Light Induced Cobalt(III) Carbene Radical Formation from Dimethyl Malonate As Carbene Precursor.

Radical-type carbene transfer catalysis is an efficient method for the direct functionalization of C-H and C=C bonds. However, carbene radical complexes are currently formed via high-energy carbene precursors, such as diazo compounds or iodonium ylides. Many of these carbene precursors require additional synthetic steps, have an explosive nature, or generate halogenated waste. Consequently, the utilization of carbene radical catalysis is limited by specific carbene precursors that access the carbene radical intermediate. In this study, we generate a cobalt(III) carbene radical complex from dimethyl malonate, which is commercially available and bench-stable. EPR and NMR spectroscopy were used to identify the intermediates and showed that the cobalt(III) carbene radical complex is formed upon light irradiation. In the presence of styrene, carbene transfer occurred, forming cyclopropane as the product. With this photochemical method, we demonstrate that dimethyl malonate can be used as an alternative carbene precursor in the formation of a cobalt(III) carbene radical complex.

Rapid and scalable photocatalytic C(sp2)-C(sp3) Suzuki-Miyaura cross-coupling of aryl bromides with alkyl boranes.

In recent years, there has been a growing demand for drug design approaches that incorporate a higher number of sp3-hybridized carbons, necessitating the development of innovative cross-coupling strategies to reliably introduce aliphatic fragments. Here, we present a powerful approach for the light-mediated B-alkyl Suzuki-Miyaura cross-coupling between alkyl boranes and aryl bromides. Alkyl boranes were easily generated via hydroboration from readily available alkenes, exhibiting excellent regioselectivity and enabling the selective transfer of a diverse range of primary alkyl fragments onto the arene ring under photocatalytic conditions. This methodology eliminates the need for expensive catalytic systems and sensitive organometallic compounds, operating efficiently at room temperature within just 30 min. We further demonstrate the translation of the present protocol to continuous-flow conditions, enhancing scalability, safety, and overall efficiency of the method. This versatile approach offers significant potential for accelerating drug discovery efforts by enabling the introduction of complex aliphatic fragments in a straightforward and reliable manner.

Diazirine-Functionalized Polyurethane Crosslinkers for Isocyanate-Free Curing of Polyol-Based Coatings.

Polyurethane coatings have strong material properties due to the hydrogen bonding inherent to the urethane groups. However, installing this urethane moiety usually requires curing through difficult-to-handle isocyanates. In this work, we show the development of a polyurethane-based crosslinker that can be used to formulate a one-component polyurethane coating with material properties similar to those of isocyanate-based polyurethane coatings. To achieve this, we used diazirine functionalities that generate carbenes upon heating, which react with alcohol functionalities in a polyol to generate a crosslinked network with a high storage modulus.

N-Heterocyclic Carbene Analogues of Wittig Hydrocarbon.

N-Heterocyclic carbene (NHC) analogues of Wittig hydrocarbon, [(NHC)(Stil)(NHC)] (3a-c) (NHC = SIPr (1a) = C[N(Dipp)CH2]2, Dipp = 2,6-iPr2C6H3; IPr (1b) = C[N(Dipp)CH]2; Me-IPr (1c) = C[N(Dipp)CMe]2 and Stil = C6H4CHCHC6H4) have been reported as crystalline solids. 3a-c are prepared by two-electron reductions of the corresponding bis-1,3-imidazoli(ni)um bromides [(NHC)(Stil)NHC)](Br)2 (2a-c) with KC8 in >94 % yields. 2a-c are accessible by the nickel catalyzed direct C-C coupling of NHCs (1a-c) with (E)-4,4'-dibromostilbene. One-electron oxidation of 3a,b yields the corresponding radical cations [(NHC)(Stil)NHC)]B(C6F5)4 4a,b. All compounds have been characterized by UV-Vis/NMR/EPR spectroscopy as well as 2a, 3a, and 3b by single crystal X-ray diffraction. The electronic structures of representative systems have been analyzed by quantum chemical calculations.

