Organometallic Transformations Research Articles

Organometallic Chemistry Tools for Building Biologically Relevant Nanoscale Systems.

The recent emergence of organometallic chemistry for modification of biomolecular nanostructures has begun to rewrite the long-standing assumption among practitioners that small-molecule organometallics are fundamentally incompatible with biological systems. This Perspective sets out to clarify some of the existing misconceptions by focusing on the growing organometallic toolbox for biomolecular modification. Specifically, we highlight key organometallic transformations in constructing complex biologically relevant systems on the nanomolecular scale, and the organometallic synthesis of hybrid nanomaterials composed of classical nanomaterial components combined with biologically relevant species. As research progresses, many of the challenges associated with applying organometallic chemistry in this context are rapidly being reassessed. Looking to the future, the growing utility of organometallic transformations will likely make them more ubiquitous in the construction and modification of biomolecular nanostructures.

Small Molecule Activation at the acriPNP Pincer-Supported Nickel Sites.

ConspectusNickel pincer systems have recently attracted much attention for applications in various organometallic reactions and catalysis involving small molecule activation. Their exploration is in part motivated by the presence of nickel in natural systems for efficient catalysis. Among such systems, the nickel-containing metalloenzyme carbon monoxide dehydrogenase (CODH) efficiently and reversibly converts CO2 to CO at its active site. The generated CO moves through a channel from the CODH active site and is transported to a dinuclear nickel site of acetyl-coenzyme A synthase (ACS), which catalyzes organometallic C-S and C-C bond forming reactions. An analogous C-S bond activation process is also mediated by the nickel containing enzyme methyl-coenzyme M reductase (MCR). The nickel centers in these systems feature sulfur- and nitrogen-rich environments, and in the particular case of lactate racemase, an organometallic nickel pincer motif revealing a Ni-C bond is observed. These bioinorganic systems inspired the development of several nickel pincer scaffolds not only to mimic enzyme active sites and their reactivity but also to further extend low-valent organonickel chemistry. In this Account, we detail our continuing efforts in the chemistry of nickel complexes supported by acridane-based PNP pincer ligands focusing on our long-standing interest in biomimetic small molecule activation. We have employed a series of diphosphinoamide pincer ligands to prepare various nickel(II/I/0) complexes and to study the conversion of C1 chemicals such as CO and CO2 to value-added products. In the transformation of C1 chemicals, the key C-O bond cleavage and C-E bond (E = C, N, O, or S, etc.) formation steps typically require overcoming high activation barriers. Interestingly, enzymatic systems overcome such difficulties for C1 conversion and operate efficiently under ambient conditions with the use of nickel organometallic chemistry. Furthermore, we have extended our efforts to the conversion of NOx anions to NO via the sequential deoxygenation by nickel mediated carbonylation, which was applied to catalytic C-N coupling to produce industrially important organonitrogen compound oximes as a strategy for NOx conversion and utilization (NCU). Notably, the rigidified acriPNP pincer backbone that enforces a planar geometry at nickel was found to be an important factor for diversifying organometallic transformations including (a) homolysis of various σ-bonds mediated by T-shaped nickel(I) metalloradical species, (b) C-H bond activation mediated by a nickel(0) dinitrogen species, (c) selective CO2 reactivity of nickel(0)-CO species, (d) C-C bond formation at low-valent nickel(I or 0)-CO sites with iodoalkanes, and (e) catalytic deoxygenation of NOx anions and subsequent C-N coupling of a nickel-NO species with alkyl halides for oxime production. Broadly, our results highlight the importance of molecular design and the rich chemistry of organonickel species for diverse small molecule transformations.

DFT Struggles to Predict the Energy Landscape for Iron Pyridine Diimine-Catalyzed [2 + 2] Cycloaddition of Alkenes: Insights into the Problem and Alternative Solutions.

