Directional multiobjective optimization of metal complexes at the billion-system scale.

The discovery of transition metal complexes (TMCs) with optimal properties requires large ligand libraries and efficient multiobjective optimization algorithms. Here we provide the tmQMg-L library, containing 30k diverse and synthesizable ligands with robustly assigned charges and metal coordination modes. tmQMg-L enabled the generation of 1.37 million palladium TMCs, which were used to develop and benchmark the Pareto-Lighthouse multiobjective genetic algorithm (PL-MOGA). With fine control over aim and scope, this algorithm maximized both the polarizability and highest occupied molecular orbital-lowest unoccupied molecular orbital gap of the TMCs within selected regions of the Pareto front, without requiring prior knowledge on the objective limits. Instead of genetic operations on small ligand fragments, the PL-MOGA did whole-ligand mutation and crossover operations, which in chemical spaces containing billions of systems, yielded thousands of highly diverse TMCs in an interpretable manner.

Cyclometalated (N,C) Au(III) Complexes: The Impact of Trans Effects on Their Synthesis, Structure, and Reactivity.

ConspectusThe early years of gold catalysis were dominated by Au(I) complexes and inorganic Au(III) salts. Thanks to the development of chelating ligands, more sophisticated Au(III) complexes can now be easily prepared and handled. The choice of the ancillary ligand has great consequences for the synthesis, properties, and reactivity of the Au(III) complex in question. Among the major factors controlling reactivity are the "trans effect" and the "trans influence" that a ligand imparts at the ligand trans to itself. The kinetic trans effect manifests itself with an increased labilization of the ligand trans to a given ligand and arises from an interplay between ground-state and transition-state effects. The term trans influence, on the other hand, is a ground-state effect only, describing the tendency of a given ligand to weaken the metal-ligand bond trans to itself. Herein, we will use the term "trans effect" to describe both the kinetic and the thermodynamic properties, whereas the term "trans influence" will refer only to thermodynamic properties. We will describe how these trans effects strongly impact the chemistry of the commonly encountered cyclometalated (N,C) Au(III) complexes, a class of complexes we have studied for more than a decade. We found that the outcome of reactions like alkylation, arylation, and alkynylation as well as halide metathesis are dictated by the different trans influence of the two termini of the chelating tpy ligand in (tpy)Au(OAcF)2 (tpy = 2-(p-tolyl)pyridine, OAcF = OCOCF3, tpy-C > tpy-N). There is a strong preference for high trans influence ligands to end up trans to tpy-N, whereas the lower trans influence ligands end up trans to tpy-C. Taking advantage of these preferences, tailor-made (N,C)Au(III) complexes could be prepared. For the functionalization of alkenes at (tpy)Au(OAcF)2, the higher trans effect of tpy-C would suggest that the coordination site trans to tpy-C would be kinetically more available than the one trans to tpy-N. However, due to the thermodynamic preference of having the σ-bonded ligand, resulting from the nucleophilic addition to alkenes, trans to tpy-N, functionalization of alkenes was only observed trans to tpy-N. However, for a catalytic process, the reaction should happen trans to tpy-C, as was observed for the trifluoroacetoxylation of acetylene. When functionalizing acetylene in the coordination site trans to tpy-N, protolytic cleavage of the Au-C(vinyl) bond to release the product did not occur at all, whereas trans to tpy-C protolytic cleavage of the Au-C(vinyl) bond occurred readily, in agreement with the higher trans influence of tpy-C over tpy-N. The large impact of the trans effects in Au(III) complexes is finally exemplified with the synthesis of [(tpy)Au(π-allyl)]+[NTf2]-, which resulted in a highly asymmetric π + σ bonding of the allyl moiety. Here, the bonding is such that the most thermodynamically favorable situation is achieved, with the carbon trans to tpy-N bonded in a σ-fashion and the π-allyl double bond being coordinated trans to tpy-C.

Exploring the Parameters Controlling Product Selectivity in Electrochemical CO2 Reduction in Competition with Hydrogen Evolution Employing Manganese Bipyridine Complexes.

