- Facile H/D exchange at (hetero)aromatic hydrocarbons catalyzed by a stable trans-dihydride n-heterocyclic carbene (NHC) iron complex
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Earth-abundant metal pincer complexes have played an important role in homogeneous catalysis during the last ten years. Yet, despite intense research efforts, the synthesis of iron PCcarbeneP pincer complexes has so far remained elusive. Here we report the synthesis of the first PCNHCP functionalized iron complex [(PCNHCP)FeCl2] (1) and the reactivity of the corresponding trans-dihydride iron(II) dinitrogen complex [(PCNHCP)- Fe(H)2N2)] (2). Complex 2 is stable under an atmosphere of N2 and is highly active for hydrogen isotope exchange at (hetero)aromatic hydrocarbons under mild conditions (50 °C, N2). With benzene-d6 as the deuterium source, easily reducible functional groups such as esters and amides are well tolerated, contributing to the overall wide substrate scope (e.g., halides, ethers, and amines). DFT studies suggest a complex assisted σ-bond metathesis pathway for C(sp2)-H bond activation, which is further discussed in this study.
- De Ruiter, Graham,Garhwal, Subhash,Kaushansky, Alexander,Fridman, Natalia,Shimon, Linda J.W.
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supporting information
p. 17131 - 17139
(2020/11/09)
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- Iron-catalysed tritiation of pharmaceuticals
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A thorough understanding of the pharmacokinetic and pharmacodynamic properties of a drug in animal models is a critical component of drug discovery and development. Such studies are performed in vivo and in vitro at various stages of the development process-ranging from preclinical absorption, distribution, metabolism and excretion (ADME) studies to late-stage human clinical trials-to elucidate a drug molecule's metabolic profile and to assess its toxicity. Radiolabelled compounds, typically those that contain 14C or 3H isotopes, are one of the most powerful and widely deployed diagnostics for these studies. The introduction of radiolabels using synthetic chemistry enables the direct tracing of the drug molecule without substantially altering its structure or function. The ubiquity of C-H bonds in drugs and the relative ease and low cost associated with tritium (3H) make it an ideal radioisotope with which to conduct ADME studies early in the drug development process. Here we describe an iron-catalysed method for the direct 3H labelling of pharmaceuticals by hydrogen isotope exchange, using tritium gas as the source of the radioisotope. The site selectivity of the iron catalyst is orthogonal to currently used iridium catalysts and allows isotopic labelling of complementary positions in drug molecules, providing a new diagnostic tool in drug development.
- Pony Yu, Renyuan,Hesk, David,Rivera, Nelo,Pelczer, Istvan,Chirik, Paul J.
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p. 195 - 199
(2016/01/25)
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- The thermal conversions of 6,6-difluorobicyclo[3.1.0]hex-2-enes to fluorobenzenes. An interesting dichotomy of mechanisms
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A kinetic study of the thermal, dehydrofluorinative aromatization reactions of two ostensibly-similar 6,6-difluorobicyclo[3.1.0]hex-2-ene systems led to the conclusion that drastically different mechanisms operate for the two reactions. Activation parameters, solvent effects, kinetic isotope effects, isotope labelling experiments and observation of reactive intermediates all contributed to the conclusion that the reaction of 6,6-difluorobicyclo[3.1.0]hex-2-ene, 1, proceeds via a homolytic hydrogen-shift rearrangement, while the reaction of 2,3-benzo-6,6-difluorobicyclo[3.1.0]hex-2-ene, 6, proceeds via a solvolytic mechanism involving rate-determining carbocation formation.
- Dolbier Jr.,Keaffaber,Burkholder,Koroniak,Pradhan
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p. 9649 - 9660
(2007/10/02)
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- Thermoneutral Isotope Exchange Reactions of Cations in the Gas Phase
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Rate constants have been measured for reactions of the type AD2+ + MH --> MD + ADH+, where AD2+ is CD3CND+, CD3CDOD+, (CD3COCD3)D+, or (C2D5)2OD+ and the MH molecules are alcohols, acids, mercaptanes, H2S, AsH3, PH3, or aromatic molecules.Rate constants are also presented for the reactions ArHD+ + D2O --> ArDD+ + HDO, where ArHD+ is a deuteronated aromatic molecule and ArDD+ is the same species with a D atom incorporated on the ring.In all but two cases, the competing deuteron transfer is sufficiently endothermic that it cannot be observed under the conditions of the ICR experiments at 320 - 420 K.The efficiencies of the isotope exchange reactions are interpreted in terms of estimated potential surface cross sections for the reactions AD2+ + MH --> 2+*MH> --> +> --> +*MD> --> ADH+ + MD.When the formation of the +> complex is estimated to be thermoneutral or slightly endothermic, the isotope exchange process is inefficient (probability of a reactive collision 2+*MH> --> +> is exothermic.For most of the systems, trends in reaction efficiency appear to be related to factors such as dipole moments of reactant species (or for aromatic compounds, the electron-donating or -withdrawing properties of ring substituents) which influence the relative orientation of the two reactant species in the complex.
- Ausloos, P.,Lias, S. G.
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p. 3641 - 3647
(2007/10/02)
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