Gas Evolution as a Tool to Study Reaction Kinetics Under Biomimetic Conditions.

The field of bioorthogonal chemistry is rapidly growing, presenting successful applications of organic and transition metal-catalysed reactions in cells and living systems (in vivo). The development of such reactions typically proceeds through many iterative steps focused on biocompatibility and fast reaction kinetics to ensure product formation. However, obtaining kinetic data, even under simulated biological (biomimetic) conditions, remains a challenge due to substantial concentrations of salts and biomolecules hampering the use of typically employed solution-phase analytical techniques. In this study, we explored the suitability of gas evolution as a probe to study kinetics under biomimetic conditions. As proof of concept, we show that the progress of two transition metal-catalysed bioorthogonal chemical reactions can be accurately monitored, regardless of the complexity of the medium. As such, we introduce a protocol to gain more insight into the performance of a catalytic system under biomimetic conditions to further progress iterative catalyst development for in vivo applications.

PhenTAA: A Redox-Active N4-Macrocyclic Ligand Featuring Donor and Acceptor Moieties.

Here, we present the development and characterization of the novel PhenTAA macrocycle as well as a series of [Ni(R2PhenTAA)]n complexes featuring two sites for ligand-centered redox-activity. These differ in the substituent R (R = H, Me, or Ph) and overall charge of the complex n (n = -2, -1, 0, +1, or +2). Electrochemical and spectroscopic techniques (CV, UV/vis-SEC, X-band EPR) reveal that all redox events of the [Ni(R2PhenTAA)] complexes are ligand-based, with accessible ligand charges of -2, -1, 0, +1, and +2. The o-phenylenediamide (OPD) group functions as the electron donor, while the imine moieties act as electron acceptors. The flanking o-aminobenzaldimine groups delocalize spin density in both the oxidized and reduced ligand states. The reduced complexes have different stabilities depending on the substituent R. For R = H, dimerization occurs upon reduction, whereas for R = Me/Ph, the reduced imine groups are stabilized. This also gives electrochemical access to a [Ni(R2PhenTAA)]2- species. DFT and TD-DFT calculations corroborate these findings and further illustrate the unique donor-acceptor properties of the respective OPD and imine moieties. The novel [Ni(R2PhenTAA)] complexes exhibit up to five different ligand-based oxidation states and are electrochemically stable in a range from -2.4 to +1.8 V for the Me/Ph complexes (vs Fc/Fc+).

Cobalt-Catalyzed Asymmetric Hydrogenation: Substrate Specificity and Mechanistic Variability.

Asymmetric hydrogenation finds widespread application in academia and industry. And indeed, a number of processes have been implemented for the production of pharma and agro intermediates as well as flavors & fragrances. Although these processes are all based on the use of late transition metals as catalysts, there is an increasing interest in the use of base metal catalysis in view of their lower cost and the expected different substrate scope. Catalysts based on cobalt have already shown their potential in enantioselective hydrogenation chemistry. This review outlines the impressive progress made in recent years on cobalt-catalyzed asymmetric hydrogenation of different unsaturated substrates. We also illustrate the ligand dependent substrate specificity as well as the mechanistic variability in detail. This may well guide further catalyst development in this research area.

meta-C-H Arylation of Aniline Derivatives via Palladium/ S,O-Ligand/Norbornene Cooperative Catalysis.

Aromatic amines are ubiquitous moieties in organic molecules and their direct functionalization is of great interest in many research areas due to their prevalence in pharmaceuticals and organic electronics. While several synthetic tools exist for the ortho- and para-functionalization of anilines, the functionalization of the less reactive meta-position is not easy to achieve with current methods. To date, the meta-C-H arylation of aniline derivatives has been restricted to either the use of directing groups & templates, or their transformation into anilides & quaternary anilinium salts. Herein, we report the first general and efficient meta-C-H-arylation of non-directed aniline derivatives via cooperative catalysis with a palladium-S,O-ligand-norbornene system. The reaction proceeds under mild conditions with a wide range of aniline derivatives and aryl iodides, while being operationally simple and scalable. Our preliminary mechanistic investigation-including the isolation of several palladium complexes and deuterium experiments-reveal useful insights into the substituent-effects of both the aniline-substrate and the norbornene-mediator during the meta-C-H activation step.