Selective reduction of CO2 is an efficient solution for producing nonfossil-based chemical feedstocks and simultaneously alleviating the increasing atmospheric concentration of this greenhouse gas. With this aim, molecular electrocatalysts are being extensively studied, although selectivity remains an issue. In this work, a combined experimental-computational study explores how the molecular structure of Mn-based complexes determines the dominant product in the reduction of CO2 to HCOOH, CO, and H2. In contrast to previous Mn(bpy-R)(CO)3Br catalysts containing alkyl amines in the vicinity of the Br ligand, here, we report that bpy-based macrocycles locking these amines at the side opposite to the Br ligand change the product selectivity from HCOOH to H2. Ab initio molecular dynamics simulations of the active species showed that free rotation of the Mn(CO)3 moiety allows for the approach of the protonated amine to the reactive center yielding a Mn-hydride intermediate, which is the key in the formation of H2 and HCOOH. Additional studies with DFT methods showed that the macrocyclic moiety hinders the insertion of CO2 to the metal hydride favoring the formation of H2 over HCOOH. Further, our results suggest that the minor CO product observed experimentally is formed when CO2 adds to Mn on the side opposite to the amine ligand before protonation. These results show how product selectivity can be modulated by ligand design in Mn-based catalysts, providing atomistic details that can be leveraged in the development of a fully selective system.

Important Role of NH-Carbazole in Aryl Amination Reactions Catalyzed by 2-Aminobiphenyl Palladacycles.

2-Aminobiphenyl palladacycles are among the most successful precatalysts for Pd-catalyzed cross-coupling reactions, including aryl amination. However, the role of NH-carbazole, a byproduct of precatalyst activation, remains poorly understood. Herein, the mechanism of the aryl amination reactions catalyzed by a cationic 2-aminobiphenyl palladacycle supported by a terphenyl phosphine ligand, PCyp2ArXyl2 (Cyp = cyclopentyl; ArXyl2 = 2,6-bis(2,6-dimethylphenyl)phenyl), P1, has been thoroughly investigated. Combining computational and experimental studies, we found that the Pd(II) oxidative addition intermediate reacts with NH-carbazole in the presence of the base (NaO t Bu) to yield a stable aryl carbazolyl Pd(II) complex. This species functions as the catalyst resting state, providing the amount of monoligated LPd(0) species required for catalysis and minimizing Pd decomposition. In the case of a reaction with aniline, an equilibrium between the carbazolyl complex and the on-cycle anilido analogue is established, which allows for a fast reaction at room temperature. In contrast, heating is required in a reaction with alkylamines, whose deprotonation involves coordination to the Pd center. A microkinetic model was built combining computational and experimental data to validate the mechanistic proposals. In conclusion, our study shows that despite the rate reduction observed in some reactions by the formation of the aryl carbazolyl Pd(II) complex, this species reduces catalyst decomposition and could be considered an alternative precatalyst in cross-coupling reactions.

Unmasking the constitution and bonding of the proposed lithium nickelate "Li3NiPh3(solv)3": revealing the hidden C6H4 ligand.

More than four decades ago, a complex identified as the planar homoleptic lithium nickelate "Li3NiPh3(solv)3" was reported by Taube and co-workers. This and subsequent reports involving this complex have lain dormant since; however, the absence of an X-ray diffraction structure leaves questions as to the nature of the Ni-PhLi bonding and the coordination geometry at Ni. By systematically evaluating the reactivity of Ni(COD)2 with PhLi under different conditions, we have found that this classical molecule is instead a unique octanuclear complex, [{Li3(solv)2Ph3Ni}2(µ-η2:η2-C6H4)] (5). This is supported by X-ray crystallography and solution-state NMR studies. A theoretical bonding analysis from NBO, QTAIM, and ELI perspectives reveals extreme back-bonding to the bridging C6H4 ligand resulting in dimetallabicyclobutane character, the lack of a Ni-Ni bond, and pronounced σ-bonding between the phenyl carbanions and nickel, including a weak σC-Li → sNi interaction with the C-Li bond acting as a σ-donor. Employing PhNa led to the isolation of [Na2(solv)3Ph2NiCOD]2 (7) and [Na2(solv)3Ph2(NaC8H11)Ni(COD)]2 (8), which lack the benzyne-derived ligand. These findings provide new insights into the synthesis, structure, bonding and reactivity of heterobimetallic nickelates, whose prevalence in organonickel chemistry and catalysis is likely greater than previously believed.

Selective Functionalization of Arene C(sp2)-H Bonds by Gold Catalysis: The Role of Carbene Substituents.

