Class Of Substrates Research Articles

Uniform, Strain-Free, Large-Scale Graphene and h-BN Monolayers Enabled by Hydrogel Substrates.

Translation of the unique properties of 2D monolayers from non-scalable micron-sized samples to macroscopic scale is a longstanding challenge obstructed by the substrate-induced strains, interface nonuniformities, and sample-to-sample variations inherent to the scalable fabrication methods. So far, the most successful strategies to reduce strain in graphene are the reduction of the interface roughness and lattice mismatch by using hexagonal boron nitride (h-BN), with the drawback of limited uniformity and applicability to other 2D monolayers, and liquid water, which is not compatible with electronic devices. This work demonstrates a new class of substrates based on hydrogels that overcome these limitations and excel h-BN and water substrates at strain relaxation enabling superiorly uniform and reproducible centimeter-sized sheets of unstrained monolayers. The ultimate strain relaxation and uniformity are rationalized by the extreme structural adaptability of the hydrogel surface owing to its high liquid content and low Young's modulus, and are universal to all 2D materials irrespective of their crystalline structure. Such platforms can be integrated into field effect transistors and demonstrate enhanced charge carrier mobilities in graphene. These results present a universal strategy for attaining uniform and strain-free sheets of 2D materials and underline the opportunities enabled by interfacing them with soft matter.

Efficient biotransformations in Cunninghamella elegans and Streptomyces sp. JCM9888 of selectively fluorinated benzoic acids to the corresponding benzamides and benzyl alcohols

An efficient conversion of ortho, meta and para fluoro- and trifluoromethyl-substituted benzoic acids to the corresponding benzamides in fermentations of the soil bacterium Streptomyces sp. JCM9888 is described. We also report the efficient reduction of the same class of substrates to the corresponding benzyl alcohols with the fungi Cunninghamella elegans. These biotransformations were surprisingly efficient and may have value as disruptive technologies in process chemistry.

Metabolite Profiling in the Liver, Plasma and Milk of Dairy Cows Exposed to Tansy Ragwort (Senecio jacobae) Pyrrolizidine Alkaloids.

Plant-derived pyrrolizidine alkaloids (PAs) in feed cause metabolic disturbances in farm animals resulting in high economic losses worldwide. The molecular pathways affected by these PAs in cells and tissues are not yet fully understood. The objective of the study was to examine the dose-dependent effects of orally applied PAs derived from tansy ragwort in midlactation dairy cows. Twenty Holstein dairy cows were treated with target exposures of 0, 0.47, 0.95 and 1.91 mg of total PA/kg of body weight/d in control, PA1, PA2 and PA3, respectively, for 28 days. Liver tissue biopsy and plasma and milk samples were taken at day 28 of treatment to assess changes in metabolic pathways. A targeted metabolomics approach was performed to detect the metabolite profiles in all compartments. The PA-affected metabolite profiling in liver tissue, plasma and milk revealed changes in three substrate classes: acylcarnitines (ACs), phosphatidylcholines (PCs) and sphingomyelins (SMs). In addition, in the plasma, amino acid concentrations were affected by PA exposure. PA exposure disturbed liver metabolism at many sites, especially devastating pathways related to energy metabolism and to amino acid utilization, most likely based on mitochondrial oxidative stress. The effects on the milk metabolite profile may have consequences for milk quality.

Highly Selective C(sp3)-H Bond Oxygenation at Remote Methylenic Sites Enabled by Polarity Enhancement.

