Coordination-induced bond weakening and small molecule activation by low-valent titanium complexes.

Bond activation of small molecules through coordination to low valent metal complexes in M⋯X-H type interactions (where X = O, N, B, Si, etc.) leads to the formation of unusually weak X-H bonds and provides a powerful approach for the synthesis of target compounds under very mild conditions. Coordination of small molecules like water, amides, silanes, boranes, and dinitrogen to Ti(III) or Ti(II) complexes results in the synergetic redistribution of electrons between the metal orbitals and the ligand orbitals which weakens and enables the facile cleavage of the X-H or N-N bonds of the ligands. This review presents an overview of coordination-induced bond activation of small molecules by low valent titanium complexes. In particular, the applications of low valent titanium-induced bond weakening in nitrogen fixation are presented. The review concludes with potential future directions for work in this area including low-valent Ti-based PCET systems, photocatalytic nitrogen reduction, and approaches to tailoring complexes for optimal bond activation.

Accessing Unusual Reactivity through Chelation-Promoted Bond Weakening.

Highly reducing Sm(II) reductants and protic ligands were used as a platform to ascertain the relationship between low-valent metal-protic ligand affinity and degree of ligand X-H bond weakening with the goal of forming potent proton-coupled electron transfer (PCET) reductants. Among the Sm(II)-protic ligand reductant systems investigated, the samarium dibromide N-methylethanolamine (SmBr2-NMEA) reagent system displayed the best combination of metal-ligand affinity and stability against H2 evolution. The use of SmBr2-NMEA afforded the reduction of a range of substrates that are typically recalcitrant to single-electron reduction including alkynes, lactones, and arenes as stable as biphenyl. Moreover, the unique role of NMEA as a chelating ligand for Sm(II) was demonstrated by the reductive cyclization of unactivated esters bearing pendant olefins in contrast to the SmBr2-water-amine system. Finally, the SmBr2-NMEA reagent system was found to reduce substrates analogous to key intermediates in the nitrogen fixation process. These results reveal SmBr2-NMEA to be a powerful reductant for a wide range of challenging substrates and demonstrate the potential for the rational design of PCET reagents with exceptionally weak X-H bonds.

Coordination-Induced Bond Weakening.

Coordination-induced bond weakening is a phenomenon wherein ligand X-H bond homolysis occurs in concert with the energetically favorable oxidation of a coordinating metal complex. The coupling of these two processes enables thermodynamically favorable proton-coupled electron transfer reductions to form weak bonds upon formal hydrogen atom transfer to substrates. Moreover, systems utilizing coordination-induced bond weakening have been shown to facilitate the dehydrogenation of feedstock molecules including water, ammonia, and primary alcohols under mild conditions. The formation of exceptionally weak substrate X-H bonds via small molecule homolysis is a powerful strategy in synthesis and has been shown to enable nitrogen fixation under mild conditions. Coordination-induced bond weakening has also been identified as an integral process in biophotosynthesis and has promising applications in renewable chemical fuel storage systems. This review presents a discussion of the advances made in the study of coordination-induced bond weakening to date. Because of the broad range of metal and ligand species implicated in coordination-induced bond weakening, each literature report is discussed individually and ordered by the identity of the low-valent metal. We then offer mechanistic insights into the basis of coordination-induced bond weakening and conclude with a discussion of opportunities for further research into the development and applications of coordination-induced bond weakening systems.

Challenges in initiating a lung cancer screening program: Experiences from two VA medical centers.

Establishing a lung cancer screening (LCS) program is an important endeavor that delivers life-saving healthcare to an at-risk population. However, developing a comprehensive LCS program requires critical elements including obtaining institutional level buy-in, hiring necessary personnel, developing appropriate infrastructure and actively engaging primary care providers, subspecialty services, and radiology. The process required to connect such services to deliver an organized LCS program that reaches all eligible candidates must be individualized to each institution's needs and infrastructure. Here we provide detailed experiences from two successful LCS programs, one using a primary care provider-based service and the other using a consult-based service. In each case, we provide the pros and cons of each system. We propose that the decision to setup an ideal LCS program could include a hybrid design that combines aspects of each system.