Markovnikov-Selective Cobalt-Catalyzed Wacker-Type Oxidation of Styrenes into Ketones under Ambient Conditions Enabled by Hydrogen Bonding.

The replacement of palladium catalysts for Wacker-type oxidation of olefins into ketones by first-row transition metals is a relevant approach for searching more sustainable protocols. Besides highly sophisticated iron catalysts, all the other first-row transition metal complexes have only led to poor activities and selectivities. Herein, we show that the cobalt-tetraphenylporphyrin complex is a competent catalyst for the aerobic oxidation of styrenes into ketones with silanes as the hydrogen sources. Remarkably, under room temperature and air atmosphere, the reactions were exceedingly fast (up to 10 minutes) with a low catalyst loading (1 mol %) while keeping an excellent chemo- and Markovnikov-selectivity (up to 99 % of ketone). Unprecedently high TOF (864 h-1 ) and TON (5,800) were reached for the oxidation of aromatic olefins under these benign conditions. Mechanistic studies suggest a reaction mechanism similar to the Mukaiyama-type hydration of olefins with a change in the last fundamental step, which controls the chemoselectivity, thanks to a unique hydrogen bonding network between the ethanol solvent and the cobalt peroxo intermediate.

C-H Bond Activation by Iridium(III) and Iridium(IV) Oxo Complexes.

Oxidation of an iridium(III) oxo precursor enabled the structural, spectroscopic, and quantum-chemical characterization of the first well-defined iridium(IV) oxo complex. Side-by-side examination of the proton-coupled electron transfer thermochemistry revealed similar driving forces for the isostructural oxo complexes in two redox states due to compensating contributions from H+ and e- transfer. However, C-H activation of dihydroanthracene revealed significant hydrogen tunneling for the distinctly more basic iridium(III) oxo complex. Our findings complement the growing body of data that relate tunneling to ground state properties as predictors for the selectivity of C-H bond activation.

Copper-Catalyzed Sulfimidation in Aqueous Media: a Fast, Chemoselective and Biomolecule-Compatible Reaction.

Performing transition metal-catalyzed reactions in cells and living systems has equipped scientists with a toolbox to study biological processes and release drugs on demand. Thus far, an impressive scope of reactions has been performed in these settings, but many are yet to be introduced. Nitrene transfer presents a rather unexplored new-to-nature reaction. The reaction products are frequently encountered motifs in pharmaceuticals, presenting opportunities for the controlled, intracellular synthesis of drugs. Hence, we explored the transition metal-catalyzed sulfimidation reaction in water for future in vivo application. Two Cu(I) complexes containing trispyrazolylborate ligands (Tpx ) were selected, and the catalytic system was evaluated with the aid of three fitness factors. The excellent nitrene transfer reactivity and high chemoselectivity of the catalysts, coupled with good biomolecule compatibility, successfully enabled the sulfimidation of thioethers in aqueous media. We envision that this copper-catalyzed sulfimidation reaction could be an interesting starting point to unlock the potential of nitrene transfer catalysis in vivo.

Pd12MnL24 (for n = 6, 8, 12) nanospheres by post-assembly modification of Pd12L24 spheres.

