Using metal substrates to enhance the reactivity of graphene towards Diels-Alder reactions.

The Diels-Alder (DA) reaction, a classic cycloaddition reaction involving a diene and a dienophile to form a cyclohexene, is among the most versatile organic reactions. Theories have predicted thermodynamically unfavorable DA reactions on pristine graphene owing to its low chemical reactivity. We hypothesized that metals like Ni could enhance the reactivity of graphene towards DA reactions through charge transfer. The results indeed showed that metal substrates enhanced the reactivity of graphene in the DA reactions with a diene, 2,3-dimethoxy butadiene (DMBD), and a dienophile, maleic anhydride (MAH), with the activity enhancement in the order of Ni > Cu, and both are more reactive than graphene supported on silicon wafer. The rate constants were estimated to be two times higher for graphene supported on Ni than on silicon wafer. The computational results support the experimentally obtained rate trend of Ni > Cu, both predicted to be greater than unsupported graphene, which is explained by the enhanced graphene-substrate interaction reflected in charge transfer effects with the strongly interacting Ni. This study opens up a new avenue for enhancing the chemical reactivity of pristine graphene through substrate selection.

On the Reactivity Enhancement of Graphene by Metallic Substrates towards Aryl Nitrene Cycloadditions.

Pristine graphene is fairly inert chemically, and as such, most application-driven studies use graphene oxide, or reduced graphene oxide. Using substrates to modulate the reactivity of graphene represents a unique strategy in the covalent functionalization of this otherwise fairly inert material. It was found that the reactivity of pristine graphene towards perfluorophenyl azide (PFPA) can be enhanced by a metal substrate on which graphene is supported. Results on the extent of functionalization, defect density, and reaction kinetics all show that graphene supported on Ni (G/Ni) has the highest reactivity toward PFPA, followed by G/Cu and then G/silicon wafer. DFT calculations suggest that the metal substrate stabilizes the physisorbed nitrene through enhanced electron transfer to the singlet nitrene from the graphene surface assisted by the electron rich metal substrate. The G/Ni substantially stabilizes the singlet nitrene relative to G/Cu and the free-standing graphene. The product structure is also predicted to be substrate dependent. These findings open up opportunities to enhance the reactivity of pristine graphene simply through the selection of the substrate. This also represents a new and powerful approach to increasing the reactivity of singlet nitrenes through direct electronic communication with graphene.

Pathway Bifurcations in the Activation of Allylic Halides by Palladium and Their Influence on the Dynamics of η1 and η3 Allyl Intermediates.

Transition-metal-catalyzed allylic substitution often exhibits complex product selectivity patterns, which have been primarily attributed to π ↔ σ ↔ π isomerization of the η1 and η3 allyl intermediates. Product selectivity may be even further complicated if η1- and η3-allyls share a single transition state (TS), leading to their formation resulting in a post-transition-state bifurcation (PTSB). In this work, density functional theory calculations using ab initio molecular dynamics (AIMD) have been carried out that support the presence of a PTSB in Pd-catalyzed allylic halide activation directly influencing product selectivity. The AIMD results initiated from the TS predict the η1-allyl to be favored in the gas phase and a low dielectric (ε < 2.5) for trialkylphosphines, while the selectivity shifts toward the η3-allyl in higher dielectrics. The minimum energy path is also predicted to shift in product preference, consistent with the dynamics predictions. The bifurcation in allylic chloride activation is predicted to largely favor the η3-allyl at any solvent polarity. A PTSB was also discovered to be present in Ni and Pt allylic activation but with less bifurcation. These results offer a unique view into the mechanism of metal-catalyzed allylic substitution.

Two-Step Synthesis of Heptacyclo[6.6.0.02,6 .03,13 .04,11 .05,9 .010,14 ] tetradecane from Norbornadiene: Mechanism of the Cage Assembly and Post-synthetic Functionalization.

A selective and scalable two-step approach to the dimerization of norbornadiene (NBD) into its thermodynamically most stable dimer, heptacyclo[6.6.0.02,6 .03,13 .04,11 .05,9 .010,14 ] tetradecane, (HCTD) is reported. Calculations indicate that the reaction starts with the Rh-catalyzed stepwise homo Diels-Alder cyclisation of NBD into its exo-cis-endo dimer. Treatment of this compound with acid promotes its evolution to HCTD via a [1,2]-sigmatropic rearrangement. The assemblies of 7,12-disubstituted cages from 7-(alkyl/aryl) NBDs, as well as the selective post-synthetic C-H functionalization of the core HCTD scaffold at position C1, or positions C1 and C4 are described.