Dasatinib-Induced Bilateral Pleural Effusions.

Fluid accumulation in the form of pleural effusions and ascites may be attributed to a single etiology. Diagnosis depends on a thorough clinical history as well as fluid analysis. We present the case of a 60-year-old man with chronic myeloid leukemia (CML) on dasatinib, recent right-sided ischemic stroke, alcohol-associated liver disease, cocaine and alcohol use disorders in early remission, and hypertension who presented with subacute-onset of bilateral pleural effusions and ascites. Pleural fluid analysis showed an exudative effusion, while ascitic fluid analysis showed a transudative collection. After an extensive workup, the bilateral effusions were attributed to dasatinib therapy, which was also suspected to play an unclear role in the worsening ascites. Although peripheral edema and pleural effusions are well-recognized and common side effects of tyrosine kinase inhibitors (TKIs), this case represents the first description of a patient presenting with bilateral TKI-induced pleural effusions as well as concomitant ascites of unclear origin.

Ammonia Solvation vs Aqueous Solvation of Samarium Diiodide. A Theoretical and Experimental Approach to Understanding Bond Activation Upon Coordination to Sm(II).

Coordination-induced desolvation or ligand displacement by cosolvents and additives is a key feature responsible for the reactivity of Sm(II)-based reagent systems. High-affinity proton donor cosolvents such as water and glycols also demonstrate coordination-induced bond weakening of the O-H bond, facilitating reduction of a broad range of substrates. In the present work, the coordination of ammonia to SmI2 was examined using Born-Oppenheimer molecular dynamics simulations and mechanistic studies, and the SmI2-ammonia system is compared to the SmI2-water system. The coordination number and reactivity of the SmI2-ammonia solvent system were found to be similar to those of SmI2-water but exhibited an order of magnitude greater rate of arene reduction by SmI2-ammonia than by SmI2-water at the same concentrations of cosolvent. In addition, upon coordination of ammonia to SmI2, the Sm(II)-ammonia solvate demonstrates one of the largest degrees of N-H bond weakening reported in the literature compared to known low-valent transition metal ammonia complexes.

Left ventricular assist device deactivation following cardiac recovery and pump thrombosis.

Left ventricular assist devices (LVADs) have become an increasingly important component of the management of severe heart failure not only as bridge therapy to eventual orthotopic heart transplantation, but also as destination therapy. Timely diagnosis and management of device complications are of vital importance. Rarely, LVAD placement can result in cardiac recovery that may necessitate device removal. While there are reports of minimally invasive LVAD deactivation, there are currently no guidelines for device extraction or deactivation in the setting of cardiac recovery. This is a case of both cardiac recovery and pump thrombosis following LVAD implantation, managed with device inactivation and driveline excision.

Hypercalcaemia in Mycobacterium kansasii pulmonary infection.

A gentleman in his 60s with end-stage kidney disease status post kidney transplantation on prednisone and tacrolimus presented with generalised weakness for 7 days, associated with altered mental status. Investigations revealed pancytopenia, acute kidney injury, hypercalcaemia, decreased parathyroid hormone (PTH) and normal calcitriol levels. CT of the chest showed multifocal lung opacities suspicious for malignancy. Bronchoscopy with biopsy yielded no malignant cells, and bronchoalveolar lavage specimens grew Mycobacterium kansasii The patient was treated with bisphosphonates, calcitonin and antibiotics for non-tuberculous mycobacteria pulmonary infection, with improvement in serum calcium levels, and was discharged after 5 weeks of hospitalisation.The work-up for hypercalcaemia begins with PTH measurement, and low PTH levels are consistent with malignancy, immobilisation and granulomatous diseases. Hypercalcaemia in the lattermost is classically caused by overproduction of calcitriol by activated macrophages. However, there are case reports of mycobacterial infections with hypercalcaemia despite normal calcitriol levels, supporting the existence of an additional mechanism of hypercalcaemia in granulomatous infections.

Streptococcus gordonii septic arthritis of the glenohumeral joint following deltoid intramuscular vaccination.