A detailed study on the C(sp3)-H bond oxygenation reactions with H2O2 catalyzed by the [Mn(OTf)2(TIPSmcp)] complex at methylenic sites of cycloalkyl and 1-alkyl substrates bearing 19 different electron-withdrawing functional groups (EW FGs) was carried out. Oxidations in MeCN were compared to the corresponding ones in the strong hydrogen bond donating (HBD) solvents 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and nonafluoro tert-butyl alcohol (NFTBA). Formation of the products deriving from oxygenation at the most remote methylenic sites was observed, with yields, product ratios (PR) for oxygenation at the most remote over the next methylenic sites, and associated site-selectivities that significantly increased going from MeCN to HFIP and NFTBA. Unprecedented site-selectivities were obtained in the oxidation of cyclohexyl, cycloheptyl, cyclooctyl, 1-pentyl, 1-hexyl, and 1-heptyl substrates, approaching >99%, >99%, 90%, >99%, 93%, and 88% (PR >99, >99, 9.4, >99, 14, and 7.5) with cyclohexyl-2-pyridinecarboxylate, cycloheptyl-2-pyridinecarboxylate, cyclooctyl-4-nitrobenzenesulfonamide, 1-pentyl-3,5-dinitrobenzoate, 1-hexyl-3,5-dinitrobenzoate, and 1-heptyl-3,5-dinitrobenzoate, respectively. The results are rationalized on the basis of a polarity enhancement effect via synergistic electronic deactivation of proximal methylenic sites imparted by the EWG coupled to solvent HB. Compared to previous procedures, polarity enhancement provides the opportunity to tune site-selectivity among multiple methylenes in different substrate classes, extending the strong electronic deactivation determined by native EWGs by two carbon atoms. This study uncovers a simple procedure for predictable, high-yielding, and highly site-selective oxidation at remote methylenes of cycloalkyl and 1-alkyl substrates that occurs under mild conditions, with a large substrate scope, providing an extremely powerful tool to be implemented in synthetically useful procedures.

Interrogating the Crucial Interactions at Play in the Chiral Cation-Directed Enantioselective Borylation of Arenes.

Rendering a common ligand scaffold anionic and then pairing it with a chiral cation represents an alternative strategy for developing enantioselective versions of challenging transformations, as has been recently demonstrated in the enantioselective borylation of arenes using a quinine-derived chiral cation. A significant barrier to the further generalization of this approach is the lack of understanding of the specific interactions involved between the cation, ligand, and substrate, given the complexity of the system. We have embarked on a detailed computational study probing the mechanism, the key noncovalent interactions involved, and potential origin of selectivity for the desymmetrizing borylation of two distinct classes of substrate. We describe a deconstructive, stepwise approach to tackling this complex challenge, which involves building up a detailed understanding of the pairwise components of the nominally three component system before combining together into the full 263-atom reactive complex. This approach has revealed substantial differences in the noncovalent interactions occurring at the stereodetermining transition state for C-H oxidative addition to iridium for the two substrate classes. Each substrate engages in a unique mixture of diverse interactions, a testament to the rich and privileged structure of the cinchona alkaloid-derived chiral cations. Throughout the study, experimental support is provided, and this culminates in the discovery that prochiral phosphine oxide substrates, lacking hydrogen bond donor functionality, can also give very encouraging levels of enantioselectivity, potentially through direct interactions with the chiral cation. We envisage that the findings in this study will spur further developments in using chiral cations as controllers in asymmetric transition-metal catalysis.

Exploring the "misfolding problem" by systematic discovery and analysis of functional-but-degraded proteins.

In both health and disease, the ubiquitin-proteasome system (UPS) degrades point mutants that retain partial function but have decreased stability compared with their wild-type counterparts. This class of UPS substrate includes routine translational errors and numerous human disease alleles, such as the most common cause of cystic fibrosis, ΔF508-CFTR. Yet, there is no systematic way to discover novel examples of these "minimally misfolded" substrates. To address that shortcoming, we designed a genetic screen to isolate functional-but-degraded point mutants, and we used the screen to study soluble, monomeric proteins with known structures. These simple parent proteins yielded diverse substrates, allowing us to investigate the structural features, cytotoxicity, and small-molecule regulation of minimal misfolding. Our screen can support numerous lines of inquiry, and it provides broad access to a class of poorly understood but biomedically critical quality-control substrates.

Catalytic Photochemical Deracemization via Short-Lived Intermediates.

