An integrated console for capsule-based,automated organic synthesis

The current laboratory practices of organic synthesis are labor intensive, impose safety and environmental hazards, and hamper the implementation of artificial intelligence guided drug discovery. Using a combination of reagent design, hardware engineering, and a simple operating system we provide an instrument capable of executing complex organic reactions with prepacked capsules. The machine conducts coupling reactions and delivers the purified products with minimal user involvement. Two desirable reaction classes – the synthesis of saturated N-heterocycles and reductive amination – were implemented, along with multi-step sequences that provide drug-like organic molecules in a fully automated manner. We envision that this system will serve as a console for developers to provide synthetic methods as integrated, user-friendly packages for conducting organic synthesis in a safe and convenient fashion.

Using a combination of reagent design, hardware engineering, and a simple operating system we provide an instrument capable of executing complex organic reactions using prepacked capsules with minimal user involvement.     

Coligand role in the NHC nickel catalyzed C–F bond activation: investigations on the insertion of bis(NHC) nickel into the C–F bond of hexafluorobenzene

The reaction of [Ni(Mes₂Im)₂] (1) (Mes₂Im = 1,3-dimesityl-imidazolin-2-ylidene) with polyfluorinated arenes as well as mechanistic investigations concerning the insertion of 1 and [Ni(ⁱPr₂Im)₂] (1ipr) (ⁱPr₂Im = 1,3-diisopropyl-imidazolin-2-ylidene) into the C–F bond of C₆F₆ is reported. The reaction of 1 with different fluoroaromatics leads to formation of the nickel fluoroaryl fluoride complexes trans-[Ni(Mes₂Im)₂(F)(Ar^F)] (Ar^F = 4-CF₃-C₆F₄2, C₆F₅3, 2,3,5,6-C₆F₄N 4, 2,3,5,6-C₆F₄H 5, 2,3,5-C₆F₃H₂6, 3,5-C₆F₂H₃7) in fair to good yields with the exception of the formation of the pentafluorophenyl complex 3 (less than 20%). Radical species and other diamagnetic side products were detected for the reaction of 1 with C₆F₆, in line with a radical pathway for the C–F bond activation step using 1. The difluoride complex trans-[Ni(Mes₂Im)₂(F)₂] (9), the bis(aryl) complex trans-[Ni(Mes₂Im)₂(C₆F₅)₂] (15), the structurally characterized nickel(i) complex trans-[Ni^I(Mes₂Im)₂(C₆F₅)] (11) and the metal radical trans-[Ni^I(Mes₂Im)₂(F)] (12) were identified. Complex 11, and related [Ni^I(Mes₂Im)₂(2,3,5,6-C₆F₄H)] (13) and [Ni^I(Mes₂Im)₂(2,3,5-C₆F₃H₂)] (14), were synthesized independently by reaction of trans-[Ni(Mes₂Im)₂(F)(Ar^F)] with PhSiH₃. Simple electron transfer from 1 to C₆F₆ was excluded, as the redox potentials of the reaction partners do not match and [Ni(Mes₂Im)₂]⁺, which was prepared independently, was not detected. DFT calculations were performed on the insertion of [Ni(ⁱPr₂Im)₂] (1ipr) and [Ni(Mes₂Im)₂] (1) into the C–F bond of C₆F₆. For 1ipr, concerted and NHC-assisted pathways were identified as having the lowest kinetic barriers, whereas for 1, a radical mechanism with fluoride abstraction and an NHC-assisted pathway are both associated with almost the same kinetic barrier.

A combined experimental and theoretical study on the mechanism of the C–F bond activation of C₆F₆ with [Ni(NHC)₂] is provided.     

Über sechsgliedrige Heterocyclen mit Phosphor-, Stickstoff- und Schwefelatomen im Ring

Cyclic sulphurylphosphazochloride (I: formula see ?Inhaltsübersicht”?) reacts with ammonia or methylamine forming the. tetramide(II) and (III), respectively, and with aniline or dimethylamine forming the diamide (IV) resp. (V). The synthesis of the diphenyl derivative (VI) is achieved starting from C₆H₅? PCl₄. (II) gives with PCl₅ the ionic compound (VII).     

Hierarchical dynamics in allostery following ATP hydrolysis monitored by single molecule FRET measurements and MD simulations

We report on a study that combines advanced fluorescence methods with molecular dynamics (MD) simulations to cover timescales from nanoseconds to milliseconds for a large protein. This allows us to delineate how ATP hydrolysis in a protein causes allosteric changes at a distant protein binding site, using the chaperone Hsp90 as test system. The allosteric process occurs via hierarchical dynamics involving timescales from nano- to milliseconds and length scales from Ångstroms to several nanometers. We find that hydrolysis of one ATP is coupled to a conformational change of Arg380, which in turn passes structural information via the large M-domain α-helix to the whole protein. The resulting structural asymmetry in Hsp90 leads to the collapse of a central folding substrate binding site, causing the formation of a novel collapsed state (closed state B) that we characterise structurally. We presume that similar hierarchical mechanisms are fundamental for information transfer induced by ATP hydrolysis through many other proteins.