The complete regioselective incorporation of carbene units to nonactivated arene rings has been achieved employing gold(I) catalysts bearing alkoxydiaminophosphine ligands, with readily available, nonelaborated ethyl 2-phenyldiazoacetate as the carbene source. These results are in contrast with the scarce precedents which required highly elaborated diazo substrates. Density functional theory (DFT) calculations have revealed the important role of the R group in the C(R)CO2Et fragment, which dramatically affects the energy profile of this transformation.

Synthesis of substituted (N,C) and (N,C,C) Au(III) complexes: the influence of sterics and electronics on cyclometalation reactions.

Cyclometalated Au(III) complexes are of interest due to their catalytic, medicinal, and photophysical properties. Herein, we describe the synthesis of derivatives of the type (N,C)Au(OAcF)2 (OAcF = trifluoroacetate) and (N,C,C)AuOAcF by a cyclometalation route, where (N,C) and (N,C,C) are chelating 2-arylpyridine ligands. The scope of the synthesis is explored by substituting the 2-arylpyridine core with electron donor or acceptor substituents at one or both rings. Notably, a variety of functionalized Au(III) complexes can be obtained in one step from the corresponding ligand and Au(OAc)3, eliminating the need for organomercury intermediates, which is commonly reported for similar syntheses. The influence of substituents in the ligand backbone on the resulting complexes was assessed using DFT calculations, 15N NMR spectroscopy and single-crystal X-ray diffraction analysis. A correlation between the electronic properties of the (N,C) ligands and their ability to undergo cyclometalation was found from experimental studies combined with natural charge analysis, suggesting the cyclometalation at Au(III) to take place via an electrophilic aromatic substitution-type mechanism. The formation of Au(III) pincer complexes from tridentate (N,C,C) ligands was investigated by synthesis and DFT calculations, in order to assess the feasibility of C(sp3)-H bond activation as a synthetic pathway to (N,C,C) cyclometalated Au(III) complexes. It was found that C(sp3)-H bond activation is feasible for ligands containing different alkyl groups (isopropyl and ethyl), although the C-H activation is less energetically favored compared to a ligand containing tert-butyl groups.

Development of an experimental model of septic knee arthritis in rats through intra-articular inoculation of Staphylococcus aureus.

Haematogenous models of septic arthritis have some inherent disadvantages, such as the manifestation of arthritis relies on chance, the size of the inoculum is unknown and the number of animals to be studied cannot be reduced because the animals cannot serve as their own controls. This study aimed to develop a rat model of knee septic arthritis by injecting a known inoculum of Staphylococcus aureus into the joint. The left knees of 27 Sprague Dawley rats were injected with four different inoculum concentrations of a sensitive strain of S. aureus (30,000 colony-forming units (CFUs), n = 3; 18,550 CFUs, n = 6; 15,500 CFUs, n = 9; and 7700 CFUs, n = 9); the right knees served as controls. Clinical, microbiological and histological variables were assessed two and seven days later. The main criterion for diagnosing septic arthritis was a positive culture of synovial fluid. The rate of microbiologically confirmed septic arthritis was high for all inoculum concentrations (3/3, 6/6, 8/9 and 7/9, respectively), and the rate of bacteraemia was also high. Animal welfare was better for the two lowest inoculum concentrations. No animal reached the pre-established humane end points. Overall, the third inoculum was considered the most suitable. Thus, acute septic arthritis can be caused in rats by inoculating 15,000 CFUs of an ATCC strain of S. aureus directly into the knee joint. Overall, the model seems to be useful for studying the effectiveness of drugs for the treatment of acute septic arthritis.

Influence of Defects and H2O on the Hydrogenation of CO2 to Methanol over Pt Nanoparticles in UiO-67 Metal-Organic Framework.

