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Catalysis of the reduction of nitrogen to ammonia under mild conditions by a tris(phosphine)borane-supported iron complex indicates that a single iron site may be capable of stabilizing the various N x H y intermediates generated during catalytic ammonia formation. In search of an easy fix for nitrogen Industrial nitrogen fixation is performed on a vast scale by the Haber–Bosch process, which uses a solid-state iron catalyst at very high temperatures and pressures. Synthetic chemists have searched for decades for small metal-containing complexes to catalyse the transformation of nitrogen into ammonia in less extreme conditions, taking their lead from the nitrogenases found in plants and bacteria. To that end Jonas Peters and colleagues describe a tris(phosphine)borane-supported iron complex that catalyses the reduction of nitrogen into ammonia under mild conditions with reasonable efficiency. This suggests that a single iron site is sufficient for mediating nitrogen fixation, in line with recent biochemical and spectroscopic data that point to iron rather than the molybdenum also present in the FeMo cofactor or nitrogenase as the site of nitrogen binding and activation. The reduction of nitrogen (N 2 ) to ammonia (NH 3 ) is a requisite transformation for life 1 . Although it is widely appreciated that the iron-rich cofactors of nitrogenase enzymes facilitate this transformation 2 , 3 , 4 , 5 , how they do so remains poorly understood. A central element of debate has been the exact site or sites of N 2 coordination and reduction 6 , 7 . In synthetic inorganic chemistry, an early emphasis was placed on molybdenum 8 because it was thought to be an essential element of nitrogenases 3 and because it had been established that well-defined molybdenum model complexes could mediate the stoichiometric conversion of N 2 to NH 3 (ref. 9 ). This chemical transformation can be performed in a catalytic fashion by two well-defined molecular systems that feature molybdenum centres 10 , 11 . However, it is now thought that iron is the only transition metal essential to all nitrogenases 3 , and recent biochemical and spectroscopic data have implicated iron instead of molybdenum as the site of N 2 binding in the FeMo-cofactor 12 . Here we describe a tris(phosphine)borane-supported iron complex that catalyses the reduction of N 2 to NH 3 under mild conditions, and in which more than 40 per cent of the proton and reducing equivalents are delivered to N 2 . Our results indicate that a single iron site may be capable of stabilizing the various N x H y intermediates generated during catalytic NH 3 formation. Geometric tunability at iron imparted by a flexible iron–boron interaction in our model system seems to be important for efficient catalysis 13 , 14 , 15 . We propose that the interstitial carbon atom recently assigned in the nitrogenase cofactor may have a similar role 16 , 17 , perhaps by enabling a single iron site to mediate the enzymatic catalysis through a flexible iron–carbon interaction 18 .

A simple and mild strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes that acts via a radical-mediated mechanism and uses commercial photocatalysts. Light-induced trifluoromethylation of potential drugs Premature metabolic decomposition can stop potentially promising drugs from reaching their intended targets. One way of blocking this metabolism involves the addition of a trifluoromethyl (CF 3 ) group to aromatic or heteroaromatic moieties in a candidate drug molecule. David Nagib and David MacMillan report a new method for this synthesis that is more economical than current methods in terms of both raw materials and energy input. They use an energy-saving compact fluorescent light bulb to excite a variety of commercially available photocatalysts, which promote the addition of CF 3 to unactivated arenes and heteroarenes through a radical-mediated mechanism. The potential of the method is demonstrated by the trifluoromethylation of three molecules: a uracil analogue, a precursor of the acetylcholinesterase inhibitor donepezil and a vitamin (flavone). Modern drug discovery relies on the continual development of synthetic methodology to address the many challenges associated with the design of new pharmaceutical agents 1 . One such challenge arises from the enzymatic metabolism of drugs in vivo by cytochrome P450 oxidases, which use single-electron oxidative mechanisms to rapidly modify small molecules to facilitate their excretion 2 . A commonly used synthetic strategy to protect against in vivo metabolism involves the incorporation of electron-withdrawing functionality, such as the trifluoromethyl (CF 3 ) group, into drug candidates 3 . The CF 3 group enjoys a privileged role in the realm of medicinal chemistry because its incorporation into small molecules often enhances efficacy by promoting electrostatic interactions with targets, improving cellular membrane permeability, and increasing robustness towards oxidative metabolism of the drug 4 , 5 , 6 . Although common pharmacophores often bear CF 3 motifs in an aromatic system, access to such analogues typically requires the incorporation of the CF 3 group, or a surrogate moiety, at the start of a multi-step synthetic sequence. Here we report a mild, operationally simple strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes through a radical-mediated mechanism using commercial photocatalysts and a household light bulb. We demonstrate the broad utility of this transformation through addition of CF 3 to a number of heteroaromatic and aromatic systems. The benefit to medicinal chemistry and applicability to late-stage drug development is also shown through examples of the direct trifluoromethylation of widely prescribed pharmaceutical agents.

