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Synthetic access to a variety of aliphatic and vinylic pentafluorosulfanylated building blocks remains a major challenge in contemporary organofluorine chemistry hampering its investigation in the context of medicinal chemistry, agrochemistry and functional materials. Herein, we report a bench-top protocol to access the virtually unknown class of α-SF5 -enamines under mild reaction conditions in good to excellent yields (up to 95 %). This reaction combines the protodesilylation of the commercially available precursor TASP with the inâ situ hydroamination of HC≡C-SF5 . The on-site use of highly toxic gases or corrosive reagents is avoided, making access to this motif applicable to a wide chemical audience. The excellent E-diastereoselectivity of this two-step cascade reaction is suggested to be the result of the convergence of the fast Z-/E- isomerization of a vinyl anion as well as the isomerization of the iminium ion. The remarkable thermal stability of these SF5 -enamines encourages further studies of their synthetic utility.
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A tridentate ligand L with a P,NH,N donor motif was synthesized in few steps from commercially available precursors. Upon reaction with [MnBr(CO)5], an octahedral 18-electron complex [Mn(CO)3(L)]Br (1) is obtained in which L adopts a facial arrangement. After deprotonation of the NH group in the cationic complex unit, a neutral Mn(I) amido complex [Mn(CO)2(L-H)] (2) is formed under loss of CO. Rearrangement of L-H leads to a trigonal bipyramidal structure in which the P and N donor centers are in trans position. Further deprotonation of 2 results in a dep-blue anionic complex fragment [Mn(CO)2(L-2H)]- (3). DFT calculations and a QTAIM analysis show that the amido complexâ 2 contains a Mn-N bond with partial double bond character and 3 an aromatic MnN2C2 ring. The anion [Mn(CO)2(L-2H)]- reacts with Ph2PH to give a phosphido complex, which serves as phosphide transfer reagent to activated olefins. But the catalytic activity is low. However, the neutral amido complexâ 2 is an excellent catalyst and with loadings as low as 0.04â mol %, turn over frequencies of >40'000â h-1 can be achieved. Furthermore, secondary and primary alkyl phosphines as well as PH3 can be added in a catalytic hydrophosphination reaction to a wide range of activated olefins such as α,ß-unsaturated aldehydes, ketones, esters, and nitriles. But also, vinyl pyridine and some styrene derivatives are converted into the corresponding phosphanes.
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The aim of this article, while reviewing part of my research activities, is to illustrate the somewhat chaotic way leading from one specific topic to another - from e.g. ferrocenyl ligands for asymmetric catalysis, to asymmetric fluorination, to reagents for perfluoroalkylation, just to mention some of the most fruitful ones. That the way meandering through several areas of research in chemical synthesis can be described as chaotic is not primarily due to my inability to plan the work of my research group. In the contrary, it is argued that academic research, viewed as mean to educating and forming young researchers, should resist the temptation towards an increasing projectification, milestone mentality, the myth of societal relevance, and consciously aim for a more anarchical trait, much in the sense of Feyerabend's "anything goes".
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This article is a broad personal reflection about the language of chemistry, deriving from decades of experience in both research and teaching. The three levels of thought as represented by the Johnstone triangle, a critical attitude towards systematic nomenclature, the concept of pure substance, and the central significance of structural formulas as the most prominent form of representation in chemistry, are the main topics discussed. The chemical transliteration of the Platonic solids is presented as a mean of expression unique to chemistry.
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We report here a mechanistic, DFT and catalytic study on a series of Mn(I) complexes 1, 2(a-d), 3, 4. The studies apprehended the requirements for Mn(I) complexes to be active in both asymmetric direct (AH) and transfer hydrogenations (ATH). The investigations disclosed 6 vital factors accelerating the formation of a resting species, which plays a significant role in lowering the activities of the Mn(I) complex 1 in ATH and AH, respectively. In addition, we also report here a base free Mn(I) catalyzed ATH of aryl alkyl ketones with high enantioselectivity (up to 98 %â ee) and improved activity. More significantly, a novel and simple single-step process for recycling the resting species from the catalytic leftover has been discovered. Notably, the studies provide evidence for the existence of two different temperature dependent mechanisms for AH and ATH, in contrast to previous studies on related systems.