In recent years, noninnocent pyridine diimine (PDI) complexes featuring first-row transition metals have emerged as prominent catalysts, demonstrating efficacy in a diverse range of vital organometallic transformations. However, the inherent complexity of the fundamental reactivity paradigm in these systems arises from the presence of a noninnocent ligand and the multispin feasibility of 3d metals. While density functional theory (DFT) has been widely used to unravel mechanistic insights, its limitations as a single-reference method can potentially misrepresent spin-state energetics, compromising our understanding of these intricate systems. In this study, we employ extensive high-level ab initio state averaged-complete active space self-consistent field/N-electron valence state perturbation theory (SA-CASSCF/NEVPT2) calculations in combination with DFT to investigate an iron-PDI-catalyzed [2 + 2] cycloaddition reaction of alkenes. The transformation proceeds through two major steps: oxidative cyclization and reductive elimination. Contrary to the predictions of DFT calculations, which suggest two-state reactivity in the reaction and identify reductive elimination as the turnover-limiting step, SA-CASSCF/NEVPT2-corrected results unequivocally establish a single-state reactivity scenario with oxidative cyclization as the turnover-limiting step. SA-CASSCF/NEVPT2-based insights into electronic ground states and electron distribution elucidate the intriguing interactions between the PDI ligand and the iron center, revealing the highly multiconfigurational nature of these species and providing a precise depiction of metal-ligand cooperativity throughout the transformation. A comparative assessment of several widely recognized DFT functionals against SA-CASSCF/NEVPT2-corrected data indicates that single-point energy calculations using the modern density functional MN15 on TPSSh geometries offer the most reliable density functional methodology, in scenarios where SA-CASSCF/NEVPT2 computational cost is a consideration.

Flash Organometallic Catalysis Uncovered by Continuous Microfluidic Devices.

The flash organometallic catalysis is a new concept that refers to the study of fast and controlled organometallic catalytic reactions by using microfluidic devices. Flash reactions' kinetics (ms-s scale) is often ignored due to the lack of proper research tool in organometallic chemistry. The development of microfluidic systems offers the opportunity to discover under-studied mechanisms and new reactions. In this concept, the basic theory of kinetic measurement in a microreactor is briefly reviewed and then two examples on studying flash organometallic catalytic transformation are introduced. One example is the discovery of a highly active palladium catalytic species for Suzuki Coupling and the other example is the study of a neglected isomerization catalytic cycle with a time scale of seconds before isomerization-hydroformylation by customized microfluidic devices. The last part is summary and prospect of this new area. Customizing a microfluidic device with good engineering design for a target reaction supports flash reactions' kinetic experimentation and could become a general strategy in chemistry lab.

Modulating Transition Metal Reactivity with Force

AbstractThe reactivity and selectivity of a transition metal catalyst is intimately related to its ligand‐sphere geometry, and, in many cases, the ideal ligand geometry for one step of a catalytic cycle is poorly matched to the ideal ligand geometry for another. For this reason, methods for reversibly modulating ligand geometry on the time scale of catalytic turnover or monomer enchainment are highly desirable. Mechanical force represents a heretofore untapped approach to modulate catalyst geometry and/or reactivity, with the potential to do so on the timescale of catalytic turnover or monomer enchainment. Macroscopic mechanical forces are large, directional and localized to an extent that differentiates them from other forms of energy input such as heat or light. In this Concept, we describe our efforts to address the fundamental challenges associated with force‐modulated transition metal catalysis by employing molecular force probe ligands comprising a stiff stilbene photoswitch tethered to rotationally flexible biaryl bisphosphine ligand. Our efforts to date include the modulation of catalytic activity through force‐mediated ligand perturbations, quantification of the force‐coupled ligand effects on the energetics of elementary organometallic transformations, and evaluation of the mechanisms of force transduction in these systems.

Silane‐Bearing Borasilsesquioxanes: Synthetic Protocol and Unsuspected Redistribution Reactions

The presented work is a continuation of research on the reactivity of unsaturated borasilsesquioxanes under the conditions of common organometallic transformations. The catalytic hydrosilylation reaction with silanes, siloxanes and silsesquioxanes in presence of platinum catalyst was explored. The majority of the products were obtained in high yields (>90 %) and their structures were confirmed and characterized by spectroscopy and spectrometry, i. e. NMR and MALDI-TOF-MS. The most significant segment of the work is research on the spontaneous redistribution reaction of the alkoxy group from silane to borane moiety occurring in the obtained products, not being limited to the heterosilsesquioxane chemistry, however. The products were confirmed using GC-MS, ESI-MS methods and B3LYP exchange-correlation, in order to ascertain formation of the silicon-boron hybrid molecule.

Chiral Cyclic Alkyl Amino Carbene (CAAC) Transition-Metal Complexes: Synthesis, Structural Analysis, and Evaluation in Asymmetric Catalysis

Despite recent advances in the field of cyclic alkyl amino carbenes (CAACs) including a few complementary synthetic strategies affording CAACs with various substitution patterns, the application potential of chiral CAACs to efficiently catalyze asymmetric organometallic transformations remains largely underdeveloped. Herein, we describe a convenient and robust route that incorporates common chiral primary amine allowing access of a broad range of chiral CAACs precursors. The corresponding transition-metal complexes with Cu, Au, Ru, Rh, Ir, and Pd were obtained in a straightforward manner. The steric parameters of the complexes were comprehensively collected by X-ray single-crystal analysis to serve as a source of information for further ligand design. The preliminary application potential of the copper CAAC complexes was tested in asymmetric conjugate borylation of an α,β-unsaturated ester providing 89:11 er, thus illustrating the potential of chiral CAACs in asymmetric catalysis.