Half-Sandwich Ruthenium Carbene Complexes Link trans-Hydrogenation and gem-Hydrogenation of Internal Alkynes.

The hydrogenation of internal alkynes with [Cp*Ru]-based catalysts is distinguished by an unorthodox stereochemical course in that E-alkenes are formed by trans-delivery of the two H atoms of H2. A combined experimental and computational study now provides a comprehensive mechanistic picture: a metallacyclopropene (η2-vinyl complex) is primarily formed, which either evolves into the E-alkene via a concerted process or reacts to give a half-sandwich ruthenium carbene; in this case, one of the C atoms of the starting alkyne is converted into a methylene group. This transformation represents a formal gem-hydrogenation of a π-bond, which has hardly any precedent. The barriers for trans-hydrogenation and gem-hydrogenation are similar: whereas DFT predicts a preference for trans-hydrogenation, CCSD(T) finds gem-hydrogenation slightly more facile. The carbene, once formed, will bind a second H2 molecule and evolve to the desired E-alkene, a positional alkene isomer or the corresponding alkane; this associative pathway explains why double bond isomerization and over-reduction compete with trans-hydrogenation. The computed scenario concurs with para-hydrogen-induced polarization transfer (PHIP) NMR data, which confirm direct trans-delivery of H2, the formation of carbene intermediates by gem-hydrogenation, and their evolution into product and side products alike. Propargylic -OR (R = H, Me) groups exert a strong directing and stabilizing effect, such that several carbene intermediates could be isolated and characterized by X-ray diffraction. The gathered information spurred significant preparative advances: specifically, highly selective trans-hydrogenations of propargylic alcohols are reported, which are compatible with many other reducible functional groups. Moreover, the ability to generate metal carbenes by gem-hydrogenation paved the way for noncanonical hydrogenative cyclopropanations, ring expansions, and cycloadditions.

Progressive cationic functionalization of chlorin derivatives for antimicrobial photodynamic inactivation and related vancomycin conjugates.

It is known that multiple cationic charges are required to produce broad-spectrum antimicrobial photosensitizers (PS) for photodynamic inactivation (aPDI) or photodynamic therapy of bacteria and fungi. In the present study we describe the synthesis and aPDI testing of a set of derivatives prepared from the parent pheophytin molecule with different numbers of attached side arms (1-3) each consisting of five quaternized cationic groups (pentacationic), producing the corresponding [Zn2+]pheophorbide-a-N(C2N+C1C3)5 (Zn-Phe-N5+, 5 charges), [Zn2+]chlorin e6-[N(C2N+C1C3)5]2 (Zn-Chl-N10+, 10 charges) and [Zn2+]mesochlorin e6-[N(C2N+C1C3)5]3 (Zn-mChl-N15+, 15 charges). Moreover, a conjugate between Zn-Phe-N5+ and the antibiotic vancomycin called Van-[Zn2+]-m-pheophorbide-N(C2N+C1C3)5 (Van-Zn-mPhe-N5+) was also prepared. The aPDI activities of all compounds were based on Type-II photochemistry (1O2 generation). We tested these compounds against Gram-positive methicillin-resistant Staphylococcus aureus (MRSA), Gram-negative Escherichia coli, and the fungal yeast Candida albicans. All three compounds were highly active against MRSA, giving eradication (≥6 logs of killing) with <1.0 µM and 10 J cm-2 of 415 nm light. The order of activity was Zn-Phe-N5+ > Zn-Chl-N10+ > Zn-mChl-N15+. In the case of E coli the activity was much lower (eradication was only possible with 50 µM Zn-mChl-N15+ and 20 J cm-2). The order of activity was the reverse of that found with MRSA (Zn-mChl-N15+ > Zn-Chl-N10+ > Zn-Phe-N5+). Activity against C. albicans was similar to E. coli with Zn-mChl-N15+ giving eradication. The activity of Van-Zn-mPhe-N5+ was generally lower than that of Zn-Phe-N5+ (except for E. coli). Red (660 nm) light was also effective as might be expected from the absorption spectra. An initial finding that Van-Zn-mPhe-N5+ might have higher activity against vancomycin resistant Enterococcus fecium (VRE) strains (compared to vancomycin sensitive strains) was disproved when it was found that VRE strains were also more sensitive to aPDI with Zn-Phe-N5+. The minimum inhibitory concentrations of Van-Zn-mPhe-N5+ were higher than those of Van alone, showing that the antibiotic properties of the Van moiety were lessened in the conjugate. In conclusion, Zn-Phe-N5+ is a highly active PS against Gram-positive species and deserves further testing. Increasing the number of cationic charges increased aPDI efficacy on C. albicans and Gram-negative E. coli.