In catalysts for CO2 hydrogenation, the interface between metal nanoparticles (NPs) and the support material is of high importance for the activity and reaction selectivity. In Pt NP-containing UiO Zr-metal-organic frameworks (MOFs), key intermediates in methanol formation are adsorbed at open Zr-sites at the Pt-MOF interface. In this study, we investigate the dynamic role of the Zr-node and the influence of H2O on the CO2 hydrogenation reaction at 170 °C, through steady state and transient isotope exchange experiments, H2O cofeed measurements, and density functional theory (DFT) calculations. The study revealed that an increased number of Zr-node defects increase the formation rates to both methanol and methane. Transient experiments linked the increase to a higher number of surface intermediates for both products. Experiments involving either dehydrated or prehydrated Zr-nodes showed higher methanol and methane formation rates over the dehydrated Zr-node. Transient experiments suggested that the difference is related to competitive adsorption between methanol and water. DFT calculations and microkinetic modeling support this conclusion and give further insight into the equilibria involved in the competitive adsorption process. The calculations revealed weaker adsorption of methanol in defective or dehydrated nodes, in agreement with the larger gas phase concentration of methanol observed experimentally. The microkinetic model shows that [Zr2(µ-O)2]4+ and [Zr2(µ-OH)(µ-O)(OH)(H2O)]4+ are the main surface species when the concentration of water is lower than the number of defect sites. Lastly, although addition of water was found to promote methanol desorption, water does not change the methanol steady state reaction rate, while it has a substantial inhibiting effect on CH4 formation. These results indicate that water can be used to increase the reaction selectivity to methanol and encourages further detailed investigations of the catalyst system.

Rational selection of co-catalysts for the deaminative hydrogenation of amides.

The catalytic hydrogenation of amides is an atom economical method to synthesize amines. Previously, it was serendipitously discovered that the combination of a secondary amide co-catalyst with (iPrPNP)Fe(H)(CO) (iPrPNP = N[CH2CH2(PiPr2)]2 -), results in a highly active base metal system for deaminative amide hydrogenation. Here, we use DFT to develop an improved co-catalyst for amide hydrogenation. Initially, we computationally evaluated the ability of a series of co-catalysts to accelerate the turnover-limiting proton transfer during C-N bond cleavage and poison the (iPrPNP)Fe(H)(CO) catalyst through a side reaction. TBD (triazabicyclodecene) was identified as the leading co-catalyst. It was experimentally confirmed that when TBD is combined with (iPrPNP)Fe(H)(CO) a remarkably active system for amide hydrogenation is generated. TBD also enhances the activity of other catalysts for amide hydrogenation and our results provide guidelines for the rational design of future co-catalysts.

Cu-catalyzed N-3-Arylation of Hydantoins Using Diaryliodonium Salts.

A general Cu-catalyzed, regioselective method for the N-3-arylation of hydantoins is described. The protocol utilizes aryl(trimethoxyphenyl)iodonium tosylate as the arylating agent in the presence of triethylamine and a catalytic amount of a simple Cu-salt. The method is compatible with structurally diverse hydantoins and operates well with neutral aryl groups or aryl groups bearing weakly donating/withdrawing elements. It is also applicable for the rapid diversification of pharmaceutically relevant hydantoins.

Hydrogenation of CO2 to Methanol by Pt Nanoparticles Encapsulated in UiO-67: Deciphering the Role of the Metal-Organic Framework.

Metal-organic frameworks (MOFs) show great prospect as catalysts and catalyst support materials. Yet, studies that address their dynamic, kinetic, and mechanistic role in target reactions are scarce. In this study, an exceptionally stable MOF catalyst consisting of Pt nanoparticles (NPs) embedded in a Zr-based UiO-67 MOF was subject to steady-state and transient kinetic studies involving H/D and 13C/12C exchange, coupled with operando infrared spectroscopy and density functional theory (DFT) modeling, targeting methanol formation from CO2/H2 feeds at 170 °C and 1-8 bar pressure. The study revealed that methanol is formed at the interface between the Pt NPs and defect Zr nodes via formate species attached to the Zr nodes. Methanol formation is mechanistically separated from the formation of coproducts CO and methane, except for hydrogen activation on the Pt NPs. Careful analysis of transient data revealed that the number of intermediates was higher than the number of open Zr sites in the MOF lattice around each Pt NP. Hence, additional Zr sites must be available for formate formation. DFT modeling revealed that Pt NP growth is sufficiently energetically favored to enable displacement of linkers and creation of open Zr sites during pretreatment. However, linker displacement during formate formation is energetically disfavored, in line with the excellent catalyst stability observed experimentally. Overall, the study provides firm evidence that methanol is formed at the interface of Pt NPs and linker-deficient Zr6O8 nodes resting on the Pt NP surface.

A Highly Asymmetric Gold(III) η3 -Allyl Complex.