Interactions between ceria (CeO 2 ) and supported metals greatly enhance rates for a number of important reactions. However, direct relationships between structure and function in these catalysts have been difficult to extract because the samples studied either were heterogeneous or were model systems dissimilar to working catalysts. We report rate measurements on samples in which the length of the ceria-metal interface was tailored by the use of monodisperse nickel, palladium, and platinum nanocrystals. We found that carbon monoxide oxidation in ceria-based catalysts is greatly enhanced at the ceria-metal interface sites for a range of group VIII metal catalysts, clarifying the pivotal role played by the support.

Enzymes provide an exquisitely tailored chiral environment to foster high catalytic activities and selectivities, but their native structures are optimized for very specific biochemical transformations. Designing a protein to accommodate a non-native transition metal complex can broaden the scope of enzymatic transformations while raising the activity and selectivity of small-molecule catalysis. Here, we report the creation of a bifunctional artificial metalloenzyme in which a glutamic acid or aspartic acid residue engineered into streptavidin acts in concert with a docked biotinylated rhodium(III) complex to enable catalytic asymmetric carbon-hydrogen (C-H) activation. The coupling of benzamides and alkenes to access dihydroisoquinolones proceeds with up to nearly a 100-fold rate acceleration compared with the activity of the isolated rhodium complex and enantiomeric ratios as high as 93:7.

It is shown that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild, direct and operationally simple formation of medicinally relevant carbon–carbon bonds while reacting in a complementary fashion to other innate carbon–hydrogen functionalization methods. Functionalized heterocycle synthesis Nitrogen-rich heterocycles feature widely in pharmaceuticals, and their synthesis has been simplified by a series of advances in transition-metal-mediated cross-coupling reactions. However, the development of practical and selective C–H functionalization methods that do not rely upon pre-functionalized starting materials is an underdeveloped area. Here the authors report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for a mild, direct and operationally simple formation of medicinally relevant C–C bonds while reacting in an orthogonal fashion to other innate C–H functionalization methods. Nitrogen-rich heterocyclic compounds have had a profound effect on human health because these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition-metal-mediated cross-coupling have simplified the synthesis of such molecules; however, C–H functionalization of medicinally important heterocycles that does not rely on pre-functionalized starting materials is an underdeveloped area 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 . Unfortunately, the innate properties of heterocycles that make them so desirable for biological applications—such as aqueous solubility and their ability to act as ligands—render them challenging substrates for direct chemical functionalization. Here we report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild (moderate temperature, 50 °C or less), direct and operationally simple formation of medicinally relevant C–C bonds while reacting in a complementary fashion to other innate C–H functionalization methods 2 , 3 , 4 , 5 , 6 (Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated C–H insertion and C–H deprotonation). We prepared a toolkit of these reagents and studied their reactivity across a wide range of heterocycles (natural products, drugs and building blocks) without recourse to protecting-group chemistry. The reagents can even be used in tandem fashion in a single pot in the presence of water and air.

