Publications by authors named "Antonio Togni"

81 Publications

Chemoproteomic Profiling by Cysteine Fluoroalkylation Reveals Myrocin G as an Inhibitor of the Nonhomologous End Joining DNA Repair Pathway.

J Am Chem Soc 2021 Dec 24;143(48):20332-20342. Epub 2021 Nov 24.

Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.

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 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 (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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http://dx.doi.org/10.1021/jacs.1c09724DOI Listing
December 2021

Fluorine: A Very Special Element and Its Very Special Impacts on Chemistry.

J Org Chem 2021 12 22;86(23):16213-16219. Epub 2021 Nov 22.

Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zurich, Vladimir-Prelog-Weg 2, 8093Zurich, Switzerland.

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http://dx.doi.org/10.1021/acs.joc.1c02745DOI Listing
December 2021

Fluorine: A Very Special Element and Its Very Special Impacts on Chemistry.

Org Lett 2021 Dec 22;23(23):9013-9019. Epub 2021 Nov 22.

Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zurich, Vladimir-Prelog-Weg 2, 8093Zurich, Switzerland.

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http://dx.doi.org/10.1021/acs.orglett.1c03799DOI Listing
December 2021

Fluorine: A Very Special Element and Its Very Special Impacts on Chemistry.

Inorg Chem 2021 Dec 22;60(23):17419-17425. Epub 2021 Nov 22.

Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zurich, Vladimir-Prelog-Weg 2, 8093 Zurich, Switzerland.

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http://dx.doi.org/10.1021/acs.inorgchem.1c03509DOI Listing
December 2021

70 Years Ferrocene!

Authors:
Antonio Togni

Chimia (Aarau) 2021 Sep;75(9):805-806

Department of Chemistry and Applied Biosciences, ETH Zurich, HCI H 105, Vladimir-Prelog-Weg 1, CH-8093 Zurich, Switzerland;, Email:

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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http://dx.doi.org/10.2533/chimia.2021.805DOI Listing
September 2021

Radical α-Trifluoromethoxylation of Ketones under Batch and Flow Conditions by Means of Organic Photoredox Catalysis.

Org Lett 2021 09 1;23(18):7088-7093. Epub 2021 Sep 1.

Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131 Padova, Italy.

The first light-driven method for the α-trifluoromethoxylation of ketones is reported. Enol carbonates react with -trifluoromethoxy-4-cyano-pyridinium, using the photoredox catalyst 4-CzIPN under 456 nm irradiation, affording the α-trifluoromethoxy ketones in ≤50% isolated yield and complete chemoselectivity. As shown by 29 examples, the reaction is general and proceeds very rapidly under batch (1 h) and flow conditions (2 min). Diverse product manipulations demonstrate the synthetic potential of the disclosed method in accessing elusive trifluoromethoxylated bioactive ingredients.
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http://dx.doi.org/10.1021/acs.orglett.1c02494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453633PMC
September 2021

Superlatives in Teaching General Chemistry.

Authors:
Antonio Togni

Chimia (Aarau) 2021 Apr;75(4):343-344

Department of Chemistry and Applied Biosciences, ETH Zürich, HCI H 105, Vladimir-Prelog-Weg 1, CH-8093 Zürich, Switzerland;, Email:

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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http://dx.doi.org/10.2533/chimia.2021.343DOI Listing
April 2021

Evaluation of the Chemistry Knowledge of Students Entering the ETH Zurich with a Moodle Quiz.

Chimia (Aarau) 2021 Feb;75(1):89-97

Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 3, CH-8093 Zurich, Switzerland.

The basic chemistry knowledge of first-year students in the disciplines , , , and 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 (AC1) and (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 () 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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http://dx.doi.org/10.2533/chimia.2021.89DOI Listing
February 2021

The Supramolecular Structural Chemistry of Pentafluorosulfanyl and Tetrafluorosulfanylene Compounds.

Chemistry 2021 Apr 3;27(19):6086-6093. Epub 2021 Mar 3.

Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zurich, Vladimir-Prelog-Weg 2, 8093, Zurich, Switzerland.