In this contribution, we describe a post-assembly modification approach to selectively coordinate transition metals in Pd12L24 cuboctahedra. The herein reported approach involves the preparation of Pd12L24 nanospheres with protonated nitrogen donor ligands that are covalently linked at the interior. The so obtained Pd12(LH+)24 nanospheres are shown to be suitable for coordinative post-modification after deprotection by deprotonation. Selective formation of tetra-coordinated MB in Pd12MB6L24, tri-coordinated MB in Pd12MB8L24 nanospheres and two-coordinated MB in Pd12MB12L24 nanospheres is achieved as a result of different nitrogen donor ligands. A combination of pulsed EPR spectroscopy (DEER) to measure Cu-Cu distances in the different spheres, NMR studies and computational investigations, support the presence of the complexes at precise locations of the Pd12MB6L24 nanosphere. The general post-assembly modification methodology can be extended using other transition metal precursors or supramolecular systems and can guide precise formation and investigation of novel transition metal-complex containing nanospheres with well-defined composition.

A Co(TAML)-based artificial metalloenzyme for asymmetric radical-type oxygen atom transfer catalysis.

We show that the incorporation of a biotinylated Co(TAML) cofactor within streptavidin enables asymmetric radical-type oxygen atom transfer catalysis with improved activity and enantioselectivity.

Thermal/Blue Light Induced Cross-Linking of Acrylic Coatings with Diazo Compounds.

The thermal curing of industrial coatings (e.g., car painting and metal coil coatings) is accompanied by a substantial energy consumption due to the intrinsically high temperatures required during the curing process. Therefore, the development of new photochemical curing processes-preferably using visible light-is in high demand. This work describes new diazo-based cross-linkers that can be used to photocure acrylic coatings using blue light. This work demonstrates that the structure of the tethered diazo compounds influences the cross-linking efficiency, finding that side reactions are suppressed upon engineering greater molecular flexibility. Importantly, this work shows that these diazo compounds can be employed as either thermal or photochemical cross-linkers, exhibiting identical crosslinking performances. The performance of diazo-cross-linked coatings is evaluated to reveal excellent water resistance and demonstrably similar material properties to UV-cured acrylates. These studies pave the way for further usage of diazo-functionalized cross-linkers in the curing of paints and coatings.

Creating Conjugated C-C Bonds between Commercial Carbon Electrode and Molecular Catalyst for Oxygen Reduction to Hydrogen Peroxide.

Immobilizing molecular catalysts on electrodes is vital for electrochemical applications. However, creating robust electrode-catalyst interactions while maintaining good catalytic performance and rapid electron transfer is challenging. Here, without introducing any foreign elements, we show a bottom-up synthetic approach of constructing the conjugated C-C bond between the commercial Vulcan carbon electrode and an organometallic catalyst. Characterization results from FTIR, XPS, aberration-corrected TEM and EPR confirmed the successful and uniform heterogenization of the complex. The synthesized Vulcan-LN4 -Co catalyst is highly active and selective in the oxygen reduction reaction in neutral media, showing an 80 % hydrogen peroxide selectivity and a 0.72 V (vs. RHE) onset potential which significantly outperformed the homogenous counterpart. Based on single-crystal XRD and NMR data, we built a model for density functional theory calculations which showed a nearly optimal binding energy for the *OOH intermediate. Our results show that the direct conjugated C-C bonding is an effective approach for heterogenizing molecular catalysts on carbon, opening new opportunities for employing molecular catalysts in electrochemical applications.

Understanding the Oxidative Properties of Nickel Oxyhydroxide in Alcohol Oxidation Reactions.

