Synthesis, Structure, and Hydrogenolysis of Pyridine Dicarbene Iron Dialkyl Complexes.

Two methods for the synthesis of bis(imidazol-2-ylidene)pyridine iron dialkyl complexes, (CNC)Fe(CH2SiMe3)2, have been developed. The first route consists of addition of two equivalents of LiCH2SiMe3 to the iron dihalide complex, (CNC)FeBr2, while the second relies on addition of the free CNC ligand to readily-prepared (py)2Fe(CH2SiMe3)2 (py = pyridine). With aryl-substituted CNC ligands, octahedral complexes of the type ( Ar CNC)Fe(CH2SiMe3)2(N2) ( Ar CNC = bis(arylimidazol-2-ylidene)pyridine) were isolated, where the dinitrogen ligand occupies the site trans to the pyridine of the CNC-chelate. In contrast, the alkyl-substituted variant, (tBuACNC)Fe(CH2SiMe3)2 (tBuACNC = 2,6-(tBu-imidazol-2-ylidene)2pyridine) was isolated as the five-coordinate compound lacking dinitrogen. Exposure of the ( Ar CNC)Fe(CH2SiMe3)2(N2) derivatives to an H2 atmosphere resulted in formation of the corresponding iron hydride complexes ( Ar CNC)FeH4. These compounds catalyzed hydrogen isotope exchange between the deuterated benzene solvent and H2, generating isotopologues and isotopomers of ( Ar CNC)Fe(H n )(D4-n ) (n = 0-4). When (3,5-Me2 MesCNC)Fe(CH2SiMe3)2(N2) (3,5-Me2 MesCNC = 2,6-(2,4,6-Me3-C6H2-imidazol-2-ylidene)2-3,5-Me2-pyridine) was treated successively with H2 and then N2, the corresponding reduced dinitrogen complex (3,5-Me2 MesCNC)Fe(N2)2 was isolated. The same product was also obtained following addition of pinacolborane to (3,5-Me2 MesCNC)Fe(CH2SiMe3)2(N2).

Iron-catalysed tritiation of pharmaceuticals.

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 (14)C or (3)H 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 ((3)H) 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 (3)H 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.

Electronic Structure Determination of Pyridine N-Heterocyclic Carbene Iron Dinitrogen Complexes and Neutral Ligand Derivatives.

The electronic structures of pyridine N-heterocyclic dicarbene (iPrCNC) iron complexes have been studied by a combination of spectroscopic and computational methods. The goal of these studies was to determine if this chelate engages in radical chemistry in reduced base metal compounds. The iron dinitrogen example (iPrCNC)Fe(N2)2 and the related pyridine derivative (iPrCNC)Fe(DMAP)(N2) were studied by NMR, Mössbauer, and X-ray absorption spectroscopy and are best described as redox non-innocent compounds with the iPrCNC chelate functioning as a classical π acceptor and the iron being viewed as a hybrid between low-spin Fe(0) and Fe(II) oxidation states. This electronic description has been supported by spectroscopic data and DFT calculations. Addition of N,N-diallyl-tert-butylamine to (iPrCNC)Fe(N2)2 yielded the corresponding iron diene complex. Elucidation of the electronic structure again revealed the CNC chelate acting as a π acceptor with no evidence for ligand-centered radicals. This ground state is in contrast with the case for the analogous bis(imino)pyridine iron complexes and may account for the lack of catalytic [2π + 2π] cycloaddition reactivity.

Catalytic hydrogenation activity and electronic structure determination of bis(arylimidazol-2-ylidene)pyridine cobalt alkyl and hydride complexes.