The analysis of crystal structures of SF - or SF -containing molecules revealed that these groups are often surrounded by hydrogen or other fluorine atoms. Even though fluorine prefers F⋅⋅⋅H over F⋅⋅⋅F contacts, the latter appeared to be important in many compounds. In a significant number of datasets, the closest F⋅⋅⋅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 SF groups was identified, including different supramolecular dimers and infinite chains. Among SF -containing molecules, the study focused on SF Cl compounds, including the first solid-state structure analyses of these reactive species. Additionally, electrostatic potential surfaces of a series of Ph-SF derivatives were calculated, pointing out the substituent influence on the ability of F⋅⋅⋅X contact formation (X=F or other electronegative atom). Interaction energies were calculated for different dimeric arrangements of Ph-SF , which were extracted from experimental crystal structure determinations.
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http://dx.doi.org/10.1002/chem.202100163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048635PMC
April 2021

Direct Trifluoromethylation of Alcohols Using a Hypervalent Iodosulfoximine Reagent.

Chemistry 2021 Feb 14;27(8):2638-2642. Epub 2021 Jan 14.

Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zurich, Vladimir-Prelog-Weg 2, 8093, Zurich, Switzerland.

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 6.0 equivalents of the alcohol with 1.0 equivalent of the reagent, with the majority of reactions complete within 2 h with 2.5 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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http://dx.doi.org/10.1002/chem.202005104DOI Listing
February 2021

Deoxygenative Fluorination of Phosphine Oxides: A General Route to Fluorinated Organophosphorus(V) Compounds and Beyond.

Angew Chem Int Ed Engl 2020 Dec 2;59(50):22790-22795. Epub 2020 Oct 2.

Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland.

Fluorinated organophosphorus(V) compounds are a very versatile class of compounds, but the synthetic methods available to make them bear the disadvantages of 1) occasional handling of toxic or pyrophoric P starting materials and 2) a dependence on hazardous fluorinating reagents such as XeF . 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 R PF , R PF , and RPF 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) new difluorophosphonium ions, 2) hexafluorophosphate salts, and 3) fluorinated antimony- and arsenic- compounds.
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http://dx.doi.org/10.1002/anie.202010943DOI Listing
December 2020

The Molecule of the Week: A Didactic Tool for Teaching General Chemistry.

Authors:
Antonio Togni

Chimia (Aarau) 2020 Aug;74(7):615-617

Department of Chemistry and Applied Biosciences, ETH Zürich, HCI H 239, Vladimir-PrelogWeg 2, CH-8093 Zurich;, Email:

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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http://dx.doi.org/10.2533/chimia.2020.615DOI Listing
August 2020

Palladium(II)-η -Allyl Complexes Bearing N-Trifluoromethyl N-Heterocyclic Carbenes: A New Generation of Anticancer Agents that Restrain the Growth of High-Grade Serous Ovarian Cancer Tumoroids.

Chemistry 2020 Sep 6;26(51):11868-11876. Epub 2020 Aug 6.

Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zürich, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland.

The first palladium organometallic compounds bearing N-trifluoromethyl N-heterocyclic carbenes have been synthesized. These η -allyl complexes are potent antiproliferative agents against different cancer lines (for the most part, IC values fall in the range 0.02-0.5 μm). 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 η -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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http://dx.doi.org/10.1002/chem.202002199DOI Listing
September 2020

Monohydride-Dichloro Rhodium(III) Complexes with Chiral Diphosphine Ligands as Catalysts for Asymmetric Hydrogenation of Olefinic Substrates.

Chemistry 2020 Jul 25;26(40):8749-8759. Epub 2020 Jun 25.

Department of Chemistry, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka, 560-8531, Japan.

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] and [Rh(cod) ] [BF ] upon mixing with (S)-DTBM-SEGPHOS under dihydrogen.
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http://dx.doi.org/10.1002/chem.202000542DOI Listing
July 2020

Merging hypervalent iodine and sulfoximine chemistry: a new electrophilic trifluoromethylation reagent.

Chem Sci 2019 Dec 27;10(45):10516-10523. Epub 2019 Sep 27.

Institut Lavoisier de Versailles , UMR CNRS 8180 , Université de Versailles-Saint-Quentin , 45 Avenue des Etats-Unis , 78035 Versailles Cedex , France . Email:

Electrophilic trifluoromethylation is at the forefront of methodologies available for the installation of the CF moiety to organic molecules; research in this field is largely spurred by the availability of stable and accessible trifluoromethylation reagents, of which hypervalent iodine and sulfoximine based compounds have emerged as two prominent reagent classes. Herein, we describe the facile synthesis of an electrophilic trifluoromethylation reagent which merges these two scaffolds in a novel hypervalent iodosulfoximine compound. This presents the first analogue of the well-known Togni reagents which neither compromises stability or reactivity. The electronic and physical properties of this new compound were fully explored by X-ray crystallography, cyclic voltammetry, TGA/DSC and DFT analysis. This solution stable, crystalline reagent was found to be competent in the electrophilic trifluoromethylation of a variety of nucleophiles as well as a source of the trifluoromethyl radical. Furthermore, the possibility of enantioinductive transformations could be probed with the isolation of the first enantiopure hypervalent iodine compound bearing a CF group, thus this new reagent scaffold offers the opportunity of structurally diversifying the reagent towards asymmetric synthesis.
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http://dx.doi.org/10.1039/c9sc04289jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020794PMC
December 2019

Understanding Te NMR chemical shifts in disymmetric organo-telluride compounds from natural chemical shift analysis.