α-Dicationic Chelating Phosphines: Synthesis and Application to the Hydroarylation of Dienes.

A series of new P^P-chelating ligands constituted by a dicationic -[P(H2Im)2]+2 unit (H2Im = 1,3-dimethyl-4,5-dihydroimidazol-2-ylidene) and a -PPh2 group connected through structurally different backbones have been synthesized. Evaluation of their reactivity toward different metal centers provides evidence that the dicationic fragment, otherwise reluctant to coordinate metals, readily participates in the formation of chelates when embedded into such a scaffold. Moreover, it significantly enhances the Lewis acidity of the metals to which it coordinates. This property has been used to develop a Rh catalyst that efficiently triggers the hydroarylation of dienes with electron-rich aromatic molecules. Kinetic studies and deuterium-labeling experiments, as well as density functional theory calculations, were performed in order to rationalize these findings.

Computational Study on the Co-Mediated Intramolecular Pauson-Khand Reaction of Fluorinated and Chiral N-Tethered 1,7-Enynes.

The Co2(CO)8-mediated intramolecular Pauson-Khand reaction is an elegant approach to obtain cyclopentenone derivatives containing asymmetric centers. In this work, we employed density functional theory calculations at the M11/6-311+G(d,p) level of theory to investigate the mechanism and reactivity for the Pauson-Khand reaction of fluorinated and asymmetric N-tethered 1,7-enynes. The rate-determining step was found to be the intramolecular alkene insertion into the carbon-cobalt bond. The stereoselectivity of the alkene insertion step was rationalized by the different transition states showing the coordination of the alkene through the Re- and Si-face. The effects of different fluorine groups and steric effects on both the alkenyl and alkynyl moieties were also theoretically investigated.

The relationship between obesity, hemoglobin A1c and the severity of COVID-19 at an urban tertiary care center in New York City: a retrospective cohort study.

OBJECTIVES: To determine if obesity and diabetes are risk factors for severe outcomes in COVID-19 and to compare patient outcomes in those two conditions. DESIGN: Retrospective cohort study. SETTING: Urban tertiary care center in New York City. PARTICIPANTS: 302 patients admitted in an inpatient setting, ≥18 years old, with a laboratory-confirmed diagnosis of COVID-19 via nasal PCR swab were randomly selected. Patients were separated into two cohorts based on their body mass index and hemoglobin A1c. 150 patients were placed in the non-obese, non-diabetic cohort and 152 patients were placed in the corresponding cohort (obesity alone, obesity and diabetes, and diabetes alone). MEASUREMENTS: Primary outcomes were development of acute kidney injury, commencement of renal replacement therapy, aminotransferase elevation, troponin elevation, lactic acidosis, development of septic shock, use of vasopressors, presence of acute respiratory distress syndrome (ARDS) and intubation. The secondary outcomes were length of stay in days and mortality. RESULTS: Patients with obesity and/or diabetes were more likely to develop ARDS (79 patients vs 57 patients, p<0.0001) and to be intubated (71 patients vs 45 patients, p=0.0031). Patients with obesity and/or diabetes were more likely to require vasopressors (60 patients vs 41 patients, p=0.0284) and to develop lactic acidosis (median 3.15 mmol/L, IQR 1.8 to 5.2 mmol/L, p=0.0432). When comparing patients with diabetes with and without obesity against patients with obesity alone, they were more likely to develop ARDS (87.5%, p=0.0305). Despite these findings, there was no difference in mortality. CONCLUSIONS: In patients hospitalised with COVID-19, those with obesity and/or diabetes were more likely to suffer severe complications, but had negligible differences in mortality. This highlights the importance of close monitoring of patients with these conditions and additional areas of research needed to explain the mortality findings.

A bifunctional electrode engineered by sulfur vacancies for efficient electrocatalysis.