Organometallic S-arylation Reagents for Rapid PEGylation of Biomolecules.

Bioconjugation techniques for biomolecule-polymer conjugation are numerous; however, slow kinetics and steric challenges generally necessitate excess reagents or long reaction times. Organometallic transformations are known to circumvent these issues; yet, harsh reaction conditions, incompatibility in aqueous media, and substrate promiscuity often limit their use in a biological context. The work reported herein demonstrates a facile and benign organometallic Au(III) S-arylation approach that enables the synthesis of poly(ethylene glycol) monomethyl ether (mPEG)-protein conjugates with high efficiency. Isolable and bench-stable 2, 5, and 10 kDa mPEG-Au(III) reagents were synthesized via oxidative addition into terminal aryl iodide substituents installed on mPEG substrates with a (Me-DalPhos)Au(I)Cl precursor. Reaction of the isolable mPEG-Au(III) oxidative addition complexes with a cysteine thiol on a biomolecule resulted in facile and selective cysteine arylation chemistry, forging covalent S-aryl linkages and affording the mPEG-biomolecule conjugates. Notably, low polymer reagent loadings were used to achieve near quantitative conversion at room temperature in 1 min due to the rapid kinetics and high chemoselectivity of this Au-based bioconjugation approach. Therefore, this work represents an important addition to the protein-polymer conjugation chemical toolbox.

Factors Promoting Alkene Migratory Insertion into Metal-nitrogen Bond During Hydroamination in Recent Studies

: Migratory insertion is a fundamental organometallic transformation that enables the functionalization of an unsaturated bond. Recent reports on catalytic hydroamination provide evidence that supports an intermolecular migratory insertion pathway featuring alkene insertion into metalnitrogen (M-N) bonds. This article presents factors influencing the rate of migratory insertion in latetransition metal-catalyzed hydroamination, including steric and electronic effects from ligands, alkenes, and metal centers, along with stabilization from coordinated amine intermediates and ordered transition states.

The Thermochemistry of Alkyne Insertion into a Palladacycle Outlines the Solvation Conundrum in DFT

AbstractIn an effort to determine the thermochemistry of established organometallic transformation, the well documented reaction of alkynes with a palladacycle was investigated by isothermal titration calorimetry (ITC). Although the mechanism of the insertion of unsaturated substrates into the Pd−C bond of cyclopalladated compounds is known, no information is available so far about their thermochemistry. The enthalpies of the reactions of Ph−C≡C−Ph and MeOC(O)−C≡C(O)COMe with the bisacetonitrilo salt of the N,N‐benzylamine palladacycle were determined by ITC in chlorobenzene after having optimized the conditions to ensure that only the double and a single insertion of alkynes were occurring respectively. The reaction energy profile established by DFT for the double insertion process involving Ph−C≡C−Ph confirmed earlier conclusions on the rate determining character of the first insertion. Further computations of reaction enthalpies reveal significant discrepancies between ITC and DFT‐D/continuum solvation enthalpies, that are suspected to arise from an unexpected explicit noncovalent interaction of PhCl with the components of the reaction.

Exporting Metal‐Carbene Chemistry to Live Mammalian Cells: Copper‐Catalyzed Intracellular Synthesis of Quinoxalines Enabled by N−H Carbene Insertions

AbstractImplementing catalytic organometallic transformations in living settings can offer unprecedented opportunities in chemical biology and medicine. Unfortunately, the number of biocompatible reactions so far discovered is very limited, and essentially restricted to uncaging processes. Here, we demonstrate the viability of performing metal carbene transfer reactions in live mammalian cells. In particular, we show that copper (II) catalysts can promote the intracellular annulation of alpha‐keto diazocarbenes with ortho‐amino arylamines, in a process that is initiated by an N‐H carbene insertion. The potential of this transformation is underscored by the in cellulo synthesis of a product that alters mitochondrial functions, and by demonstrating cell selective biological responses using targeted copper catalysts. Considering the wide reactivity spectrum of metal carbenes, this work opens the door to significantly expanding the repertoire of life‐compatible abiotic reactions.

Exporting Metal-Carbene Chemistry to Live Mammalian Cells: Copper-Catalyzed Intracellular Synthesis of Quinoxalines Enabled by N-H Carbene Insertions.