Electrochemical conversion of carbon dioxide (CO₂) to carbon monoxide (CO) is a potentially useful step in the desirable transformation of the greenhouse gas to fuels and commodity chemicals. We have found that modification of iron tetraphenylporphyrin through the introduction of phenolic groups in all ortho and ortho' positions of the phenyl groups considerably speeds up catalysis of this reaction by the electrogenerated iron(0) complex. The catalyst which uses one of the most earth-abundant metals, manifests a CO faradaic yield above 90% through 50 million turnovers over 4 hours of electrolysis at low overpotential (0.465 volt), with no observed degradation. The basis for the enhanced activity appears to be the high local concentration of protons associated with the phenolic hydroxyl substituents.

Despite the growing importance of fluorinated organic compounds in drug development, there are no direct protocols for the fluorination of aliphatic C-H bonds using conveniently handled fluoride salts. We have discovered that a manganese porphyrin complex catalyzes alkyl fluorination by fluoride ion under mild conditions in conjunction with stoichiometric oxidation by iodosylbenzene. Simple alkanes, terpenoids, and even steroids were selectively fluorinated at otherwise inaccessible sites in 50 to 60% yield. Decalin was fluorinated predominantly at the C2 and C3 methylene positions. Bornyl acetate was converted to exo-5-fluoro-bornyl acetate, and 5α-androstan-17-one was fluorinated selectively in the A ring. Mechanistic analysis suggests that the regioselectivity for C-H bond cleavage is directed by an oxomanganese(V) catalytic intermediate followed by F delivery via an unusual manganese(IV) fluoride that has been isolated and structurally characterized.

Fluorination to the fore When incorporated into organic compounds, fluorine atoms often impart useful properties. For example, fluorination improves the thermal stability of some materials, and enhances the metabolic stability of some pharmaceuticals. Recent advances make it possible to create carbon–fluorine bonds at specific positions in complex organic molecules, paving the way for a new and potentially productive era in fluorination chemistry. In this Review, Furuya et al . describe the inherent challenges associated with carbon–fluorine bond-formation reactions, discuss the breakthroughs that have helped to overcome these problems and outline the likely direction of future research. Recent advances in catalysis have made the incorporation of fluorine into complex organic molecules easier than ever before, but selective, general and practical fluorination reactions remain sought after. Fluorination of molecules often imparts desirable properties, such as metabolic and thermal stability, and fluorinated molecules are therefore frequently used as pharmaceuticals or materials. But the formation of carbon−fluorine bonds in complex molecules is a significant challenge. Here we discuss reactions to make organofluorides that have emerged within the past few years and which exemplify how to overcome some of the intricate challenges associated with fluorination.

The direct β-activation of saturated aldehydes and ketones has long been an elusive transformation. We found that photoredox catalysis in combination with organocatalysis can lead to the transient generation of 5π-electron β-enaminyl radicals from ketones and aldehydes that rapidly couple with cyano-substituted aryl rings at the carbonyl β-position. This mode of activation is suitable for a broad range of carbonyl β-functionalization reactions and is amenable to enantioselective catalysis.

Improving the sluggish kinetics for the electrochemical reduction of water to molecular hydrogen in alkaline environments is one key to reducing the high overpotentials and associated energy losses in water-alkali and chlor-alkali electrolyzers. We found that a controlled arrangement of nanometer-scale Ni (OH)₂ clusters on platinum electrode surfaces manifests a factor of 8 activity increase in catalyzing the hydrogen evolution reaction relative to state-of-the-art metal and metal-oxide catalysts. In a bifunctional effect, the edges of the Ni(OH)₂ clusters promoted the dissociation of water and the production of hydrogen intermediates that then adsorbed on the nearby Pt surfaces and recombined into molecular hydrogen. The generation of these hydrogen intermediates could be further enhanced via Li⁺-induced déstabilisation of the HO-H bond, resulting in a factor of 10 total increase in activity.