Mechanistic Origin of Ligand Effects on Exhaustive Functionalization During Pd-Catalyzed Cross-Coupling of Dihaloarenes.

We describe a detailed investigation into why bulky ligands-those that enable catalysis at "12e -" Pd0-tend to promote overfunctionalization during Pd-catalyzed cross-couplings of dihalogenated substrates. After one cross-coupling event takes place, PdL initially remains coordinated to the π system of the nascent product. Selectivity for mono- vs. difunctionalization arises from the relative rates of π-decomplexation versus a second oxidative addition. Under the Suzuki coupling conditions in this work, direct dissociation of 12e - PdL from the π-complex cannot outcompete oxidative addition. Instead, Pd must be displaced from the π-complex as 14e - PdL(L') by a second incoming ligand L'. The incoming ligand is another molecule of dichloroarene if the reaction conditions do not include π-coordinating solvents or additives. More overfunctionalization tends to result when increased ligand or substrate sterics raises the energy of the bimolecular transition state for separating 14e - PdL(L') from the mono-cross-coupled product. This work has practical implications for optimizing selectivity in cross-couplings involving multiple halogens. For example, we demonstrate that small coordinating additives like DMSO can largely suppress overfunctionalization and that precatalyst structure can also impact selectivity.

Unconventional Site Selectivity in Palladium-Catalyzed Cross-Couplings of Dichloroheteroarenes under Ligand-Controlled and Ligand-Free Systems.

Halides adjacent to nitrogen are conventionally more reactive in Pd-catalyzed cross-couplings of dihalogenated N-heteroarenes. However, a very sterically hindered N-heterocyclic carbene ligand is shown to promote room-temperature cross-coupling at C4 of 2,4-dichloropyridines with high selectivity (∼10:1). This work represents the first highly selective method with a broad scope for C4-coupling of these substrates where selectivity is clearly under ligand control. Under the optimized conditions, diverse substituted 2,4-dichloropyridines and related compounds undergo cross-coupling to form C4-C(sp2) and C4-C(sp3) bonds using organoboron, -zinc, and -magnesium reagents. The synthetic utility of this method is highlighted in multistep syntheses that combine C4-selective cross-coupling with subsequent nucleophilic aromatic substitution reactions. The majority of the products herein (71%) have not been previously reported, emphasizing the ability of this methodology to open up underexplored chemical space. Remarkably, we find that ligand-free "Jeffery" conditions enhance the C4 selectivity of Suzuki coupling by an order of magnitude (>99:1). These ligand-free conditions enable the first C5-selective cross-couplings of 2,5-dichloropyridine and 2,5-dichloropyrimidine.

Different Oxidative Addition Mechanisms for 12- and 14-Electron Palladium(0) Explain Ligand-Controlled Divergent Site Selectivity.

In cross-coupling reactions, dihaloheteroarenes are usually most reactive at C─halide bonds adjacent to a heteroatom. This selectivity has been previously rationalized. However, no mechanistic explanation exists for anomalous reports in which specific ligands effect inverted selectivity with dihalopyridines and -pyridazines. Here we provide evidence that these ligands uniquely promote oxidative addition at 12e- Pd(0). Computations indicate that 12e- and 14e- Pd(0) can favor different mechanisms for oxidative addition due to differences in their HOMO symmetries. These mechanisms are shown to lead to different site preferences, where 12e- Pd(0) can favor oxidative addition at an atypical site distal to nitrogen.

Impact of 360° vs 2D Videos on Engagement in Anatomy Education.

Medical education is constantly evolving, especially as students were forced to study from home during the coronavirus disease 2019 (COVID-19) pandemic, and new technologies have driven the rapid development of supplemental online educational resources. In this study, we examine if 360° videos can promote increased engagement over standard two-dimensional (2D) videos among medical students learning anatomy. We enrolled 39 fourth-year medical students to watch two four-minute videos of anatomy lab exercises in a 360° three-dimensional format using an immersive headset or in a 2D format on a laptop computer. Every two minutes, students were asked to rate their engagement from 0-100. Following the videos, they reported their degree of agreement with 14 statements related to engagement, practicality, and interest in the technology. While watching the videos, the average engagement reported by the 360° video group was higher at each time point than the engagement reported by the two-dimensional group. Further, the engagement remained high in the 360° group through the six- and eight-minute timepoints. In the post-video survey, the 360° group reported a statistically significantly higher average engagement in seven of eight measures on the assessment. A 360° video was rated as more practical and interesting than a two-dimensional video. No significant difference existed in the perceived ease of learning. Overall, the use of 360° video may improve engagement for short videos used in medical education. However, developing a better understanding of its impact on learning outcomes will be critical for determining the overall value and effectiveness of this tool.