Upon irradiation in the presence of a suitable chiral catalyst, racemic compound mixtures can be converted into enantiomerically pure compounds with the same constitution. The process is called photochemical deracemization and involves the formation of short-lived intermediates. By opening different reaction channels for the forward reaction to the intermediate and for the re-constitution of the chiral molecule, the entropically disfavored process becomes feasible. Since the discovery of the first photochemical deracemization in 2018, the field has been growing rapidly. This review comprehensively covers the research performed in the area and discusses current developments. It is subdivided according to the mode of action and the respective substrate classes. The focus of this review is on the scope of the individual reactions and on a discussion of the mechanistic details underlying the presented reaction.

Katalytische photochemische Deracemisierung über kurzlebige Intermediate

AbstractBei Bestrahlung können Racemate in Gegenwart eines geeigneten chiralen Katalysators in enantiomerenreine Verbindungen mit gleicher Struktur umgewandelt werden. Dieser Prozess wird photochemische Deracemisierung genannt und beinhaltet die Bildung kurzlebiger Intermediate. Das Eröffnen unterschiedlicher Reaktionswege für die Vorwärtsreaktion zum Intermediat sowie für die Rückbildung des chiralen Moleküls ermöglicht diesen entropisch ungünstigen Prozess. Seit der Entdeckung der ersten photochemischen Deracemisierung im Jahr 2018 hat sich das Forschungsgebiet rapide entwickelt. Die vorliegende Übersicht beinhaltet die in diesem Bereich durchgeführte Forschung und diskutiert aktuelle Entwicklungen. Sie wurde unterteilt gemäß der Art der Differenzierung und den jeweiligen Substratklassen. Der Schwerpunkt dieser Übersicht liegt auf der Substratpalette einzelner Reaktionen und auf einer Diskussion der mechanistischen Details, die der vorgestellten Reaktion zugrunde liegen.

Photochemical Desaturation and Epoxidation with Oxygen by Sequential Flavin Catalysis.

Catalytic desaturations are important strategies for the functionalization of organic molecules. In nature, flavoenzymes mediate the formation of α,β-unsaturated carbonyl compounds by concomitant cofactor reduction. Contrary to many laboratory methods for these reactions, such as the Saegusa-Ito oxidation, no transition metal reagents or catalysts are required. However, a molecular flavin-mediated variant has not been reported so far. We disclose a photochemical approach for silyl enol ether oxidation, which leads to α,β-unsaturated ketones (13 examples) in very good yields. The flavin catalysts are stable throughout the desaturation reaction, and we successfully applied them in a subsequent aerobic epoxidation by simply changing the reaction conditions. This protocol allowed us to directly convert silyl enol ethers into α,β-epoxyketones in a one-pot fashion (12 examples). Sequential flavin catalysis is not limited to one specific reactivity combination and can, inter alia, couple the photochemical oxidation with radical additions. We anticipate that flavin-catalyzed desaturation will be applicable to other substrate classes and that its sequential catalytic activity will enable rapid substrate diversification.

Photochemical Desaturation and Epoxidation with Oxygen by Sequential Flavin Catalysis

AbstractCatalytic desaturations are important strategies for the functionalization of organic molecules. In nature, flavoenzymes mediate the formation of α,β‐unsaturated carbonyl compounds by concomitant cofactor reduction. Contrary to many laboratory methods for these reactions, such as the Saegusa‐Ito oxidation, no transition metal reagents or catalysts are required. However, a molecular flavin‐mediated variant has not been reported so far. We disclose a photochemical approach for silyl enol ether oxidation, which leads to α,β‐unsaturated ketones (13 examples) in very good yields. The flavin catalysts are stable throughout the desaturation reaction, and we successfully applied them in a subsequent aerobic epoxidation by simply changing the reaction conditions. This protocol allowed us to directly convert silyl enol ethers into α,β‐epoxyketones in a one‐pot fashion (12 examples). Sequential flavin catalysis is not limited to one specific reactivity combination and can, inter alia, couple the photochemical oxidation with radical additions. We anticipate that flavin‐catalyzed desaturation will be applicable to other substrate classes and that its sequential catalytic activity will enable rapid substrate diversification.

Unlocking New Prenylation Modes: Azaindoles as a New Substrate Class for Indole Prenyltransferases.