Phys Chem Chem Phys 2020 Jan 13;22(4):2319-2326. Epub 2020 Jan 13.

ETH Zürich, Department of Chemistry and Applied Sciences, Vladimir-Prelog-Weg 2, CH-8093 Zürich, Switzerland.

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 Te chemical shift of a series of perfluoroalkyl aryl tellurides to their electronic structure, the chemical shielding tensors of the Te 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 Te 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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http://dx.doi.org/10.1039/c9cp05934bDOI Listing
January 2020

Pyridinium Salts as Redox-Active Functional Group Transfer Reagents.

Angew Chem Int Ed Engl 2020 Jun 7;59(24):9264-9280. Epub 2020 Apr 7.

Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 1-5, 8093, Zürich, Switzerland.

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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http://dx.doi.org/10.1002/anie.201911660DOI Listing
June 2020

Difluoro(aryl)(perfluoroalkyl)-λ -sulfanes and Selanes: Missing Links of Trichloroisocyanuric Acid/Potassium Fluoride Chemistry.

Angew Chem Int Ed Engl 2019 12 18;58(52):18937-18941. Epub 2019 Nov 18.

Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland.

The TCICA/KF approach to oxidative fluorination of heteroatoms has emerged as a surprisingly simple, safe, and versatile surrogate to classically challenging fluorination reactions. Although polyfluorination (or chlorofluorination) of diaryl disulfides, diaryl diselenides, diaryl ditellurides, aryl iodides, and aryl(perfluoroalkyl)tellanes has been described, the application of this TCICA/KF methodology to aryl(perfluoroalkyl)sulfanes and selanes remains an area of unexplored chemical space. Accordingly, to address the "missing links" in the developing series of chalcogen-based substrate reactivity, we report mild syntheses of metastable difluoro(aryl)(perfluoroalkyl)-λ -sulfanes and selanes. As only limited examples of these species exist in the current literature (accessible only by using F or XeF /HF), we have carried out detailed structural analyses, primarily using NMR and SC-XRD data. In addition, we investigate the effect of the perfluoroalkyl chain on the outcome of oxidative fluorination, and, finally, we provide preliminary evidence that difluoro(aryl)(trifluoro-methyl)-λ -sulfanes may act as fluorinating reagents.
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http://dx.doi.org/10.1002/anie.201910594DOI Listing
December 2019

Substituent-controlled, mild oxidative fluorination of iodoarenes: synthesis and structural study of aryl I(iii)- and I(v)-fluorides.

Chem Sci 2019 Aug 5;10(30):7251-7259. Epub 2019 Jun 5.

Department of Chemistry and Applied Biosciences , ETH Zürich , Vladimir-Prelog-Weg 2 , 8093 Zürich , Switzerland . Email:

We report a mild approach to the synthesis of difluoro(aryl)-λ-iodanes (aryl-IF compounds) and tetrafluoro(aryl)-λ-iodanes (aryl-IF compounds) using trichloroisocyanuric acid (TCICA) and potassium fluoride (KF). Under these reaction conditions, selective access to either the I(iii)- or I(v)-derivatives is predictable based solely on the substitution pattern of the iodoarene starting material. Moreover, the discovery of this TCICA/KF approach prompted detailed dynamic NMR, kinetic, computational, and crystallographic studies on the relationship between the IF group and the -substituents on carefully designed probe molecules. It was during these experiments that the role of the -substituent in inhibiting further oxidative fluorination of I(iii)-compounds to I(v)-compounds during the reaction with TCICA and KF was revealed. Additionally, a notable exception to this empirical trend is discussed herein.
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http://dx.doi.org/10.1039/c9sc02162kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685355PMC
August 2019

Pentafluoro(aryl)-λ -tellanes and Tetrafluoro(aryl)(trifluoromethyl)-λ -tellanes: From SF to the TeF and TeF CF Groups.

