Computational study on the boundary between the concerted and stepwise mechanism of bimolecular SNAr reactions

The text-book mechanism of bimolecular nucleophilic aromatic substitutions (SNAr) reactions is a stepwise process that proceeds via a so-called Meisenheimer intermediate. Only recently the alternative, concerted version of this mechanism has gained acceptance as more and more examples thereof have been reported. But so far only isolated examples of concerted SNAr reactions have been described and a coherent picture of when a SNAr reaction proceeds via a stepwise and when via a concerted mechanism has not yet been established. Here key factors are identified that influence the mechanistic choice of SNAr reactions. Moreover, the electron affinity is used as a simple descriptor to make a prediction on whether a given aryl fluoride substrate favors a concerted or stepwise mechanism

N-Silylation of amines mediated by Et3SiH/KOtBu

Silylation of primary and secondary amines is reported, using triethylsilane as the silylating reagent in the presence of potassium tert-butoxide (KOtBu). The reaction proceeds well in the presence of 0.2 equiv of KOtBu. In competition experiments, aniline is selectively silylated over aliphatic amines. Computational studies support a catalytic mechanism which is initiated by KOtBu interacting with the silane to form KH and silylated amine. The KH then takes over the role of base in the propagation of the cyclic mechanism, and deprotonates the amine. This reacts with R3SiH to afford the product R3SiNR’R” and regenerate KH

Convergence of multiple synthetic paradigms in a universally programmable chemical synthesis machine

Although the automatic synthesis of molecules has been established, each reaction class uses bespoke hardware. This means that the connection of multi-step syntheses in a single machine to run many different protocols and reactions is not possible, as manual intervention is required. Here we show how the Chemputer synthesis robot can be programmed to perform many different reactions, including solid-phase peptide synthesis, iterative cross-coupling and accessing reactive, unstable diazirines in a single, unified system with high yields and purity. Developing universal and modular hardware that can be automated using one software system makes a wide variety of batch chemistry accessible. This is shown by our system, which performed around 8,500 operations while reusing only 22 distinct steps in 10 unique modules, with the code able to access 17 different reactions. We also demonstrate a complex convergent robotic synthesis of a peptide reacted with a diazirine-a process requiring 12 synthetic steps

A Case of Hypereosinophilic Syndrome Presenting With Multiorgan Infarctions Associated With Disseminated Intravascular Coagulation

Thromboembolism is one of the most critical complications of hypereosinophilic syndrome (HES). We report here a case of multi-organ infarctions related to HES. A 23-year-old woman was referred to our hospital with hemoptysis. Not only pulmonary, but also renal and splenic infarctions were detected on computed tomography images. Blood tests showed profound peripheral eosinophilia. She was diagnosed with HES with disseminated intravascular coagulation (DIC). We initiated infusion of corticosteroids, which effectively suppressed peripheral eosinophilia. However, consumptive coagulopathy did not improve and intracerebral hemorrhage related to thrombosis then developed. Addition of interferon-alpha resulted in the correction of the DIC associated with HES

Neutrophil extracellular traps enhance early inflammatory response in Sendai virus-induced asthma phenotype

Paramyxoviral infection in childhood has been linked to a significant increased rate of asthma development. In mice, paramyxoviral infection with the mouse parainfluenza virus type I, Sendai virus (Sev), causes a limited bronchiolitis followed by persistent asthma traits. We have previously shown that the absence of cysteine protease dipeptidyl peptidase I (DPPI) dampened the acute lung inflammatory response and the subsequent asthma phenotype induced by Sev. Adoptive transfer of wild type neutrophils into DPPI-deficient mice restored leukocyte influx, the acute cytokine response, and the subsequent mucous cell metaplasia that accompanied Sev-induced asthma phenotype. However, the exact mechanism by which DPPI-sufficient neutrophils promote asthma development following Sev infection is still unknown. We hypothesize that neutrophils recruited to the alveolar space following Sev infection elaborate neutrophil extracellular traps (NETs) that propagate the inflammatory cascade, culminating in the eventual asthma phenotype. Indeed, we found that Sev infection was associated with NET formation in the lung and release of cell-free DNA complexed to myeloperoxidase (MPO) in the alveolar space and plasma that peaked on day 2-post infection. Absence of DPPI significantly attenuated Sev-induced NET formation in vivo and in vitro. Furthermore, concomitant administration of DNase 1, which dismantled NETs, or inhibition of peptidylarginine deiminase 4 (PAD4), an essential mediator of NET formation, suppressed the early inflammatory responses to Sev infection. Lastly, NETs primed bone marrow derived cells to release cytokines that can amplify the inflammatory cascade