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Cetonas , Catálisis , HidrogenaciónRESUMEN
In synthetic method development, the most rewarding path is seldom a straight line. While our initial entry into pentafluorosulfanyl (SF5 ) chemistry did not go according to plan (due to inaccessibility of reagents such as SF5 Cl at the time), a "detour" led us to establish mild and inexpensive oxidative fluorination conditions that made aryl-SF5 compound synthesis more accessible. The method involved the use of potassium fluoride and trichloroisocyanuric acid (TCICA)-a common swimming pool disinfectant-as opposed to previously employed reagents such as F2 , XeF2 , HF, and Cl2 . Thereafter, curiosity led us to explore applications of TCICA/KF as a more general approach to the synthesis of fluorinated Group 15, 16, and 17 heteroatoms in organic scaffolds; this, in turn, prompted SC-XRD, VT-NMR, computational, and physical organic studies. Ultimately, it was discovered that TCICA/KF can be used to synthesize SF5 Cl, enabling SF5 chemistry in an unexpected way.
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Fluoruros , Halogenación , Fluoruros/química , Indicadores y Reactivos , Estrés Oxidativo , Compuestos de Potasio , TriazinasRESUMEN
Chemoproteomic profiling of cysteines has emerged as a powerful method for screening the proteome-wide targets of cysteine-reactive fragments, drugs, and natural products. Herein, we report the development and an in-depth evaluation of a tetrafluoroalkyl benziodoxole (TFBX) as a cysteine-selective chemoproteomic probe. We show that this probe features numerous key improvements compared to the traditionally used cysteine-reactive probes, including a superior target occupancy, faster labeling kinetics, and broader proteomic coverage, thus enabling profiling of cysteines directly in live cells. In addition, the fluorine "signature" of probe 7 constitutes an additional advantage resulting in a more confident adduct-amino acid site assignment in mass-spectrometry-based identification workflows. We demonstrate the utility of our new probe for proteome-wide target profiling by identifying the cellular targets of (-)-myrocin G, an antiproliferative fungal natural product with a to-date unknown mechanism of action. We show that this natural product and a simplified analogue target the X-ray repair cross-complementing protein 5 (XRCC5), an ATP-dependent DNA helicase that primes DNA repair machinery for nonhomologous end joining (NHEJ) upon DNA double-strand breaks, making them the first reported inhibitors of this biomedically highly important protein. We further demonstrate that myrocins disrupt the interaction of XRCC5 with DNA leading to sensitization of cancer cells to the chemotherapeutic agent etoposide as well as UV-light-induced DNA damage. Altogether, our next-generation cysteine-reactive probe enables broader and deeper profiling of the cysteinome, rendering it a highly attractive tool for elucidation of targets of electrophilic small molecules.
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Cisteína/química , Compuestos Heterocíclicos con 2 Anillos/química , Hidrocarburos Fluorados/química , Sondas Moleculares/química , Proteómica/métodos , Alquilación , Reparación del ADN por Unión de Extremidades/efectos de los fármacos , Diterpenos/farmacología , Inhibidores Enzimáticos/farmacología , Células HEK293 , Células HeLa , Humanos , Autoantígeno Ku/antagonistas & inhibidores , Autoantígeno Ku/químicaRESUMEN
The direct trifluoromethylation of a variety of aliphatic alcohols using a hypervalent iodosulfoximine reagent afforded the corresponding ethers in moderate to good yields (14-72 %). Primary, secondary, and even tertiary alcohols, including examples derived from natural products, underwent this transformation in the presence of catalytic amounts of zinc bis(triflimide). Typical reaction conditions involved a neat mixture of 6.0â equivalents of the alcohol with 1.0â equivalent of the reagent, with the majority of reactions complete within 2â h with 2.5â mol % of the Lewis acid catalyst. Furthermore, experimental evidence was provided that the C-O bond-forming process occurred via the coordination of the alcohol to the iodine atom and subsequent reductive elimination.
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The analysis of crystal structures of SF5 - or SF4 -containing molecules revealed that these groups are often surrounded by hydrogen or other fluorine atoms. Even though fluorine prefers Fâ â â H over Fâ â â F contacts, the latter appeared to be important in many compounds. In a significant number of datasets, the closest Fâ â â F contacts are below 95 % of the van der Waals distance of two F atoms. Moreover, a number of repeating structural motifs formed by contacts between SF5 groups was identified, including different supramolecular dimers and infinite chains. Among SF4 -containing molecules, the study focused on SF4 Cl compounds, including the first solid-state structure analyses of these reactive species. Additionally, electrostatic potential surfaces of a series of Ph-SF5 derivatives were calculated, pointing out the substituent influence on the ability of Fâ â â X contact formation (X=F or other electronegative atom). Interaction energies were calculated for different dimeric arrangements of Ph-SF5 , which were extracted from experimental crystal structure determinations.