Effect of Cardiac Surgery on One-Year Patient-Reported Outcomes: A Prospective Cohort Study.

BACKGROUND: Current cardiac surgery risk algorithms and quality measures focus on perioperative outcomes. However, delivering high-value, patient-centered cardiac care will require a better understanding of long-term patient-reported quality of life after surgery. Our objective was to prospectively assess the effect of cardiac surgery on long-term patient-reported outcomes. METHODS: Patients undergoing cardiac surgery at an academic medical center (2016 to 2017) were eligible for enrollment. Patient-reported outcomes were measured using the National Institutes of Health Patient-Reported Outcomes Measurement Information System preoperatively and 1 year postoperatively across five domains: mental health, physical health, physical functioning, social satisfaction, and applied cognition. Baseline data and perioperative outcomes were obtained from The Society of Thoracic Surgeons Database. The effect of cardiac surgery on long-term patient-reported quality of life was assessed. RESULTS: Ninety-eight patients were enrolled and underwent cardiac surgery, with 92.9% (91 of 98) successful follow-up. The most common operation was coronary artery bypass graft surgery at 63.3% (62 of 98), with 60.2% (59 of 98) undergoing an elective operation. One-year all-cause mortality was 5.1% (5 of 98). Rate of major morbidity was 11.2% (11 of 98). Cardiac surgery significantly improved patient-reported outcomes at 1 year across four domains: mental health (preoperative 47.3 ± 7.7 vs postoperative 51.1 ± 8.9, P < .001), physical health (41.2 ± 8.2 vs 46.3 ± 9.3, P < .001), physical functioning (39.8 ± 8.6 vs 44.8 ± 8.5, P < .001), and social satisfaction (46.8 ± 10.9 vs 50.7 ± 10.8, P = .023). Hospital discharge to a facility did not affect 1-year patient-reported outcomes. CONCLUSIONS: Cardiac surgery improves long-term patient-reported quality of life. Mental, physical, and social well-being scores were significantly higher 1 year postoperatively. Data collection with the National Institutes of Health Patient-Reported Outcomes Measurement Information System provides meaningful, quantifiable results that may improve delivery of patient-centered care.

Microarray Analysis of Gene Expression in Saccharomyces cerevisiae kap108Δ Mutants upon Addition of Oxidative Stress.

Protein transport between the nucleus and cytoplasm of eukaryotic cells is tightly regulated, providing a mechanism for controlling intracellular localization of proteins, and regulating gene expression. In this study, we have investigated the importance of nucleocytoplasmic transport mediated by the karyopherin Kap108 in regulating cellular responses to oxidative stress in Saccharomyces cerevisiae We carried out microarray analyses on wild-type and kap108 mutant cells grown under normal conditions, shortly after introduction of oxidative stress, after 1 hr of oxidative stress, and 1 hr after oxidative stress was removed. We observe more than 500 genes that undergo a 40% or greater change in differential expression between wild-type and kap108Δ cells under at least one of these conditions. Genes undergoing changes in expression can be categorized in two general groups: 1) those that are differentially expressed between wild-type and kap108Δ cells, no matter the oxidative stress conditions; and 2) those that have patterns of response dependent upon both the absence of Kap108, and introduction or removal of oxidative stress. Gene ontology analysis reveals that, among the genes whose expression is reduced in the absence of Kap108 are those involved in stress response and intracellular transport, while those overexpressed are largely involved in mating and pheromone response. We also identified 25 clusters of genes that undergo similar patterns of change in gene expression when oxidative stresses are added and subsequently removed, including genes involved in stress response, oxidation-reduction processing, iron homeostasis, ascospore wall assembly, transmembrane transport, and cell fusion during mating. These data suggest that Kap108 is important for regulating expression of genes involved in a variety of specific cell functions.