The bis(arylimidazol-2-ylidene)pyridine cobalt methyl complex, ((iPr)CNC)CoCH3, was evaluated for the catalytic hydrogenation of alkenes. At 22 °C and 4 atm of H2 pressure, ((iPr)CNC)CoCH3 is an effective precatalyst for the hydrogenation of sterically hindered, unactivated alkenes such as trans-methylstilbene, 1-methyl-1-cyclohexene, and 2,3-dimethyl-2-butene, representing one of the most active cobalt hydrogenation catalysts reported to date. Preparation of the cobalt hydride complex, ((iPr)CNC)CoH, was accomplished by hydrogenation of ((iPr)CNC)CoCH3. Over the course of 3 h at 22 °C, migration of the metal hydride to the 4-position of the pyridine ring yielded (4-H2-(iPr)CNC)CoN2. Similar alkyl migration was observed upon treatment of ((iPr)CNC)CoH with 1,1-diphenylethylene. This reactivity raised the question as to whether this class of chelate is redox-active, engaging in radical chemistry with the cobalt center. A combination of structural, spectroscopic, and computational studies was conducted and provided definitive evidence for bis(arylimidazol-2-ylidene)pyridine radicals in reduced cobalt chemistry. Spin density calculations established that the radicals were localized on the pyridine ring, accounting for the observed reactivity, and suggest that a wide family of pyridine-based pincers may also be redox-active.

High-Activity Iron Catalysts for the Hydrogenation of Hindered, Unfunctionalized Alkenes.

The activity of aryl-substituted bis(imino)pyridine and bis(arylimidazol-2-ylidene)pyridine iron dinitrogen complexes has been evaluated in a series of catalytic olefin hydrogenation reactions. In general, more electron donating chelates with smaller 2,6-aryl substituents produce more active iron hydrogenation catalysts. Establishment of this structure-activity relationship has produced base metal catalysts that exhibit high turnover frequencies for the hydrogenation of unfunctionalized, tri- and tetrasubstituted alkenes, one of the most challenging substrate classes for homogenous hydrogenation catalysts.

Aryl C-H amination by diruthenium nitrides in the solid state and in solution at room temperature: experimental and computational study of the reaction mechanism.

Diruthenium azido complexes Ru(2)(DPhF)(4)N(3) (1a, DPhF = N,N'-diphenylformamidinate) and Ru(2)(D(3,5-Cl(2))PhF)(4)N(3) (1b, D(3,5-Cl(2))PhF = N,N'-bis(3,5-dichlorophenyl)formamidinate) have been investigated by thermolytic and photolytic experiments to investigate the chemical reactivity of the corresponding diruthenium nitride species. Thermolysis of 1b at ~100 °C leads to the expulsion of N(2) and isolation of Ru(2)(D(3,5-Cl(2))PhF)(3)NH(C(13)H(6)N(2)Cl(4)) (3b), in which a nitrogen atom has been inserted into one of the proximal aryl C-H bonds of a D(3,5-Cl(2))PhF ligand. A similar C-H insertion product is obtained upon thawing a frozen CH(2)Cl(2) solution of the nitride complex Ru(2)(DPhF)(4)N (2a), formed via photolysis at -196 °C of 1a to yield Ru(2)(DPhF)(3)NH(C(13)H(10)N(2)) (3a). Evidence is provided here that both reactions proceed via direct intramolecular attack of an electrophilic terminal nitrido nitrogen atom on a proximal aryl ring. Thermodynamic and kinetic data for this reaction are obtained from differential scanning calorimetric measurements and thermal gravimetric analysis of the thermolysis of Ru(2)(D(3,5-Cl(2))PhF)(4)N(3), and by Arrhenius/Eyring analysis of the conversion of Ru(2)(DPhF)(4)N to its C-H insertion product, respectively. These data are used to develop a detailed, experimentally validated DFT reaction pathway for N(2) extrusion and C-H functionalization from Ru(2)(D(3,5-Cl(2))PhF)(4)N(3). The diruthenium nitrido complex is an intermediate in the calculated reaction pathway, and the C-H functionalization event shares a close resemblance to a classical electrophilic aromatic substitution mechanism.

Aryl C-H bond amination by an electrophilic diruthenium nitride.

Thermolysis of the terminal azido Ru(2)(D(3,5-Cl(2))PhF)(3)N(3) (3, D(3,5-Cl(2))PhF = N,N'-bis(3,5-dichlorophenyl) formamidinate) cleanly produces Ru(2)[(D(3,5-Cl(2))PhF)(3)(D(3,5-Cl(2)-2-NH)PhF)] (4), which is proposed to result from insertion of a nitrido N atom into a ligand aryl C-H bond. This mechanism is supported by differential scanning calorimetry and thermogravimetric analysis results, which show the two-step reaction to be exothermic by -215 kJ mol(-1), in agreement with results from density functional theory calculations. This is the first example of electrophilic insertion of a terminal nitride into an aromatic C-H bond.