Angew Chem Int Ed Engl 2019 09 7;58(36):12604-12608. Epub 2019 Aug 7.

Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland.

The TeF group is significantly underexplored as a highly fluorinated substituent on an organic framework, despite it being a larger congener of the acclaimed SF group. In fact, only one aryl-TeF compound (phenyl-TeF ) has been reported to date, synthesized using XeF . Our recently developed mild TCICA/KF approach to oxidative fluorination provides an affordable and scalable alternative to XeF . Using this method, we report a scope of extensively characterized aryl-TeF compounds, along with the first SC-XRD data on this compound class. The methodology was also extended to the synthesis and structural study of heretofore unknown aryl-TeF CF compounds. Additionally, preliminary reactivity studies unveiled some inconsistencies with previous literature regarding phenyl-TeF . Although our studies conclude that the arene-based TeF (and TeF CF ) group is not quite as robust as the SF group, we find that the TeF group is more stable than previously thought, thus opening a door to explore new applications of this motif.
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http://dx.doi.org/10.1002/anie.201907359DOI Listing
September 2019

Asymmetric Hydrogenation of Aryl Perfluoroalkyl Ketones Catalyzed by Rhodium(III) Monohydride Complexes Bearing Josiphos Ligands.

Chemistry 2019 Aug 22;25(46):10818-10822. Epub 2019 Jul 22.

Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland.

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)] , 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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http://dx.doi.org/10.1002/chem.201902585DOI Listing
August 2019

A Tunable Trifluoromethyliodonium Reagent.

Angew Chem Int Ed Engl 2019 Jun 17;58(25):8585-8588. Epub 2019 May 17.

Swiss Federal Institute of Technology, ETH Zurich, Department of Chemistry and Applied Biosciences, Vladimir-Prelog-Weg 2, 8093, Zurich, Switzerland.

Four complexes of MCl (M=Ti, Zr, Hf) with the hypervalent trifluoromethyl iodine reagent trifluoromethyl-1,3-dihydro-3,3-dimethyl-1,2-benziodoxole (1,=L) are described. With TiCl , an I-O bond cleavage occurs, leading to the formation of the trifluoromethyliodonium alcoholate complexes [Ti Cl (L) ]Cl (2 a) and Ti Cl (L) (2 b). Reactions with ZrCl and HfCl form the complexes ZrCl (L) (3) and HfCl (L) (4), respectively, wherein the original I-O bond is retained and elongated compared to that in free 1. Therefore, the reactivity of 1 can be easily and practically fine-tuned by addition of different metal chlorides, following the order ZrCl /HfCl
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http://dx.doi.org/10.1002/anie.201903623DOI Listing
June 2019

Taming Radical Intermediates for the Construction of Enantioenriched Trifluoromethylated Quaternary Carbon Centers.

Angew Chem Int Ed Engl 2019 01 21;58(5):1447-1452. Epub 2018 Dec 21.

Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zürich, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland.

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 S 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.
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http://dx.doi.org/10.1002/anie.201812793DOI Listing
January 2019

Making the SF Group More Accessible: A Gas-Reagent-Free Approach to Aryl Tetrafluoro-λ -sulfanyl Chlorides.

Angew Chem Int Ed Engl 2019 02 18;58(7):1950-1954. Epub 2019 Jan 18.

Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland.

Modern pentafluorosulfanyl (SF ) chemistry has an Achilles heel: synthetic accessibility. Herein, we present the first approach to aryl-SF Cl compounds (key intermediates in state-of-the-art aryl-SF synthesis) that overcomes the reliance on hazardous fluorinating reagents and/or gas reagents (e.g. Cl ) by employing easy-to-handle trichloroisocyanuric acid, potassium fluoride, and catalytic amounts of acid. These simple, mild conditions allow direct access to aryl-SF Cl intermediates that either have not been or cannot be demonstrated using previous methods. Furthermore, the same approach provides access to aryl-SF and aryl-SeF compounds, which extend the applications of this chemistry beyond arene SF -functionalization, and demonstrate its ability to address a more general oxidative fluorination problem.
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http://dx.doi.org/10.1002/anie.201812356DOI Listing
February 2019

Pyridyl Radical Cation for C-H Amination of Arenes.

Angew Chem Int Ed Engl 2019 01 12;58(2):526-531. Epub 2018 Dec 12.

Laboratory of Organic Chemistry, ETH Zürich, Vladimir-Prelog-Weg, 8093, Zürich, Switzerland.