We report on a study that combines advanced fluorescence methods with molecular dynamics simulations to cover timescales from nanoseconds to milliseconds for a large protein, the chaperone Hsp90.     

Thermolysis of 1-(1-aryl-1-bromomethyl)cyclopropyl bromides: a reinvestigation

Two compounds, the (Z)- and (E)-isomers of 2,4-dibromo-1-p-tolyl-1-butene 2a and 3a, respectively, were isolated in 65% total yield when 1-(1-bromo-1-p-tolylmethyl)cyclopropyl bromide (1a) was heated at 150 degrees C for 1 h. 1,1-Dibromo-2-p-tolylcyclobutane (4a), previously reported to be the only product in this reaction, was not detected. The phenyl analogue of 1a reacted similarly and gave the (Z)- and (E)-isomers of 2,4-dibromo-1-phenyl-1-butene 2b and 3b, respectively, in 60% yield. A rationale for the reaction is presented.     

Bioorthogonal organic chemistry in living cells: novel strategies for labeling biomolecules

The chemical labeling of biomolecules continues to be an important tool for the study of their function and cellular fate. Attention is increasingly focused on labeling of biomolecules in living cells, since cell lysis introduces many artefacts. In addition, with the advances in biocompatible synthetic organic chemistry, a whole new field of opportunity has opened up, affording high diversity in the nature of the label as well as a choice of ligation reactions. In recent years, several different two-step labeling strategies have emerged. These rely on the introduction of a bioorthogonal attachment site into a biomolecule, then ligation of a reporter molecule to this site using bioorthogonal organic chemistry. This Perspective focuses on these techniques, their implications and future directions.     

The chemistry of the azanonaborane cluster RNH2---B8H11NHR

The preparation and properties of the R¹R²NH---B₈H₁₁NHR cluster are described. The cluster is stable to aqueous solutions and can be made water-soluble by the introduction of a few hydrophilic groups. This makes the cluster a good candidate as the boron moiety in compounds for boron neutron capture therapy. The chemistry of the cluster preparation, the stability of the cluster, and conditions for reactions of the organic moieties are reviewed. Pyridine derivatives of the cluster show electronic interaction between the cluster and the pyridine.     

Flavonoids in Leguminosae: analysis of extracts of T. pratense L., T. dubium L., T. repens L., and L. corniculatus L. leaves using liquid chromatography with UV, mass spectrometric and fluorescence detection

Reversed-phase LC on C-18 bonded silica with a methanol–ammonium formate gradient was used to determine the main flavonoids in leaves of four species of the Leguminosae family. The detection modes were diode-array UV absorbance, fluorescence, and (tandem) mass spectrometry. LC–UV was used for a general screening, sub-classification, and the calculation of total flavonoid contents. LC–FLU was included to identify isoflavones on the basis of their native fluorescence. Most structural information regarding aglycons, sugar moieties, and acidic groups was derived from LC–MS in both the full-scan and extracted-ion mode, using negative-ion atmospheric pressure chemical ionization. MS/MS did not provide much additional information, because the same fragments were observed as in full-scan MS.In T. pratense and T. repens, the main constituents were flavonoid glucoside–(di)malonates, while T. dubium and L. corniculatus mainly contained flavonoid (di)glycosides. Satellite sets comprising an aglycon, the glucoside and glucoside–malonates or –acetates, were abundantly present only in T. pratense. Generally speaking, the main aglycons and sugars in the four plant species are surprisingly different. In addition, while the results for T. pratense are similar to those reported in the literature, there is little agreement in the case of the other species. Finally, total flavonoid contents ranged from 50–65 mg/g for L. corniculatus and T. dubium, to 15 mg/g for T. pratense and only 1 mg/g for T. repens.     

Adaption of a fragment analysis technique to an automated high-throughput multicapillary electrophoresis device for the precise qualitative and quantitative characterization of microbial communities

The analysis of microbial communities is of increasing importance in life sciences and bioengineering. Traditional techniques of investigations like culture or cloning methods suffer from many disadvantages. They are unable to give a complete qualitative and quantitative view of the total amount of microorganisms themselves, their interactions among each other and with their environment. Obviously, the determination of static or dynamic balances among microorganisms is of fast growing interest. The generation of species specific and fluorescently labeled 16S ribosomal DNA (rDNA) fragments by the terminal restriction fragment length polymorphism (T-RFLP) technique is a suitable tool to overcome the problems other methods have. For the separation of these fragments polyacrylamide gel sequencers are preferred as compared to capillary sequencers using linear polymers until now because of their higher electrophoretic resolution and therefore sizing accuracy. But modern capillary sequencers, especially multicapillary sequencers, offer an advanced grade of automation and an increased throughput necessary for the investigation of complex communities in long-time studies. Therefore, we adapted a T-RFLP technique to an automated high-throughput multicapillary electrophoresis device (ABI 3100 Genetic Analysis) with regard to a precise qualitative and quantitative characterization of microbial communities.