A highly asymmetric AuIII η3 -allyl complex has been generated by treating Au(η1 -allyl)Br(tpy) (tpy=2-(p-tolyl)pyridine) with AgNTf2 . The resulting η3 -allyl complex has been characterized by NMR spectroscopy and X-ray crystallography. DFT calculations and variable temperature 1 H NMR suggest that the allyl ligand is highly fluxional.

Sevoflurano tópico como tratamiento analgésico y antimicrobiano de tenosinovitis piógena de los flexores de la mano. Caso clínico / Topical sevoflurane as analgesic and antimicrobial treatment of pyogenic flexor tenosynovitis of the hand. Case report

Presentamos el caso de un paciente con una tenosinovitis piógena del 5° dedo de la mano, tratado inicialmente con desbridamiento quirúrgico y antibioterapia empírica. La evolución fue desfavorable, pues el dedo presentaba un defecto de cobertura con signos infecciosos en la herida y las curas resultaban muy dolorosas. Al paciente se le ofertaron varias opciones quirúrgicas y, mientras se decidía por alguna, aceptó por escrito iniciar curas con sevoflurano líquido tópico (según protocolo vigente para uso de fármacos fuera de indicación). El efecto analgésico del sevoflurano apareció rápidamente, y la evolución posterior de la herida fue muy favorable, pues los signos infecciosos desaparecieron y el defecto de cobertura se había cerrado tras tres semanas de empleo de sevoflurano tópico, sin necesidad de nuevas cirugías. Este caso ejemplifica que el uso fuera de indicación de sevoflurano tópico para tratar heridas complejas puede evitar actuaciones quirúrgicas, mucho más agresivas para los pacientes.

The clinical case is presented on a patient suffering from pyogenic tenosynovitis affecting the 5th finger of the hand, which was initially treated with surgical debridement and empirical antibiotic treatment. The clinical outcome was unfavourable, since the finger presented with a coverage defect, and the wound seemed to be infected. Wound cleaning and dressings were very painful. The patient was asked to choose between several surgical therapeutic alternatives, but he gave written informed consent to be treated with topical sevoflurane, following an approved protocol for the off-label use of this drug. Pain was accurately controlled after sevoflurane application, and the wound exhibited a very good outcome with disappearance of the clinical signs of infection and complete closure of the defect coverage after three weeks of sevoflurane, with no new surgical procedures. The present clinical case illustrates how the off-label use of topical sevoflurane for the treatment of complicated wounds could be useful to avoid surgical procedures that are more aggressive for patients.

Silvoflurano tópico en infección superficial por SARM tras artroplastia de rodilla: caso clínico / Topical sevoflurane for superficial MRSA infection after knee arthroplasty: case report

Intentar el tratamiento retentivo de material protésico ante heridas quirúrgicas infectadas por gérmenes resistentes es objeto de debate, especialmente cuando el agente causal es un Staphylococcus aureus resistente a meticilina (SARM). Una paciente diabética y con obesidad tipo I sufrió infección de la herida quirúrgica tras artroplastia de rodilla que no evolucionó bien con antibioterapia empírica y terapia hiperosmolar. Se planificó una reintervención que fue demorada por motivos extramédicos (falta de terapia de presión negativa para cubrir la herida postoperatoria, pues se preveía no poder realizar cierre primario). Mientras se conseguía este material, y tras obtener el consentimiento de la paciente, se iniciaron irrigaciones de la herida con sevoflurano tópico off-label, pues ese fármaco ha mostrado capacidad antimicrobiana. La evolución clínica fue excelente desde el inicio a pesar de que en el cultivo se aisló un SARM resistente a la antibioterapia empírica, por lo que se desestimó la reintervención y se continuó con sevoflurano tópico junto a la antibioterapia dirigida por antibiograma, lográndose la curación completa de la herida tras 6 semanas. Durante ese tiempo, la paciente no experimentó ningún efecto adverso atribuible al sevoflurano. El sevoflurano tópico aparece como una valiosa nueva opción terapéutica ante heridas postoperatorias infectadas, especialmente cuando los gérmenes causantes son resistentes a los antibióticos convencionales.