Defect engineering is an efficient method to enhance electrocatalytic performance by generating more active sites, which reduces the kinetic energy barrier. However, the increased defects may induce aggregation and decrease active sites over a long period of time, which in turn impairs the catalytic performance. Thus, the development of new strategies for producing non-noble catalysts with maintained active sites for long-term stability is an attractive goal. Here we demonstrate the fabrication of defect-rich carbon nanotubes by the doping of nitrogen and the hybridization of multi-metal chalcogenides with the help of metal-organic-framework (MOF) precursors. The obtained porous carbon nanohybrids exhibit extraordinary electrocatalytic performance in alkaline environments with overpotentials as low as 116 mV for the oxygen evolution reaction (OER). Remarkably, the overpotential for the hydrogen evolution reaction (HER) significantly decreased to 137 mV after 6000 cycles. In combination with theoretical calculations, it is revealed that in this HER process, the formed sulfur vacancies can be dynamically occupied by hydrogen atoms. This hydrogen occupation may prevent the aggregation of active sites in the long term. This work thus offers an efficient strategy for improving HER and OER activities.

Jet lag: Heuristics and therapeutics.

Jet lag is one of those common medical problems, to which most people don't give a serious thought. However, it is intricately intertwined with our normal circadian rhythm. It is classified as a sleep disorder. There is also a dearth of good scientific literature, not to mention clinical trials on the subject. Slowly but steadily, the scientific community is realizing the various deleterious health effects of jet lag and is devising innovative methods to counter them. This narrative review touches upon the etiopathogenesis, clinical manifestations and therapeutic strategies effective against the nagging problem of jet lag.

Mixed Adenoneuroendocrine Carcinoma of the Gastroesophageal Junction: A Rare Find.

Neoplastic lesions that demonstrate neuroendocrine features are rare. However, esophageal tumors containing both adenocarcinomatous and neuroendocrine components are exceedingly rare. Mixed adenoneuroendocrine carcinomas (MANECs) are gastrointestinal tumors with both adenocarcinomatous and neuroendocrine differentiation. They have a tendency for early metastases but clinically manifest relatively late. Imaging studies are often nonspecific with regard to tumor type, and a histopathologic study of biopsy material is required for definitive diagnosis. The overall prognosis is poor. The current report describes a rare case of gastroesophageal MANEC tumor, with approximately 60% neuroendocrine and 40% adenocarcinomatous components. Since there is a dearth of concrete management guidelines for MANECs, we present possible management options to add to the existing literature.

Recurrent Lactobacillus Bacteremia in a Patient With Leukemia.

Lactobacillus species are a commensal flora of the human gastrointestinal and the female genitourinary tract. Lactobacilli especially the rhamnosus species, are common components of commercial probiotics. They are rarely associated with pathology in immunocompetent people, but they have been known to cause dental caries, bacteremia, and endocarditis in patients with suppressed immune function. Cases of Lactobacillus bacteremia have been reported in patients with acute myeloid leukemia, large granular lymphocytic leukemia, and in transplant recipients. In this article, we report a strange case of recurrent Lactobacillus bacteremia causing multiple episodes of fever of unknown origin in a patient with leukemia. This report is unique as Lactobacillus is not recognized as a common source of bacteremia. Moreover, the source of the bacillus continued to elude us even after extensive investigation.

Results of a Quality Improvement Project Aimed at Eliminating Healthcare Waste by Changing Medical Resident Test Ordering Behavior.

BACKGROUND: In light of rising healthcare costs and evidence of inefficient use of medical resources, there is growing interest in reducing healthcare waste by clinicians. Unwarranted lab tests may lead to further tests, prolonged hospital stays, unnecessary referrals and procedures, patient discomfort, and iatrogenic anemia, resulting in significant economic and clinical effects. Blood tests are essential in guiding medical decisions, but they are also associated with significant financial and clinical costs. We designed a quality improvement study that attempted to decrease inappropriate ordering of laboratory tests while maintaining quality of care in a large residency program. METHODS: An algorithm outlining indications for complete blood count (CBC), coagulation profile (PT/INR) and basic metabolic profile (BMP) was created by the study team. Data from 1,312 patients over a 3-month period in the pre-intervention phase and 1,255 patients during the selected intervention phase were analyzed. The primary endpoint was mortality rate and secondary endpoints were length of stay and laboratory costs. RESULTS: There were significant decreases in the number of PT/INR orders (20.6%), followed by BMP orders (12.4%), and CBC orders (9.3%). The mortality rate was 5.3% for the pre-intervention phase and 5.8% for the selected intervention phase, with a difference of 0.5% (P = 0.44). CONCLUSION: Our approach leads to a decrease in costs, preventing unnecessary downstream testing, and improving patient experience. It also brought a mental discipline while ordering blood tests amongst residents.