Aza-substitution, the replacement of aromatic CH groups with nitrogen atoms, is an established medicinal chemistry strategy for increasing solubility, but current methods of accessing functionalized azaindoles are limited. In this work, indole-alkylating aromatic prenyltransferases (PTs) were explored as a strategy to directly functionalize azaindole-substituted analogs of natural products. For this, a series of aza-l-tryptophans (Aza-Trp) featuring N-substitution of every aromatic CH position of the indole ring and their corresponding cyclic Aza-l-Trp-l-proline dipeptides (Aza-CyWP), were synthesized as substrate mimetics for the indole-alkylating PTs FgaPT2, CdpNPT, and FtmPT1. We then demonstrated most of these substrate analogs were accepted by a PT, and the regioselectivity of each prenylation was heavily influenced by the position of the N-substitution. Remarkably, FgaPT2 was found to produce cationic N-prenylpyridinium products, representing not only a new substrate class for indole PTs but also a previously unobserved prenylation mode. The discovery that nitrogenous indole bioisosteres can be accepted by PTs thus provides access to previously unavailable chemical space in the search for bioactive indolediketopiperazine analogs.

Controlling Reactivity and Selectivity in the Nondirected C-H Activation of Arenes with Palladium.

ConspectusAromatic structures are widespread motifs throughout organic chemistry, and C-H activation has been recognized as a major tool for enabling their sustainable and efficient functionalization. Through C-H activation, arenes can be modified without the need for prefunctionalization, leading to inherent atom- and step-economic advantages over traditional methods. However, for the development of synthetically useful methods, several hurdles have to be overcome. The strength of C-H bonds necessitates the development of sufficiently reactive catalysts, while the presence of multiple C-H bonds within a substrate poses challenges in terms of site-selectivity. Traditionally these challenges have been addressed by substrate control. By attaching different directing groups (DGs), the reactivity of the respective arene was significantly enhanced and the DG guided the metal in close proximity to specific C-H bonds, resulting in high site-selectivity. However, the introduction and removal of the DG add additional steps to the synthetic sequence, and the scope of the reaction is limited to a specific substrate class. The development of complementary nondirected methods that can be applied to a broad range of arenes without the necessity to carry a specific functional group that coordinates to Pd (referred to as simple arenes) is therefore highly desirable. However, the intrinsically lower reactivity of such substrates and the absence of a selectivity-determining DG pose significant challenges that can be solved only by the development of highly efficient catalysts. Consequently, the field of nondirected C-H activation, especially with respect to Pd-catalyzed methods, remained comparatively underdeveloped when we initiated our research program in 2017. At that time, state-of-the-art methods required the arene to be used in large excess, precluding its use in late-stage functionalization. Since organopalladium species are among the most versatile synthetic intermediates, we realized that developing a system, which can effectively and selectively activate C-H bonds in simple arenes with the arene as the limiting reagent, would be a powerful tool in synthetic organic chemistry. This account summarizes our groups' research toward the development and application of catalytic systems offering this desired reactivity and focuses explicitly on Pd-catalyzed nondirected C-H functionalization reactions of arenes, where the arene is employed as a limiting reagent. After an introduction that summarizes the state of Pd-catalyzed C-H activation of arenes before 2017 and the associated challenges, experimental and mechanistic details about the development of the first arene-limited, nondirected C-H functionalization of simple arenes with palladium will be discussed. This reactivity was enabled by the identification and combination of two complementary ligands, an N-heterocycle and an amino acid-derived ligand. Afterward we will discuss the expansion of this dual-ligand approach to further arene-limited transformations. Finally, we describe two methodologies that originated from the observations we made during our studies, namely, the late-stage deuteration of simple arenes and a highly selective olefination method that uses noncovalent interactions to induce meta selectivity.