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What is the strongest Brønsted acid, the strongest base, the strongest oxidizing agent? If not understood in an absolute, once-and-forever sense, the answers to such questions may help at extending and reinforcing the meaning of simple concepts in first-year chemistry courses. Moreover, they serve the purpose of introducing research aspects and linking them to general chemistry.
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Some of the most important features of ferrocene chemistry - structure, reactivity, redox properties, and applications - are presented. Their value in the context of conveying many fundamental aspects of molecular chemistry is considered.
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Metalocenos , Estructura Molecular , Oxidación-ReducciónRESUMEN
The basic chemistry knowledge of first-year students in the disciplines Chemistry, Biology, Pharmaceutical Sciences, and Health Sciences and Technology has been evaluated within the first three weeks of the Fall semester with a Moodle-based quiz at ETH Zurich. It consists of 37 small problems testing the knowledge that ETH students entering the lecture courses General Chemistry 1 (Inorganic Chemistry) (AC1) and Organic Chemistry 1 (OC1) should ideally have. An initial set of questions was developed by Bernhard Jaun (ETH Zurich) in 2007, it was combined with questions from an evaluation created in 2015 by Markus Müller (secondary school II teacher). The results of a total of 925 students who took part in the 2016 and 2017 evaluations are presented. It was found that 80% of the students of Chemistry, Chemical Engineering and Interdisciplinary Natural Sciences (AC1 course) and 70% of the students of Biology, Pharmaceutical Sciences, and Health Sciences and Technology (OC1 course) scored ≥60%. Students who took the focus course (Schwerpunktfach) Biology and Chemistry at the SEK II level (Swiss school system) performed on average 13-18% better and with a smaller standard deviation than other students. No significant differences were observed with regard to gender or the region in which the qualification for university entrance was obtained.
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We report full details of the synthesis and characterization of monohydride-dichloro rhodium(III) complexes bearing chiral diphosphine ligands, such as (S)-BINAP, (S)-DM-SEGPHOS, and (S)-DTBM-SEGPHOS, producing cationic triply chloride bridged dinuclear rhodium(III) complexes (1 a: (S)-BINAP; 1 b: (S)-DM-SEGPHOS) and a neutral mononuclear monohydride-dichloro rhodium(III) complex (1 c: (S)-DTBM-SEGPHOS) in high yield and high purity. Their solid state structure and solution behavior were determined by crystallographic studies as well as full spectral data, including DOSY NMR spectroscopy. Among these three complexes, 1 c has a rigid pocket surrounded by two chloride atoms bound to the rhodium atom together with one tBu group of (S)-DTBM-SEGPHOS for fitting to simple olefins without any coordinating functional groups. Complex 1 c exhibited superior catalytic activity and enantioselectivity for asymmetric hydrogenation of exo-olefins and olefinic substrates. The catalytic activity of 1 c was compared with that of well-demonstrated dihydride species derived in situ from rhodium(I) precursors such as [Rh(cod)Cl]2 and [Rh(cod)2 ]+ [BF4 ]- upon mixing with (S)-DTBM-SEGPHOS under dihydrogen.
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The first palladium organometallic compounds bearing N-trifluoromethyl N-heterocyclic carbenes have been synthesized. These η3 -allyl complexes are potent antiproliferative agents against different cancer lines (for the most part, IC50 values fall in the range 0.02-0.5⠵m). By choosing 1,3,5-triaza-7-phosphaadamantane (PTA) as co-ligand, we can improve the selectivity toward tumor cells, whereas the introduction of 2-methyl substituents generally reduces the antitumor activity slightly. A series of biochemical assays, aimed at defining the cellular targets of these palladium complexes, has shown that mitochondria are damaged before DNA, thus revealing a behavior substantially different from that of cisplatin and its derivatives. We assume that the specific mechanism of action of these organometallic compounds involves nucleophilic attack on the η3 -allyl fragment. The effectiveness of a representative complex, 4 c, was verified on ovarian cancer tumoroids derived from patients. The results are promising: unlike carboplatin, our compound turned out to be very active and showed a low toxicity toward normal liver organoids.
