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.

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.

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.

Non-Kekulé meta-Quinodimethane Singlet Diradicals Based on Classical N-Heterocyclic Carbenes.

Diradicals based on a meta-quinodimethane (m-QDM) scaffold generally have a triplet ground state and are rather scarce. Herein, m-QDM-based non-Kekulé diradicals [3,3'-(NHC)2BP] (3-NHC) (NHC = SIPr = C{N(Dipp)CH2}2; IPr = C{N(Dipp)CH}2, Me-IPr = C{N(Dipp)CMe}2; Dipp = 2,6-iPr2C6H3; BP = 1,1'-C6H3C6H3) featuring N-heterocyclic carbene (NHC) pendants are reported as crystalline solids. The EPR spectra of 3-NHC show both allowed (Dms = 1) and forbidden (Dms = 2; 'half-field') transitions characteristic for triplet diradicals. Variable temperature EPR studies however reveal a singlet ground state for 3-SIPr. Consistent with the EPR spectra, calculations predict a remarkably small (open-shell) singlet-triplet energy gap (ΔEST ≤ 0.26 kcal/mol) for the 3-NHC compounds. The calculated singlet diradical character for the ground states of the 3-NHC compounds amounts to ~99%.

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+).

Transition Metal Catalysis Controlled by Hydrogen Bonding in the Second Coordination Sphere.

Transition metal catalysis is of utmost importance for the development of sustainable processes in academia and industry. The activity and selectivity of metal complexes are typically the result of the interplay between ligand and metal properties. As the ligand can be chemically altered, a large research focus has been on ligand development. More recently, it has been recognized that further control over activity and selectivity can be achieved by using the "second coordination sphere", which can be seen as the region beyond the direct coordination sphere of the metal center. Hydrogen bonds appear to be very useful interactions in this context as they typically have sufficient strength and directionality to exert control of the second coordination sphere, yet hydrogen bonds are typically very dynamic, allowing fast turnover. In this review we have highlighted several key features of hydrogen bonding interactions and have summarized the use of hydrogen bonding to program the second coordination sphere. Such control can be achieved by bridging two ligands that are coordinated to a metal center to effectively lead to supramolecular bidentate ligands. In addition, hydrogen bonding can be used to preorganize a substrate that is coordinated to the metal center. Both strategies lead to catalysts with superior properties in a variety of metal catalyzed transformations, including (asymmetric) hydrogenation, hydroformylation, C-H activation, oxidation, radical-type transformations, and photochemical reactions.

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.

Thermal and (Thermo-Reversible) Photochemical Cycloisomerization of 1H-2-Benzo[c]oxocins: From Synthetic Applications to the Development of a New T-Type Molecular Photoswitch.

A novel T-type molecular photoswitch based on the reversible cyclization of 1H-2-benzo[c]oxocins to dihydro-4H-cyclobuta[c]isochromenes has been developed. The switching mechanism involves a light-triggered ring-contraction of 8-membered 1H-2-benzo[c]oxocins to 4,6-fused O-heterocyclic dihydro-4H-cyclobuta[c]isochromene ring systems, with reversion back to the 1H-2-benzo[c]oxocin state accessible through heating. Both processes are unidirectional and proceed with good efficiency, with switching properties─including reversibility and half-life time─easily adjusted via structural functionalization. Our new molecular-switching platform exhibits independence from solvent polarity, originating from its neutral-charge switching mechanism, a property highly sought-after for biological applications. The photoinduced ring-contraction involves a [2+2] conjugated-diene cyclization that obeys the Woodward-Hoffmann rules. In contrast, the reverse process initiates via a thermal ring-opening (T > 60 °C) to produce the original 8-membered 1H-2-benzo[c]oxocins, which is thermally forbidden according to the Woodward-Hoffmann rules. The thermal ring-opening is likely to proceed via an ortho-quinodimethane (o-QDM) intermediate, and the corresponding switching mechanisms are supported by experimental observations and density functional theory calculations. Other transformations of 1H-2-benzo[c]oxocins were found upon altering reaction conditions: prolonged heating of the 1H-2-benzo[c]oxocins at a significantly elevated temperature (72 h at 120 °C), with the resulting dihydronaphthalenes formed via the o-QDM intermediate. These reactions also proceed with good chemoselectivities, providing new synthetic protocols for motifs found in several bioactive molecules, but are otherwise difficult to access.

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.

Photoinduced Halogen-Atom Transfer by N-Heterocyclic Carbene-Ligated Boryl Radicals for C(sp3)-C(sp3) Bond Formation.

Herein, we present a comprehensive study on the use of N-heterocyclic carbene (NHC)-ligated boryl radicals to enable C(sp3)-C(sp3) bond formation under visible-light irradiation via Halogen-Atom Transfer (XAT). The methodology relies on the use of an acridinium dye to generate the boron-centered radicals from the corresponding NHC-ligated boranes via single-electron transfer (SET) and deprotonation. These boryl radicals subsequently engage with alkyl halides in an XAT step, delivering the desired nucleophilic alkyl radicals. The present XAT strategy is very mild and accommodates a broad scope of alkyl halides, including medicinally relevant compounds and biologically active molecules. The key role of NHC-ligated boryl radicals in the operative reaction mechanism has been elucidated through a combination of experimental, spectroscopic, and computational studies. This methodology stands as a significant advancement in the chemistry of NHC-ligated boryl radicals, which had long been restricted to radical reductions, enabling C-C bond formation under visible-light photoredox conditions.