Navigating Visible‐Light‐Triggered (aza and thia) Paternò‐Büchi Reactions for the Synthesis of Heterocycles

AbstractHarnessing visible light to trigger (aza and thia) Paternò‐Büchi reaction injects new vitality into [2+2] photocyclization reaction and enable impressive reactivity modes. The popular (aza and thia) Paternò‐Büchi reaction is one of the most efficient ways to synthesize strained four‐membered heterocycles. Recently, visible‐light‐triggered (aza and thia) Paternò‐Büchi reactions have received considerable attentions as this strategy has overcome some long‐standing challenges, and remarkable achievements have been made within this field. Strained four‐membered heterocyclics with favorable properties provide a perfect combination of stable skeletons for pharmaceutical chemistry and reaction intermediates for further transformation. In this review, we highlight the most recent advances in visible‐light‐triggered (aza and thia) Paternò‐Büchi reaction with an emphasis on reaction mechanism and applications. Organization of the review follows a subdivision according to reaction type and substrate classes.

An NHC-Catalyzed Desulfonylative Smiles Rearrangement of Pyrrole and Indole Carboxaldehydes.

The use of catalysis methods to enable Smiles rearrangement opens up new substrate classes for arylation under mild conditions. Here, we describe an N-heterocyclic carbene (NHC) catalysis system that accesses indole and pyrrole aldehyde substrates in a desulfonylative Smiles process. The reaction proceeds under mild, transition-metal-free conditions and captures acyl anion reactivity for the synthesis of a diverse array of 2-aroyl indoles and pyrroles from readily available sulfonamide starting materials.

Protecting Group‐Free Gold‐Catalyzed Synthesis of 2‐Acylidene‐3‐Oxindoles and Azaaurones via a Double Oxidation Strategy

AbstractA one‐pot synthesis of 2‐acylidene‐3‐oxindole and azaaurone derivatives starting from O‐alkynylanilines and alkynes is presented. By means of oxidative gold catalysis the two starting materials are transferred to reactive intermediates that in situ form the target products. This double oxidation strategy enables a protecting group‐free step‐economic strategy towards these valuable substrate classes.

Convergent Deboronative and Decarboxylative Phosphonylation Enabled by the Phosphite Radical Trap "BecaP".

Carbon-phosphorus bond formation is significant in synthetic chemistry because phosphorus-containing compounds offer numerous indispensable biochemical roles. While there is a plethora of methods to access organophosphorus compounds, phosphonylations of readily accessible alkyl radicals to form aliphatic phosphonates are rare and not commonly used in synthesis. Herein, we introduce a novel phosphorus radical trap "BecaP" that enables facile and efficient phosphonylation of alkyl radicals under visible light photocatalytic conditions. Importantly, the ambiphilic nature of BecaP allows redox neutral reactions with both nucleophilic (activated by single-electron oxidation) and electrophilic (activated by single-electron reduction) alkyl radical precursors. Thus, a broad scope of feedstock alkyl potassium trifluoroborate salts and redox active carboxylate esters could be employed, with each class of substrate proceeding through a distinct mechanistic pathway. The mild conditions are applicable to the late-stage installation of phosphonate motifs into medicinal agents and natural products, which is showcased by the straightforward conversion of baclofen (muscle relaxant) to phaclofen (GABAB antagonist).

SNPs in cytochrome P450 genes decide on the fate of individuals with genetic predisposition to Parkinson's disease.