Slab melting as a barrier to deep carbon subduction

Interactions between crustal and mantle reservoirs dominate the surface inventory of volatile elements over geological time, moderating atmospheric composition and maintaining a lifesupporting planet1. While volcanoes expel volatile components into surface reservoirs, subduction of oceanic crust is responsible for replenishment of mantle reservoirs2,3. Many natural, ‘superdeep’ diamonds originating in the deep upper mantle and transition zone host mineral inclusions, indicating an affinity to subducted oceanic crust4–7. Here we show that the majority of slab geotherms will intersect a deep depression along the melting curve of carbonated oceanic crust at depths of approximately 300 to 700 kilometres, creating a barrier to direct carbonate recycling into the deep mantle. Low-degree partial melts are alkaline carbonatites that are highly reactive with reduced ambient mantle, producing diamond. Many inclusions in superdeep diamonds are best explained by carbonate melt–peridotite reaction. A deep carbon barrier may dominate the recycling of carbon in the mantle and contribute to chemical and isotopic heterogeneity of the mantle reservoir

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Mechanistic studies on three areas of organic chemistry - a combined computational and experimental approach

This thesis was previously held under moratorium from 01/04/2020 to 01/04/2022This Thesis contains three results chapters. The underlying aim of these project chapters is to gain a detailed understanding of reaction mechanisms and to develop new synthetic methods based on this knowledge. The three results chapters come under the following titles. Organic Super Electron Donors Made Catalytic (Chapter 2) Neutral organic super electron donors are versatile and powerful reducing agents. So far, however, it has not been possible to use such electron donors in a catalytic sense. Also, many of these donors show significant limitations when applied in radical cascade reactions. This limitation is due to the fact that these donors form relatively long-lived radical cation species upon oxidation, which interfere with the desired radical reaction. The reason for this behaviour is, that the established classes of neutral organic electron donors are (potential) double electron donors. To address these shortcomings, this Thesis reports ways to generate and utilise neutral organic single electron donors (Scheme IV-I). According to the envisaged scheme, the organic single electron donor (i) is generated as an intermediate in a radical chain reaction. The hydrogen abstraction from (iii) by the generated radical, •R’, is the chain propagation step. It becomes evident that the scheme harbours the possibility to use the single electron donor (i) catalytically. The aminal (iii) is regenerated from the benzimidazolium salt (ii) and a hydride source. Sodium borohydride was found to be the ideal hydride source. The protocol was used to perform a range of 5-exo-trig radical cyclisation reactions and its applicability is demonstrated. Based on a combined experimental and computational approach, a plausible initiation pathway based on oxygen in the air is proposed. [Graphic here - Scheme IV-I The proposed scheme for catalytic use of an organic single electron donor (i).] The KOtBu-Et3SiH Reagent System (Chapter 3) The combination of silanes and potassium tert-butoxide allows for various different transformations. Accordingly, several mechanistic pathways and key reactive species have been proposed to account for the different reactions in the literature (Figure IV-I). Hydride transfer mechanisms have been suggested to involve the silicate (iv), which is in equilibrium with potassium hydride (v) and silyl ether (vi). Plausible radical and single electron transfer mechanisms involve (vii) and (viii). Finally, hydrogen atom transfer mechanisms via (ix) cannot be fully excluded as alternatives for many of the discussed mechanisms. The formidable challenge is to probe these different domains of reactivity separately with suitable substrates. Based on a combined approach of experimental and computational investigations, strong indications are reported for single electron transfer reactivity (presumably with species (viii) acting as the single electron donor) and hydride transfer mechanisms. Additionally, plausible mechanisms for the silylation reaction of amines (x) to give the silylated species (xi) are proposed based on computational studies (Scheme IV-II). [Graphic here - Figure IV-I Proposed key species that are responsible for the reactivity of the KOtBu-Et3SiH reagent system.] [Graphic here - Scheme IV-II What is the mechanism of the silylation reaction of simple amines with the KOtBu-Et3SiH (or more generally the KOtBu-Silane) reagent system?] Concerted vs. Stepwise SNAr Mechanism (Chapter 4) Over the last decades, more and more reports accumulated in the literature that suggested certain SNAr reactions follow a concerted pathway. These days, the combined