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Antineoplásicos/química , Cisplatino/farmacología , Complejos de Coordinación/química , Neoplasias Ováricas/patología , Paladio/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/química , Complejos de Coordinación/farmacología , Femenino , Humanos , LigandosRESUMEN
Organotellurium compounds of general formula X-Te-R display a broad range of chemical shifts that are very sensitive to the X and R substituents. In order to link the 125Te chemical shift of a series of perfluoroalkyl aryl tellurides to their electronic structure, the chemical shielding tensors of the 125Te nuclei were calculated by density functional theory (DFT) and further analyzed by a decomposition into contributions of natural localized molecular orbitals (NLMOs). The analysis indicated that the variation in 125Te chemical shifts in molecules 1-13 is mainly due to the magnetic coupling of the tellurium p-character lone pair with antibonding orbitals perpendicular to it {σ*(Te-X) and σ*(Te-C(Ar))} upon action of an external magnetic field. The strength of the coupling is affected by electronic properties of the X-substituents, polarization of the antibonding orbitals and presence of secondary interactions perturbing the energy of these orbitals. The lower in energy and the more polarized towards tellurium the antibonding orbitals are, the stronger is the coupling and the more deshielded the tellurium nucleus.
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The molecule of the week is regularly used by the author in his first-semester course General Chemistry I (Inorganic Chemistry) to illustrate, exemplify, and deepen fundamental aspects and concepts treated in the course. Pure sulfuric acid and its autoprotolysis is used to introduce the concepts of protochemical window and superacidity. The drug Auranofin serves at showing fundamental aspects of gold redox and coordination chemistry and the widely used disinfectant trichlo- roisocyanuric acid (TCICA) exemplifies redox processes with organic compounds.
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In this Review, we highlight recent advances in the understanding and design of N-functionalized pyridinium scaffolds as redox-active, single-electron, functional group transfer reagents. We provide a selection of representative methods that demonstrate reactivity and fundamental advances in this emerging field. The reactivity of these reagents can be divided into two divergent pathways: homolytic fragmentation to liberate the N-bound substituent as the corresponding radical or an alternative heterolytic fragmentation that liberates an N-centered pyridinium radical. A short description of the elementary steps involved in fragmentation induced by single-electron transfer is also critically discussed to guide readers towards fundamental processes thought to occur under these conditions.
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Fluorinated organophosphorus(V) compounds are a very versatile class of compounds, but the synthetic methods available to make them bear the disadvantages of 1)â occasional handling of toxic or pyrophoric PIII starting materials and 2)â a dependence on hazardous fluorinating reagents such as XeF2 . Herein, we present a simple solution and introduce a deoxygenative fluorination (DOF) approach that utilizes easy-to-handle phosphine oxides as starting materials and effectively replaces harsh fluorinating reagents by a combination of oxalyl chloride and potassium fluoride. The reaction has proven to be general, as R3 PF2 , R2 PF3 , and RPF4 compounds (as well as various cations and anions derived from these) are accessible in good yields and on up to a multi-gram scale. DFT calculations were used to bolster our observations. Notably, the discovery of this new method led to a convenient synthesis of 1)â new difluorophosphonium ions, 2)â hexafluorophosphate salts, and 3)â fluorinated antimony- and arsenic- compounds.
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The asymmetric hydrogenation of 2,2,2-trifluoroacetophenones and aryl perfluoroalkyl ketones was developed using a unique, well-defined chloride-bridged dinuclear rhodium(III) complex bearing Josiphos-type diphosphine ligands. These complexes were prepared from [RhCl(cod)]2 , Josiphos ligands, and hydrochloric acid. As catalyst precursors, they allow for the efficient and enantioselective synthesis (up to 99 % ee) of chiral secondary alcohols with perfluoroalkyl groups. This system does not require an activating base for the hydrogenation of 2,2,2-trifluoroacetophenones. Additionally, the enantioselective C=O hydrogenations of 2-phenyl-3-(haloacetyl)-indoles, a class of privileged structures in medicinal chemistry, is reported for the first time.
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Demonstrated herein is the construction of trifluoromethylated quaternary carbon centers by an asymmetric radical transformation. Enantioenriched trifluoromethylated oxindoles were accessed using a hypervalent iodine-based trifluoromethyl transfer reagent in combination with a magnesium Lewis acid catalyst and PyBOX-type ligands to achieve up to 99 % ee and excellent chemical yields. Mechanistic studies were performed by experimental and computational methods and suggest a single-electron transfer induced SN 2-type mechanism. This example is thereby the first report on the construction of enantioenriched trifluoromethylated carbon centers using hypervalent iodine-based reagents proceeding through such a reaction pathway.