Parkinson's disease (PD) is one of the most frequent neurological diseases affecting millions of people worldwide. While the majority of PD cases are of unknown origin (idiopathic), about 5%-10% are familial and linked to mutations in different known genes. However, there are also people with a genetic predisposition to PD who do not develop the disease. To elucidate factors leading to the manifestation of PD we compared the occurrence of single nucleotide polymorphisms (SNPs) in various cytochrome P450 (P450) genes in people with a genetic predisposition and suffering from PD (GPD) to that of people, who are genetically predisposed, but show no symptoms of the disease (GUN). We used the PPMI (Parkinson's Progression Markers Initiative) database and the gene sequences of all 57 P450s as well as their three redox partners. Corresponding odds ratios (OR) and confidence intervals (CI) were calculated to assess the incidence of the various SNPs in the two groups of individuals and consequently their relation to PD. We identified for the first time SNPs that are significantly (up to 10fold!) over- or under-represented in GPD patients compared to GUN. SNPs with OR > 5 were found in 10 P450s being involved in eicosanoid, vitamin A and D metabolism as well as cholesterol degradation pointing to an important role of endogenous factors for the manifestation of PD clinical symptoms. Moreover, 12 P450s belonging to all P450 substrate classes as well as POR have SNPs that are significantly under-represented (OR < 0.2) in GPD compared to GUN, indicating a protective role of those SNPs and the corresponding P450s regarding disease advancement. To the best of our knowledge our data for the first time demonstrate an association between known PD predisposition genes and SNPs in other genes, shown here for different P450 genes and for their redox partner POR, which promote the manifestation of the disease in familial PD. Our results thus shed light onto the pathogenesis of PD, especially the switch from GUN to GPD and might further help to advance novel strategies for preventing the development or progression of the disease.

Bis(N-Heterocyclic Carbene) Manganese(I) Complexes: Efficient and Simple Hydrogenation Catalysts.

The use of bis(NHC) manganese(I) complexes 3 as catalysts for the hydrogenation of esters was investigated. For that purpose, a series of complexes has been synthesized via an improved two step procedure utilizing bis(NHC)-BEt3 adducts. By applying complexes 3 with KHBEt3 as additive, various aromatic and aliphatic esters were hydrogenated successfully at mild temperatures and low catalyst loadings, highlighting the efficiency of the novel catalytic system. The versatility of the developed catalytic system was further demonstrated by the hydrogenation of other substrate classes like ketones, nitriles, N-heteroarenes and alkenes. Mechanistic experiments and DFT calculations indicate an inner sphere mechanism with the loss of one CO ligand and reveal the role of BEt3 as cocatalyst.

Bis(N‐Heterocyclic Carbene) Manganese(I) Complexes: Efficient and Simple Hydrogenation Catalysts

AbstractThe use of bis(NHC) manganese(I) complexes 3 as catalysts for the hydrogenation of esters was investigated. For that purpose, a series of complexes has been synthesized via an improved two step procedure utilizing bis(NHC)‐BEt3 adducts. By applying complexes 3 with KHBEt3 as additive, various aromatic and aliphatic esters were hydrogenated successfully at mild temperatures and low catalyst loadings, highlighting the efficiency of the novel catalytic system. The versatility of the developed catalytic system was further demonstrated by the hydrogenation of other substrate classes like ketones, nitriles, N‐heteroarenes and alkenes. Mechanistic experiments and DFT calculations indicate an inner sphere mechanism with the loss of one CO ligand and reveal the role of BEt3 as cocatalyst.

Extending the range of metal ions SERS detection using hybrid plasmonic/ZIF-8 particles

Nanosensors based on surface-enhanced Raman spectroscopy (SERS) have emerged as a class of promising optical tools for the ultrasensitive quantification of metal ions of environmental and biological interest. A central bottleneck in this field is the availability of suitable surface receptors able to convert the selective binding with these vibrationless analytes into measurable SERS signals. In this work, we tackle this issue by employing a hybrid substrate comprising a highly SERS-active plasmonic core and a ZIF-8 metal-organic framework (MOF) shell. The ZIF-8 shell firmly captures aromatic receptors close to the plasmonic structure regardless of their intrinsic affinity for the metallic surface and without altering their ability to coordinate metal ions. Furthermore, it imparts molecular sieving abilities enabling the direct use of the SERS sensing platform in complex media such as biological fluids. This was demonstrated by using different classes of chromogenic reagents (bathocuproine, a 2,6':2′,2″-terpyridine derivative, and Arsenazo III) which were exploited for the SERS detection of both transition and alkaline earth metal ions (i.e., divalent copper, cobalt and calcium ions). Notably, we successfully applied this approach for the detection of Cu(II) in untreated urine samples for Wilson's disease diagnosis. Overall, we believe this class of multifunctional hybrid substrates will serve as a valuable material for expanding the applicability of SERS spectroscopy in real-life environmental and biomedical metal ions analysis.