A 68-year-old woman presented for left shoulder pain, decreased range of motion (ROM) and fever 7 days following COVID-19 vaccination. Investigations showed a tender left deltoid mass, decreased shoulder ROM and elevated inflammatory markers. MRI demonstrated a large glenohumeral effusion with synovitis, and arthrocentesis confirmed septic arthritis (SA). She required subtotal bursectomy. Intraoperative joint cultures grew Streptococcus gordonii She completed 6 weeks of antibiotics and is undergoing physical therapy for post-infectious adhesive capsulitis. SA is most commonly due to Staphylococcus aureus and ß-haemolytic streptococci, and rarely due to viridans group streptococci including S. gordonii To avoid inadvertent injection into the glenohumeral joint, vaccination should be performed posteriorly and inferiorly into the deltoid musculature. Progressive pain, fever or decreased passive ROM following vaccination should raise concern for SA. Given its rarity, however, concern for secondary SA should not affect the general population's consideration for vaccination.

Pre-operative atrial fibrillation and early right ventricular failure after left ventricular assist device implantation: a systematic review and meta-analysis.

BACKGROUND: Right ventricular failure (RVF) remains a major cause of morbidity and mortality after left ventricular assist device (LVAD). Atrial fibrillation (AF) is known for its deleterious effects on cardiac function and hemodynamics. The association of pre-operative AF with the risk of early post-LVAD RVF has not been well described. METHOD: A comprehensive literature search was performed through April, 9 2021. Cohort studies comparing the risk of post-operative RVF and/or need for right ventricular assist device (RVAD) after LVAD in patients with or without AF were included. Pooled odds ratio (OR) with 95% confidence intervals (CI) and I2 statistic were calculated using the random-effects model. RESULTS: Six studies were included in the analysis. Post-operative RVF was reported in 5 studies (1,841 patients) and RVAD use was reported in 4 studies (1,355 patients). There is a non-significant trend toward a higher risk of post-operative RVF in the AF group (pooled OR=1.25, 95%CI=0.99-1.58). No significant association between AF and RVAD use is noted (pooled OR=1.17, 95%CI=0.82-1.66). CONCLUSIONS: Pre-operative AF is not significantly associated with higher risks of post-operative RVF and RVAD use after LVAD implantation, although the trend toward higher post-operative RVF is observed in patients with pre-operative AF. Additional research using a larger study population is warranted to better understand the association of pre-operative AF and the development of post-LVAD RVF.

The utility of CardioMEMS in left ventricular assist device patients with gastrointestinal bleeding.

We report a correlation between trends of hemodynamic parameters including pulmonary artery pressures (PAP) and heart rate recorded by CardioMEMS device (St. Jude Medical, St. Paul, MN, USA) and presentation of gastrointestinal (GI) bleeding in two patients with left ventricular assist devices. We observed a decline in PAP levels prior to symptom onset and reduction in hemoglobin level in both patients. Early recognition of hemodynamic changes by CardioMEMS device might help clinicians to detect the preclinical phase of GI bleeding and intervene before patients develop severe symptoms and associated morbidity. .

Proton donor effects on the reactivity of SmI2. Experimental and theoretical studies on methanol solvation vs. aqueous solvation.

Proton donors are important components of many reactions mediated by samarium diiodide (SmI2). The addition of water to SmI2 creates a reagent system that enables the reduction of challenging substrates through proton-coupled electron-transfer (PCET). Simple alcohols such as methanol are often used successfully in reductions with SmI2 but often have reduced reactivity. The basis for the change in reactivity of SmI2-H2O and SmI2-MeOH is not apparent given the modest differences between water and methanol. A combination of Born-Oppenheimer molecular dynamics simulations and mechanistic experiments were performed to examine the differences between the reductants formed in situ for the SmI2-H2O and SmI2-MeOH systems. This work demonstrates that reduced coordination of MeOH to Sm(ii) results in a complex that reduces arenes through a sequential electron proton transfer at low concentrations and that this process is significantly slower than reduction by SmI2-H2O.

