the loss of L from Ph-Ir-L to the solvento, 16-electron species, Ph-Ir(acac-O,O)_2-Sol (where Sol refers to coordinated solvent). This species then undergoes trans to cis isomerization of the acetylacetonato ligand to yield the pseudo octahedral species cis-Ph-Ir-Sol, which is followed by olefin insertion (the regioselective and rate determining step), and then activation of the C–H bond of an incoming benzene to generate the product and regenerate the catalyst

Using Reduced Catalysts for Oxidation Reactions: Mechanistic Studies of the “Periana-Catalytica” System for CH_4 Oxidation

Designing oxidation catalysts based on CH activation with reduced, low oxidation state species is a seeming dilemma given the proclivity for catalyst deactivation by overoxidation. This dilemma has been recognized in the Shilov system where reduced Pt^(II) is used to catalyze methane functionalization. Thus, it is generally accepted that key to replacing Pt^(IV) in that system with more practical oxidants is ensuring that the oxidant does not over-oxidize the reduced Pt^(II) species. The “Periana-Catalytica” system, which utilizes (bpym)Pt^(II)Cl_2 in concentrated sulfuric acid solvent at 200 °C, is a highly stable catalyst for the selective, high yield oxy-functionalization of methane. In lieu of the over-oxidation dilemma, the high stability and observed rapid oxidation of (bpym)Pt^(II)Cl_2 to Pt^(IV) in the absence of methane would seem to contradict the originally proposed mechanism involving CH activation by a reduced Pt^(II) species. Mechanistic studies show that the originally proposed mechanism is incomplete and that while CH activation does proceed with Pt^(II) there is a solution to the over-oxidation dilemma. Importantly, contrary to the accepted view to minimize Pt^(II) overoxidation, these studies also show that increasing that rate could increase the rate of catalysis and catalyst stability. The mechanistic basis for this counterintuitive prediction could help to guide the design of new catalysts for alkane oxidation that operate by CH activation

Catalytic Mechanism and Efficiency of Methane Oxidation by Hg(II) in Sulfuric Acid and Comparison to Radical Initiated Conditions

Methane conversion to methyl bisulfate by Hg^(II)(SO_4) in sulfuric acid is an example of fast and selective alkane oxidation catalysis. Dichotomous mechanisms involving C–H activation and electron transfer have been proposed based on experiments. Radical oxidation pathways have also been proposed for some reaction conditions. Hg^(II) is also of significant interest because as a d^(10) transition metal it is similar to d^(10) main-group metals that also oxidize alkanes. Density-functional calculations are presented that use both implicit and a mixture of implicit/explicit solvent models for the complete Hg_(II) catalytic cycle of methane oxidation to methyl bisulfate. These calculations are consistent with experiment and reveal that methane is functionalized to methyl bisulfate by a C–H activation and reductive metal alkyl functionalization mechanism. This reaction pathway is lower in energy than both electron transfer and proton-coupled electron transfer pathways. After methane C–H functionalization, catalysis is completed by conversion of the proposed resting state, [Hg^I(HSO_4)]_2, into Hg^0 followed by Hg^0 to Hg^(II) oxidation induced by SO_3 from dehydration of sulfuric acid. This catalytic cycle is efficient because in sulfuric acid the Hg^(II)/Hg^0 potential results in a moderate free energy barrier for oxidation (∼40 kcal/mol) and Hg^(II) is electrophilic enough to induce barriers of <40 kcal/mol for C–H activation and reductive metal alkyl functionalization. Comparison of Hg^(II) to Tl^(III) shows that while C–H activation and reductive metal alkyl functionalization have reasonable barriers for Tl^(III), the oxidation of Tl^I to Tl^(III) has a significantly larger barrier than Hg^0 to Hg^(II) oxidation and therefore Tl^(III) is not catalytic in sulfuric acid. Comparison of Hg^(II) to Cd^(II) and Zn^(II) reveals that while M^0 to M^(II) oxidation and C–H activation are feasible for these first-row and second-row transition metals, reductive metal alkyl functionalization barriers are very large and catalysis is not feasible. Calculations are also presented that outline the mechanism and energy landscape for radical-initiated (K_2S_2O_8) methane oxidation to methanesulfonic acid in sulfuric acid

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Highly Enantioselective Hydroformylation of Aryl Alkenes with Diazaphospholane Ligands

Asymmetric, rhodium-catalyzed hydroformylation of terminal and internal aryl alkenes with diazaphospholane ligands is reported. Under partially optimized reaction conditions, high enantioselectivity (>90% ee) and regioselectivities (up to 65:1 α:β) are obtained for most substrates. For terminal alkenes, both enantioselectivity and regioselectivity are proportional to the carbon monoxide partial pressure, but independent of hydrogen pressure. Hydroformylation of para-substituted styrene derivatives gives the highest regioselectivity for substrates bearing electron-withdrawing substituents. A Hammett analysis produces a positive linear correlation for regioselectivity