Revealing the Hidden Complexity and Reactivity of Palladacyclic Precatalysts:The P(o-tolyl)3 Ligand Enables a Cocktail of Active Species Utilizing the Pd(II)/Pd(IV) and Pd(0)/Pd(II) Pathways for Efficient Catalysis

The ligand, P(o-tolyl)3, is ubiquitous in applied synthetic chemistry and catalysis, particularly in Pd-catalyzed processes, which typically include Pd(OAc)2 (most commonly used as Pd3(OAc)6) as a precatalyst. The Herrmann-Beller palladacycle [Pd(C^P)(μ2-OAc)]2 (where C^P = monocyclopalladated P(o-tolyl)3) is easily formed from reaction of Pd(OAc)2 with P(o-tolyl)3. The mechanisms by which this precatalyst system operates are inherently complex, with studies previously implicating Pd nanoparticles (PdNPs) as reservoirs for active Pd(0) species in arylative cross-coupling reactions. In this study, we reveal the fascinating, complex, and nontrivial behavior of the palladacyclic group. First, in the presence of hydroxide base, [Pd(C^P)(μ2-OAc)]2 is readily converted into an activated form, [Pd(C^P)(μ2-OH)]2, which serves as a conduit for activation to catalytically relevant species. Second, palladacyclization imparts unique stability for catalytic species under reaction conditions, bringing into play a Pd(II)/Pd(IV) cross-coupling mechanism. For a benchmark Suzuki-Miyaura cross-coupling (SMCC) reaction, there is a shift from a mononuclear Pd catalytic pathway to a PdNP-controlled catalytic pathway during the reaction. The activation pathway of [Pd(C^P)(μ2-OH)]2 has been studied using an arylphosphine-stabilized boronic acid and low-temperature NMR spectroscopic analysis, which sheds light on the preactivation step, with water and/or acid being critical for the formation of active Pd(0) and Pd(II) species. In situ reaction monitoring has demonstrated that there is a sensitivity to the structure of the arylboron species in the presence of pinacol. This work, taken together, highlights the mechanistic complexity accompanying the use of palladacyclic precatalyst systems. It builds on recent findings involving related Pd(OAc)2/PPh3 precatalyst systems which readily form higher order Pdn clusters and PdNPs under cross-coupling reaction conditions. Thus, generally, one needs to be cautious with the assumption that Pd(OAc)2/tertiary phosphine mixtures cleanly deliver mononuclear “Pd(0)Ln” species and that any assessment of individual phosphine ligands may need to be taken on a case-by-case basis

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Computer vision for non-contact monitoring of catalyst degradation and product formation kinetics

We report a computer vision strategy for the extraction and colorimetric analysis of catalyst degradation and product-formation kinetics from video footage. The degradation of palladium(ii) pre-catalyst systems to form ‘Pd black’ is investigated as a widely relevant case study for catalysis and materials chemistries. Beyond the study of catalysts in isolation, investigation of Pd-catalyzed Miyaura borylation reactions revealed informative correlations between colour parameters (most notably ΔE, a colour-agnostic measure of contrast change) and the concentration of product measured by off-line analysis (NMR and LC-MS). The breakdown of such correlations helped inform conditions under which reaction vessels were compromised by air ingress. These findings present opportunities to expand the toolbox of non-invasive analytical techniques, operationally cheaper and simpler to implement than common spectroscopic methods. The approach introduces the capability of analyzing the macroscopic ‘bulk’ for the study of reaction kinetics in complex mixtures, in complement to the more common study of microscopic and molecular specifics

Antiinflammatory therapy with canakinumab for atherosclerotic disease

BACKGROUND: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31). CONCLUSIONS: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. Copyright © 2017 Massachusetts Medical Society