Titanocenes as Photoredox Catalysts Using Green-Light Irradiation.

Irradiation of Cp2 TiCl2 with green light leads to electronically excited [Cp2 TiCl2 ]*. This complex constitutes an efficient photoredox catalyst for the reduction of epoxides and for 5-exo cyclizations of suitably unsaturated epoxides. To the best of our knowledge, our system is the first example of a molecular titanium photoredox catalyst.

Experimental and Theoretical Studies on the Aqueous Solvation and Reactivity of SmCl2 and Comparison with SmBr2 and SmI2.

Water addition to Sm(II) has been shown to increase reactivity for both SmI2 and SmBr2. Previous work in our groups has demonstrated that this increase in reactivity can be attributed to coordination induced bond weakening enabling substrate reduction through proton-coupled electron transfer. The present work examines the interaction of water with samarium dichloride (SmCl2) and illustrates the importance of the Sm-X interaction and bond distance upon water addition critical for the reactivity of the reagent system. Born-Oppenheimer molecular dynamics simulations identify substantial variations among the reductants created in solution upon water addition to SmI2, SmBr2, and SmCl2 with the latter showing the least halide dissociation. This results in a lower water coordination number for SmCl2, creating a more powerful reducing system. As previously shown with the other SmX2-water systems, coordination-induced bond-weakening of the O-H bond of water bound to Sm(II) results in significant bond weakening. In the case of SmCl2, the bond weakening is estimated to be in the range of 83 to 88.5 kcal/mol.

Contrasting Effect of Additives on Photoinduced Reactions of SmI2.

The work described herein compares the effect of additives (HMPA, methanol, ethylene glycol, pinacol, N-methylethanolamine) on thermal and photochemical reactions of samarium diiodide (SmI2 ). In thermal reactions, additives that coordinate to SmI2 induce a significant increase in reaction rate. In photochemical reactions, the presence of an electronegative atom with a highly localized negative charge on the substrate leads to a rate deceleration. In order to benefit from the columbic interaction with the positively charged samarium cation, these substrates react preferentially by an inner sphere reduction mechanism. The addition of ligands prevents this close interaction causing rate retardation. Furthermore, studies demonstrate that excited state quenching of SmII by ethylene glycol and other additives indicate that it is unlikely to be the major cause for the observed rate retardation. This effect provides a simple diagnostic tool to distinguish between an inner and an outer sphere reduction mechanism.

Mechanistic Study and Development of Catalytic Reactions of Sm(II).

Samarium diiodide (SmI2) is one of the most widely used single-electron reductants available to organic chemists because it is effective in reducing and coupling a wide range of functional groups. Despite the broad utility and application of SmI2 in synthesis, the reagent is used in stoichiometric amounts and has a high molecular weight, resulting in a large amount of material being used for reactions requiring one or more equivalents of electrons. Although few approaches to develop catalytic reactions have been designed, they are not widely used or require specialized conditions. As a consequence, general solutions to develop catalytic reactions of Sm(II) remain elusive. Herein, we report mechanistic studies on catalytic reactions of Sm(II) employing a terminal magnesium reductant and trimethylsilyl chloride in concert with a noncoordinating proton donor source. Reactions using this approach permitted reductions with as little as 1 mol % Sm. Mechanistic studies provide strong evidence that during the reaction, SmI2 transforms into SmCl2, therefore broadening the scope of accessible reactions. Furthermore, this mechanistic approach enabled catalysis employing HMPA as a ligand, facilitating the development of catalytic Sm(II) 5- exo- trig ketyl olefin cyclization reactions. The initial work described herein will enable further development of both useful and user-friendly catalytic reactions, a long-standing, but elusive goal in Sm(II) chemistry.

Interplay between Substrate and Proton Donor Coordination in Reductions of Carbonyls by SmI2-Water Through Proton-Coupled Electron-Transfer.