The NiOOH electrode is commonly used in electrochemical alcohol oxidations. Yet understanding the reaction mechanism is far from trivial. In many cases, the difficulty lies in the decoupling of the overlapping influence of chemical and electrochemical factors that not only govern the reaction pathway but also the crystal structure of the in situ formed oxyhydroxide. Here, we use a different approach to understand this system: we start with synthesizing pure forms of the two oxyhydroxides, ß-NiOOH and γ-NiOOH. Then, using the oxidative dehydrogenation of three typical alcohols as the model reactions, we examine the reactivity and selectivity of each oxyhydroxide. While solvent has a clear effect on the reaction rate of ß-NiOOH, the observed selectivity was found to be unaffected and remained over 95% for the dehydrogenation of both primary and secondary alcohols to aldehydes and ketones, respectively. Yet, high concentration of OH- in aqueous solvent promoted the preferential conversion of benzyl alcohol to benzoic acid. Thus, the formation of carboxylic compounds in the electrochemical oxidation without alkaline electrolyte is more likely to follow the direct electrochemical oxidation pathway. Overoxidation of NiOOH from the ß- to γ-phase will affect the selectivity but not the reactivity with a sustained >95% conversion. The mechanistic examinations comprising kinetic isotope effects, Hammett analysis, and spin trapping studies reveal that benzyl alcohol is oxidatively dehydrogenated to benzaldehyde via two consecutive hydrogen atom transfer steps. This work offers the unique oxidative and catalytic properties of NiOOH in alcohol oxidation reactions, shedding light on the mechanistic understanding of the electrochemical alcohol conversion using NiOOH-based electrodes.

In vivo biodistribution of kinetically stable Pt2L4 nanospheres that show anti-cancer activity.

There is an increasing interest in the application of metal-organic cages (MOCs) in a biomedicinal context, as they can offer non-classical distribution in organisms compared to molecular substrates, while revealing novel cytotoxicity mechanisms. Unfortunately, many MOCs are not sufficiently stable under in vivo conditions, making it difficult to study their structure-activity relationships in living cells. As such, it is currently unclear whether MOC cytotoxicity stems from supramolecular features or their decomposition products. Herein, we describe the toxicity and photophysical properties of highly-stable rhodamine functionalized platinum-based Pt2L4 nanospheres as well as their building blocks under in vitro and in vivo conditions. We show that in both zebrafish and human cancer cell lines, the Pt2L4 nanospheres demonstrate reduced cytotoxicity and altered biodistribution within the body of zebrafish embryos compared to the building blocks. We anticipate that the composition-dependent biodistribution of Pt2L4 spheres together with their cytotoxic and photophysical properties provides the fundament for MOC application in cancer therapy.

Iron-Catalyzed Intermolecular C-N Cross-Coupling Reactions via Radical Activation Mechanism.

A concept for intermolecular C-N cross-coupling amination has been discovered using tetrazoles and aromatic and aliphatic azides with boronic acids under iron-catalyzed conditions. The amination follows an unprecedented metalloradical activation mechanism that is different from traditional metal-catalyzed C-N cross-coupling reactions. The scope of the reaction has been demonstrated by the employment of a large number of tetrazoles, azides, and boronic acids. Moreover, several late-stage aminations and a short synthesis of a drug candidate have been showcased for further synthetic utility. Collectively, this iron-catalyzed C-N cross-coupling should have wide applications in the context of medicinal chemistry, drug discovery, and pharmaceutical industries.

A photoresponsive gold catalyst based on azobenzene-functionalized NHC ligands.

An azobenzene-bearing N-heterocyclic carbene-based gold catalyst is reported of which the reactivity in a cyclization reaction depends on the isomeric state of the azobenzene. The configurations of the catalyst can be reversibly switched by light and are stable during the reaction, effectively leading to a switchable catalyst system.

Transition Metal Catalysis in Living Cells: Progress, Challenges, and Novel Supramolecular Solutions.

The importance of transition metal catalysis is exemplified by its wide range of applications, for example in the synthesis of chemicals, natural products, and pharmaceuticals. However, one relatively new application is for carrying out new-to-nature reactions inside living cells. The complex environment of a living cell is not welcoming to transition metal catalysts, as a diverse range of biological components have the potential to inhibit or deactivate the catalyst. Here we review the current progress in the field of transition metal catalysis, and evaluation of catalysis efficiency in living cells and under biological (relevant) conditions. Catalyst poisoning is a ubiquitous problem in this field, and we propose that future research into the development of physical and kinetic protection strategies may provide a route to improve the reactivity of catalysts in cells.