Electron-transfer photocatalysis provides access to the elusive and unprecedented N-pyridyl radical cation from selected N-substituted pyridinium reagents. The resulting C(sp )-H functionalization of (hetero)arenes furnishes versatile intermediates for the development of valuable aminated aryl scaffolds. Mechanistic studies that include the first spectroscopic evidence of a spin-trapped N-pyridyl radical adduct implicate SET-triggered, pseudo-mesolytic cleavage of the N-X pyridinium reagents mediated by visible light.
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http://dx.doi.org/10.1002/anie.201810261DOI Listing
January 2019

Radical Trifluoromethoxylation of Arenes Triggered by a Visible-Light-Mediated N-O Bond Redox Fragmentation.

Angew Chem Int Ed Engl 2018 10 7;57(42):13784-13789. Epub 2018 Aug 7.

Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland.

A simple trifluoromethoxylation method enables non-directed functionalization of C-H bonds on a range of substrates, providing access to aryl trifluoromethyl ethers. This light-driven process is distinctly different from conventional procedures and occurs through an OCF radical mechanism mediated by a photoredox catalyst, which triggers an N-O bond fragmentation. The pyridinium-based trifluoromethoxylation reagent is bench-stable and provides access to synthetic diversity in lead compounds in an operationally simple manner.
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http://dx.doi.org/10.1002/anie.201806296DOI Listing
October 2018

Exposing the Origins of Irreproducibility in Fluorine NMR Spectroscopy.

Angew Chem Int Ed Engl 2018 07 16;57(30):9528-9533. Epub 2018 May 16.

Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Vladimir-Prelog-Weg 2, 8093, Zürich, Switzerland.

Fluorine chemistry has taken a pivotal role in chemical reaction discovery, drug development, and chemical biology. NMR spectroscopy, arguably the most important technique for the characterization of fluorinated compounds, is rife with highly inconsistent referencing of fluorine NMR chemical shifts, producing deviations larger than 1 ppm. Herein, we provide unprecedented evidence that both spectrometer design and the current unified scale system underpinning the calibration of heteronuclear NMR spectra have unintentionally led to widespread variation in the standardization of F NMR spectral data. We demonstrate that internal referencing provides the most robust, practical, and reproducible method whereby chemical shifts can be consistently measured and confirmed between institutions to less than 30 ppb deviation. Finally, we provide a comprehensive table of appropriately calibrated chemical shifts of reference compounds that will serve to calibrate F spectra correctly.
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http://dx.doi.org/10.1002/anie.201802620DOI Listing
July 2018

Editorial.

Chimia (Aarau) 2018 Feb;72(1)

Laboratory of Inorganic Chemistry;, Email:

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February 2018

Importance of Nonclassical σ-Hole Interactions for the Reactivity of λ-Iodane Complexes.

J Org Chem 2017 11 24;82(22):11799-11805. Epub 2017 Oct 24.

Departement of Chemistry and Applied Biosciences, ETH Zürich , Vladimir-Prelog-Weg 2, CH-8093 Zürich, Switzerland.

Key for the observed reactivity of λ-iodanes, powerful reagents for the selective transfer of functional groups to nucleophiles, are the properties of the 3-center-4-electron bond involving the iodine atom and the two linearly arranged ligands. This bond is also involved in the formation of the initial complex between the λ-iodane and a nucleophile, which can be a solvent molecule or a reactant. The bonding in such complexes can be described by means of σ-hole interactions. In halogen compounds, σ-hole interaction was identified as a force in crystal packing or in the formation of supramolecular chains. More recently, σ-hole interactions were also shown to affect the reactivity of the iodine-based hypervalent reagents. Relative to their monovalent counterparts, where the σ-hole is located on the extension of the sigma-bond, in the hypervalent species our DFT calculations reveal the formation of a nonclassical σ-hole region with one or even two maxima. This observation is also made in fully relativistic calculations. The SAPT analysis shows that the σ-hole bond between the λ-iodane and the nucleophile is not necessarily of purely electrostatic nature but may also contain a significant covalent component. This covalent component may facilitate chemical transformation of the compound by means of reductive elimination or other mechanisms and is therefore an indicator for its reactivity. Here, we also show that the shape, location, and strength of the σ-holes can be tuned by the choice of ligands and measures such as Brønsted activation of the iodane reagent. At the limit, the tuning transforms the nonclassical σ-hole regions into coordination sites, which allows us to control how a nucleophile will bind and react with the iodane.
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http://dx.doi.org/10.1021/acs.joc.7b01716DOI Listing
November 2017
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