Understanding Off-Cycle and Deactivation Pathways in Radical-Type Carbene Transfer Catalysis.

Transition metal radical-type carbene transfer catalysis is a sustainable and atom-efficient method to generate C-C bonds, especially to produce fine chemicals and pharmaceuticals. A significant amount of research has therefore been devoted to applying this methodology, which resulted in innovative routes toward otherwise synthetically challenging products and a detailed mechanistic understanding of the catalytic systems. Furthermore, combined experimental and theoretical efforts elucidated the reactivity of carbene radical complexes and their off-cycle pathways. The latter can imply the formation of N-enolate and bridging carbenes, and undesired hydrogen atom transfer by the carbene radical species from the reaction medium which can lead to catalyst deactivation. In this concept paper, we demonstrate that understanding off-cycle and deactivation pathways not only affords solutions to circumvent them, but can also uncover novel reactivity for new applications. In particular, considering off-cycle species involved in metalloradical catalysis can stimulate further development of radical-type carbene transfer reactions.

Exposing Mechanisms for Defect Clearance in Supramolecular Self-Assembly: Palladium-Pyridine Coordination Revisited.

Spherical three-dimensional (3D) cages composed of palladium(II) and pyridyl ligands are a mainstay of supramolecular chemistry with demonstrated catalytic and optoelectronic applications. The widely reported self-assembly of these palladium-based cages exhibits sensitivity to the solvents, reagents, and/or reactants employed. This sensitivity, and the resulting inconsistency between synthetic protocols, hinders the development of desirable palladium-based cages. We have found that pyridyl ligand substitution─the rate-limiting step of self-assembly─is facilitated by endogenous supporting ligands derived from the solvents, reagents, and reactants employed in synthetic protocols of palladium- and platinum-based assemblies. Here, we present a systematic investigation combining 1H-NMR, electrospray ionization mass spectrometry (ESI─MS), and absorption spectroscopy to characterize the intermediates to support the mechanism of pyridyl ligand substitution on a model complex, M(py)2 (M = (N,N,N',N'-tetramethylethylenediamine)palladium(II), py = pyridine), under simulated synthetic conditions for self-assembly. Our investigation exposes mechanisms for pyridyl ligand substitution, featuring intermediates stabilized by solvent, anion, or (in situ formed) alkoxide moieties. Interrogation of destabilizing agents (2,2,2-trifluoroethanol and tetra(n-butyl)ammonium chloride) reveal similar mechanisms that ultimately facilitate the self-assembly of coordination cages. These findings rationalize widely reported solvent and anion effects in the self-assembly of coordination cages (and similar constructs) while highlighting methodologies to understand the role of supporting ligands in coordination chemistry.

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.

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.

Effector Regulated Catalytic Cyclization of Alkynoic Acids Using Pt2 L4 Cages.

Metabolic pathways are highly regulated by effector molecules that influences the rate of enzymatic reactions. Inspired by the catalytic regulation found in living cells, we report a Pt2 L4 cage of which the activity can be controlled by effectors that bind inside the cage. The cage shows catalytic activity in the lactonization of alkynoic acids, with the reaction rates dependent on the effector guest bound in the cage. Some effector guests enhance the rate of the lactonization by up to 19-fold, whereas one decreases it by 5-fold. When mixtures of specific substrates are used, both starting materials and products act as guests for the Pt2 L4 cage, enhancing its catalytic activity for one substrate while reducing its activity for the other. The reported regulatory behavior obtained by the addition of effector molecules paves the way to the development of more complex, metabolic-like catalyst systems.

Cobalt-Catalyzed Enantioselective Hydrogenation of Trisubstituted Carbocyclic Olefins: An Access to Chiral Cyclic Amides.

The enantioselective hydrogenation of cyclic enamides has been achieved using an earth-abundant cobalt-bisphosphine catalyst. Using CoCl2 /(S,S)-Ph-BPE, several trisubstituted carbocyclic enamides were reduced with high activity and excellent enantioselectivity (up to 99 %) to the corresponding saturated amides. The methodology can be extended to the synthesis of chiral amines by base hydrolysis of the hydrogenation products. Preliminary mechanistic investigations reveal the presence of a high spin cobalt (II) species in the catalytic cycle. We propose that the hydrogenation of the carbon-carbon double bond proceeds via a sigma-bond-metathesis pathway.

M6L12 Nanospheres with Multiple C70 Binding Sites for 1O2 Formation in Organic and Aqueous Media.

Singlet oxygen is a potent oxidant with major applications in organic synthesis and medicinal treatment. An efficient way to produce singlet oxygen is the photochemical generation by fullerenes which exhibit ideal thermal and photochemical stability. In this contribution we describe readily accessible M6L12 nanospheres with unique binding sites for fullerenes located at the windows of the nanospheres. Up to four C70 can be associated with a single nanosphere, presenting an efficient method for fullerene extraction and application. Depending on the functionality located on the outside of the sphere, they act as vehicles for 1O2 generation in organic or in aqueous media using white LED light. Excellent productivity in 1O2 generation and consecutive oxidation of 1O2 acceptors using C70⊂[Pd6L12], C60⊂[Pd6L12] or fullerene soot extract was observed. The methodological design principles allow preparation and application of highly effective multifullerene binding spheres.