impact of these investigations has reached a critical momentum and it seems appropriate to fundamentally question the long established mechanistic picture of the SNAr reaction. High level computational (wave-function based) methods are here employed to benchmark DFT functionals, based on whether these correctly predict the mechanism of a SNAr reaction to be stepwise or concerted. A reliable functional is then used to establish trends, which show what aspects (nucleophile, counter cation, leaving group, aromatic system) of the reaction at hand influence its mechanistic propensity, and in what way. Eventually this allowed estimation of when an SNAr reaction follows a concerted and when a stepwise pathway is taken.This Thesis contains three results chapters. The underlying aim of these project chapters is to gain a detailed understanding of reaction mechanisms and to develop new synthetic methods based on this knowledge. The three results chapters come under the following titles. Organic Super Electron Donors Made Catalytic (Chapter 2) Neutral organic super electron donors are versatile and powerful reducing agents. So far, however, it has not been possible to use such electron donors in a catalytic sense. Also, many of these donors show significant limitations when applied in radical cascade reactions. This limitation is due to the fact that these donors form relatively long-lived radical cation species upon oxidation, which interfere with the desired radical reaction. The reason for this behaviour is, that the established classes of neutral organic electron donors are (potential) double electron donors. To address these shortcomings, this Thesis reports ways to generate and utilise neutral organic single electron donors (Scheme IV-I). According to the envisaged scheme, the organic single electron donor (i) is generated as an intermediate in a radical chain reaction. The hydrogen abstraction from (iii) by the generated radical, •R’, is the chain propagation step. It becomes evident that the scheme harbours the possibility to use the single electron donor (i) catalytically. The aminal (iii) is regenerated from the benzimidazolium salt (ii) and a hydride source. Sodium borohydride was found to be the ideal hydride source. The protocol was used to perform a range of 5-exo-trig radical cyclisation reactions and its applicability is demonstrated. Based on a combined experimental and computational approach, a plausible initiation pathway based on oxygen in the air is proposed. [Graphic here - Scheme IV-I The proposed scheme for catalytic use of an organic single electron donor (i).] The KOtBu-Et3SiH Reagent System (Chapter 3) The combination of silanes and potassium tert-butoxide allows for various different transformations. Accordingly, several mechanistic pathways and key reactive species have been proposed to account for the different reactions in the literature (Figure IV-I). Hydride transfer mechanisms have been suggested to involve the silicate (iv), which is in equilibrium with potassium hydride (v) and silyl ether (vi). Plausible radical and single electron transfer mechanisms involve (vii) and (viii). Finally, hydrogen atom transfer mechanisms via (ix) cannot be fully excluded as alternatives for many of the discussed mechanisms. The formidable challenge is to probe these different domains of reactivity separately with suitable substrates. Based on a combined approach of experimental and computational investigations, strong indications are reported for single electron transfer reactivity (presumably with species (viii) acting as the single electron donor) and hydride transfer mechanisms. Additionally, plausible mechanisms for the silylation reaction of amines (x) to give the silylated species (xi) are proposed based on computational studies (Scheme IV-II). [Graphic here - Figure IV-I Proposed key species that are responsible for the reactivity of the KOtBu-Et3SiH reagent system.] [Graphic here - Scheme IV-II What is the mechanism of the silylation reaction of simple amines with the KOtBu-Et3SiH (or more generally the KOtBu-Silane) reagent system?] Concerted vs. Stepwise SNAr Mechanism (Chapter 4) Over the last decades, more and more reports accumulated in the literature that suggested certain SNAr reactions follow a concerted pathway. These days, the combined impact of these investigations has reached a critical momentum and it seems appropriate to fundamentally question the long established mechanistic picture of the SNAr reaction. High level computational (wave-function based) methods are here employed to benchmark DFT functionals, based on whether these correctly predict the mechanism of a SNAr reaction to be stepwise or concerted. A reliable functional is then used to establish trends, which show what aspects (nucleophile, counter cation, leaving group, aromatic system) of the reaction at hand influence its mechanistic propensity, and in what way. Eventually this allowed estimation of when an SNAr reaction follows a concerted and when a stepwise pathway is taken