Implementing catalytic organometallic transformations in living settings can offer unprecedented opportunities in chemical biology and medicine. Unfortunately, the number of biocompatible reactions so far discovered is very limited, and essentially restricted to uncaging processes. Here, we demonstrate the viability of performing metal carbene transfer reactions in live mammalian cells. In particular, we show that copper (II) catalysts can promote the intracellular annulation of alpha‐keto diazocarbenes with ortho‐amino arylamines, in a process that is initiated by an N‐H carbene insertion. The potential of this transformation is underscored by the in cellulo synthesis of a product that alters mitochondrial functions, and by demonstrating cell selective biological responses using targeted copper catalysts. Considering the wide reactivity spectrum of metal carbenes, this work opens the door to significantly expanding the repertoire of life‐compatible abiotic reactions.

Fundamental Basis for Implementing Oxidant‐Free Au(I)/Au(III) Catalysis

AbstractOxidant‐free Au(I)/Au(III) catalysis can still be regarded as a young and promising chemistry. Because the first examples of gold catalysis were limited to the activation and functionalization of π‐C−C bonds and very little was known on fundamental organometallic transformations at gold, countless works during the past 15 years have been devoted to disclosing the elementary reactivity of gold and implementing it in catalysis. Remarkably, great emphasis on triggering oxidative addition at Au(I) has been placed, as the high redox potential of the Au(I)/Au(III) pair disfavors this reaction. In fact, different strategies such as strain release, ligand design and photochemistry have been proven successful at allowing the bottleneck oxidative addition to occur. These approaches have led to the rational development of oxidant‐free Au(I)/Au(III) redox catalysis, particularly catalytic cycles in cross‐coupling transformations where oxidative addition is usually the entry point to the cycle. Herein, the background story, the development process, and relevant examples of oxidant‐free gold‐catalyzed cross‐coupling reactions are reviewed.

Metal–Organic Frameworks as Versatile Platforms for Organometallic Chemistry

Metal–organic frameworks (MOFs) are emerging porous materials with highly tunable structures developed in the 1990s, while organometallic chemistry is of fundamental importance for catalytic transformation in the academic and industrial world for many decades. Through the years, organometallic chemistry has been incorporated into functional MOF construction for diverse applications. Here, we will focus on how organometallic chemistry is applied in MOF design and modifications from linker-centric and metal-cluster-centric perspectives, respectively. Through structural design, MOFs can function as a tailorable platform for traditional organometallic transformations, including reaction of alkenes, cross-coupling reactions, and C–H activations. Besides, an overview will be made on other application categories of organometallic MOFs, such as gas adsorption, magnetism, quantum computing, and therapeutics.

Palladium-Catalyzed Regioselective Arylation of Unprotected Allylamines.

Palladium-catalyzed organometallic transformations of free amines are often unsuccessful due to side reactions, such as oxidation, that can occur. However, the ability to furnish the free amine products from these reactions is important for improving the utility and sustainability of these processes, especially for accessing their potential as medicinal and agrochemical agents. Notably, the 3,3-diarylallylamine motif is prevalent in a variety of biologically relevant structures, yet there are few catalytic approaches to their synthesis, and none involving the free amine. Herein, we describe a simple protocol for the arylation of cinnamylamines and the diarylation of terminal allylamines to generate a diverse group of 3,3-diarylallylamine products using a PdII precatalyst. Key features of the method are the ability to access relatively mild conditions that facilitate a broad substrate scope as well as direct diarylation of terminal allylamine substrates. In addition, several complex and therapeutically relevant molecules are included to demonstrate the utility of the transformation.

Discovery and development of organo-<italic>di</italic>-lithio reagents: serendipity & persistence

<p indent=0mm>In this account, we introduce the milestones during our scientific research since 1998, especially the serendipity and persistence in our continuous exploration into the chemistry of organo-<italic>di</italic>-lithio reagents (including but not limited to 1,4-dilithio-1,3-butadiene derivatives). Initially, the serendipity emerged from the discovery of the “cooperative effect” between organometallic reagents and Lewis acid. The effect of Lewis acid on organometallic transformations is summarized in three types: enhanced reactivity, enhanced selectivity, and changing the reaction pathway. Concurrently, during the mechanistic study of the “cooperative effect” between organometallic reagents and Lewis acid, the serendipity has led to the discovery of the intriguing reaction chemistry of organo-<italic>di</italic>-lithio reagents. The significance of its reactivity lies in the “cooperative effect” between two metal-carbon bonds, which distinguished it from the corresponding organo-<italic>mono</italic>-lithio reagents. The persistence drove us to further apply organo-<italic>di</italic>-lithio reagents in organic synthesis, leading to the development of four reaction patterns: intramolecular reactivity, intermolecular reactivity with organic substrates, transmetallation, and redox chemistry. Particularly, owing to the diverse characters of each individual metal, the transmetallation from organo-<italic>di</italic>-lithio reagents has enabled much richer reaction chemistry. Recently, our principal focus on the redox chemistry of organo-<italic>di</italic>-lithio reagents was also inspired by the initial serendipity and then led to innovative achievement following persistence.