The reduction of a carbonyl by SmI2-water is the first step in a range of reactions of synthetic importance. Although the reduction is often proposed to proceed through an initial stepwise electron-transfer-proton-transfer (ET-PT), recent work has shown that carbonyls and related functional groups are likely reduced though proton-coupled electron-transfer (PCET). In the present work, the reduction of an activated ester, aldehyde, a linear and cyclic ketone, and related sterically demanding carbonyls by SmI2-H2O was examined through a series of mechanistic experiments. Kinetic studies demonstrate that all substrates exhibit significant increases in the rate of reduction by SmI2 as [H2O] is increased. Under identical conditions, ketones and an aldehyde containing a methyl adjacent to the carbonyl are reduced slower than an unsubstituted variant by an order of magnitude, demonstrating the importance of substrate coordination. In the case of unactivated substrates, rates of reduction show excellent correlation with the calculated bond dissociation free energy of the O-H bond of the intermediate ketyl and the calculated free energy of intermediate ketyl radical anions derived from unhindered substrates: findings consistent with concerted PCET. Activated esters derived from methylbenzoate are likely reduced through stepwise or asynchronous PCET. Overall, this work demonstrates that the combination of the coordination of substrate and water to Sm(II) provides a configuration uniquely suited to a coupled electron- and proton-transfer process.

Experimental and Theoretical Studies on the Implications of Halide-Dependent Aqueous Solvation of Sm(II).

The addition of water to samarium(II) has been demonstrated to have a significant impact on the reduction of organic substrates, with the majority of research dedicated to the most widely used reagent, samarium diiodide (SmI2). The work presented herein focuses on the reducing capabilities of samarium dibromide (SmBr2) and demonstrates how the modest change in halide ligand results in observable mechanistic differences between the SmBr2-water and the SmI2-water systems that have considerable implications in terms of reactivity between the two reagents. Quantum chemical results from Born-Oppenheimer molecular dynamics simulations show significant differences between SmI2-water and SmBr2-water, with the latter displaying less dissociation of the halide, which results in a lower coordination number for water. Experimental results are consistent with computational results and demonstrate that the coordination sphere of SmBr2 is saturated at lower concentrations of water. In addition, coordination-induced bond-weakening of the O-H bond is demonstrably different for water bound to SmBr2, leading to an estimated O-H bond-weakening of at least 83 kcal/mol, nearly 10 kcal/mol larger than the bond-weakening observed in SmI2-H2O. Experimental results also demonstrate that the use of alcohols in place of water with SmBr2 leads to substrate reduction, albeit several orders of magnitude slower than for SmBr2-water. The difference in rates resulting from the change in proton donor is attributed to a rate-limiting proton-coupled electron transfer in SmBr2-water and a sequential electron transfer then proton transfer in SmBr2-alcohol systems, where electron transfer is rate-limiting.

Cp2 TiX Complexes for Sustainable Catalysis in Single-Electron Steps.

We present a combined electrochemical, kinetic, and synthetic study with a novel and easily accessible class of titanocene catalysts for catalysis in single-electron steps. The tailoring of the electronic properties of our Cp2 TiX-catalysts that are prepared in situ from readily available Cp2 TiX2 is achieved by varying the anionic ligand X. Of the complexes investigated, Cp2 TiOMs proved to be either equal or substantially superior to the best catalysts developed earlier. The kinetic and thermodynamic properties pertinent to catalysis have been determined. They allow a mechanistic understanding of the subtle interplay of properties required for an efficient oxidative addition and reduction. Therefore, our study highlights that efficient catalysts do not require the elaborate covalent modification of the cyclopentadienyl ligands.

Aza versus Oxophilicity of SmI2 : A Break of a Paradigm.

Ligands that coordinate to SmI2 through oxygen are prevalent in the literature and make up a significant portion of additives employed with the reagent to perform reactions of great synthetic importance. In the present work a series of spectroscopic, calorimetric and kinetic studies demonstrate that nitrogen-based analogues of many common additives have a significantly higher affinity for Sm than the oxygen-based counterparts. In addition, electrochemical experiments show that nitrogen-based ligands significantly enhance the reducing power of SmI2 . Overall, this work demonstrates that the use of nitrogen-based ligands provides a useful alternative approach to enhance the reactivity of reductants based on SmII .