Synthesis and Reactivity of Organometallic Intermediates Relevant to Cobalt-Catalyzed Hydroformylation.

Intermediates relevant to cobalt-catalyzed alkene hydroformylation have been isolated and evaluated in fundamental organometallic transformations relevant to aldehyde formation. The 18-electron (R,R)-(iPr DuPhos)Co(CO)2 H has been structurally characterized, and it promotes exclusive hydrogenation of styrene in the presence of 50 bar of H2 /CO gas (1:1) at 100 °C. Deuterium-labeling studies established reversible 2,1-insertion of styrene into the Co-D bond of (R,R)-(iPr DuPhos)Co(CO)2 D. Whereas rapid β-hydrogen elimination from cobalt alkyls occurred under an N2 atmosphere, alkylation of (R,R)-(iPr DuPhos)Co(CO)2 Cl in the presence of CO enabled the interception of (R,R)-(iPr DuPhos)Co(CO)2 C(O)CH2 CH2 Ph, which upon hydrogenolysis under 4 atm H2 produced the corresponding aldehyde and cobalt hydride, demonstrating the feasibility of elementary steps in hydroformylation. Both the hydride and chloride derivatives, (X=H- , Cl- ), underwent exchange with free 13 CO. Under reduced pressure, (R,R)-(iPr DuPhos)Co(CO)2 Cl underwent CO dissociation to form (R,R)-(iPr DuPhos)Co(CO)Cl.

Synthesis and Reactivity of Organometallic Intermediates Relevant to Cobalt‐Catalyzed Hydroformylation

AbstractIntermediates relevant to cobalt‐catalyzed alkene hydroformylation have been isolated and evaluated in fundamental organometallic transformations relevant to aldehyde formation. The 18‐electron (R,R)‐(iPrDuPhos)Co(CO)2H has been structurally characterized, and it promotes exclusive hydrogenation of styrene in the presence of 50 bar of H2/CO gas (1:1) at 100 °C. Deuterium‐labeling studies established reversible 2,1‐insertion of styrene into the Co−D bond of (R,R)‐(iPrDuPhos)Co(CO)2D. Whereas rapid β‐hydrogen elimination from cobalt alkyls occurred under an N2 atmosphere, alkylation of (R,R)‐(iPrDuPhos)Co(CO)2Cl in the presence of CO enabled the interception of (R,R)‐(iPrDuPhos)Co(CO)2C(O)CH2CH2Ph, which upon hydrogenolysis under 4 atm H2 produced the corresponding aldehyde and cobalt hydride, demonstrating the feasibility of elementary steps in hydroformylation. Both the hydride and chloride derivatives, (X=H−, Cl−), underwent exchange with free 13CO. Under reduced pressure, (R,R)‐(iPrDuPhos)Co(CO)2Cl underwent CO dissociation to form (R,R)‐(iPrDuPhos)Co(CO)Cl.

A Gentler Touch: Synthesis of Modern Ruthenium Olefin Metathesis Catalysts Sustained by Mechanical Force

AbstractMechanochemical synthesis of nine contemporary ruthenium catalysts used for olefin metathesis is described, being the first reported example of formation of Ru carbene organometallic complexes in solid state. Three key organometallic transformations commonly used in the synthesis of the second and third generations of Ru catalysts in solution—phosphine ligand (PCy3) exchange with in situ formed N‐heterocyclic carbene (NHC) ligand, PCy3 to pyridine ligand replacement, and benzylidene ligands interchange—were proved to work under mechanochemical conditions, affording the targets in high purity. Mechanochemical approach not only requires less amounts of organic solvent (null for synthesis, only for purification) and is scalable, but also allows for transformations that were reported impossible in the solution phase.

Mechanism of the Iron(0)-Catalyzed Hydrosilylation of Aldehydes: A Combined DFT and Experimental Investigation

Hydrosilylation is a fundamental organometallic transformation for the reduction of alkene, carbonyl, and imine functionalities. Herein, we use density functional theory (DFT) calculations, supplem...