It is challenging to try a retentive treatment of prosthetic material superinfected by resistant microorganisms, especially when the causative agent is a methicillin-resistant Staphylococcus aureus (MRSA). A diabetic, obese female patient suffered from a postoperative wound infection after a knee arthroplasty. Initial treatment with antibiotics and hyperosmolar therapy failed and clinical evolution was no good. Surgery was scheduled, but it was delayed due to nonmedical reasons (lack of negative-pressure therapy to cover the wound since primary wound closure was anticipated to be very improbable to perform). While waiting for this therapy, off-label irrigations with topical sevoflurane were started after obtaining written consent, since this drug has exhibited antimicrobial properties. Clinical evolution turned out to be excellent since the very beginning, even though a MRSA resistant to the antibiotics empirically administered was isolated. Thus, surgery was discarded, and culture-guided antibiotic therapy was added to topical sevoflurane, which was followed by a complete healing of the wound after 6 weeks. Sevoflurane treatment was well tolerated as the patient reported no adverse effects. Therefore, treating postsurgical wounds with topical sevoflurane appears as a valuable new alternative, especially when infections are caused by microorganisms resistant to conventional antibiotics.

Uncooperative Patient With an Infected Elbow Osteosynthesis: Alternative Management With Topical Sevoflurane.

INTRODUCTION: Treatment of an infected osteosynthesis is usually a complicated process, with its complexity increasing when unforeseen situations appear. Typically, the therapeutic management of such situations is challenging because they are not anticipated in the medical literature and physicians have to look for and adapt novel solutions to a specific patient condition. CASE REPORT: A 41-year-old, uncooperative, homeless man, presented to the emergency room with a left olecranon fracture. After planned surgery, the surgical wound became infected with a methicillin-sensitive Staphylococcus aureus because the treatment took place in an unhygienic outpatient hospital setting. The patient refused to remain in the hospital and also failed to complete antibiotic courses prescribed (culture-guided rifampicin 600 mg daily plus levofloxacin 500 mg daily). Instead of removing the osteosynthesis material, the infection was successfully treated by repeated applications of 5 mL of sevoflurane into the surgical wound. Subsequently, wound healing was achieved with a combination of a brief course of negative pressure wound therapy (NPWT), use of silver-impregnated dressings, and irrigation of the wound with sevoflurane. Sevoflurane also provided topical analgesic to ameliorate the pain caused by removing the NPWT sponge. Interestingly, despite extremely poor compliance by the patient to all standard treatment regimens, and the clinical decision to retain the implant, the infection was resolved, and the fracture was consolidated. CONCLUSIONS: Local application of sevoflurane in the wound bed appears to exhibit analgesic, antimicrobial, and positive healing effects. It could be a promising alternative treatment to be included as a therapeutic option for wound care.

Highly selective hydrogenation of amides catalysed by a molybdenum pincer complex: scope and mechanism.

A series of molybdenum pincer complexes has been shown for the first time to be active in the catalytic hydrogenation of amides. Among the tested catalysts, Mo-1a proved to be particularly well suited for the selective C-N hydrogenolysis of N-methylated formanilides. Notably, high chemoselectivity was observed in the presence of certain reducible groups including even other amides. The general catalytic performance as well as selectivity issues could be rationalized taking an anionic Mo(0) as the active species. The interplay between the amide C[double bond, length as m-dash]O reduction and the catalyst poisoning by primary amides accounts for the selective hydrogenation of N-methylated formanilides. The catalyst resting state was found to be a Mo-alkoxo complex formed by reaction with the alcohol product. This species plays two opposed roles - it facilitates the protolytic cleavage of the C-N bond but it encumbers the activation of hydrogen.

Synthesis of a (N,C,C) Au(iii) pincer complex via Csp3-H bond activation: increasing catalyst robustness by rational catalyst design.

A (N,CAr,CAlk) Au(iii) pincer complex has been synthesized from Au(OAc)3 (OAc = OCOCH3) and 2-(3,5-di-tert-butylphenyl)pyridine (L1) involving a Csp3-H bond activation by electrophilic substitution. In agreement with DFT calculations, the resulting complex significantly improves the performance of Au(tpy)(OAcF)2 (tpy = 2-(p-tolyl)pyridine, OAcF = OCOCF3) in the catalytic trifluoroacetylation of acetylene.

A Combined Experimental/Computational Study of the Mechanism of a Palladium-Catalyzed Bora-Negishi Reaction.

Experimental and computational efforts are reported which illuminate the mechanism of a novel boron version of the widespread Negishi coupling reaction that offers a new protocol for the formation of aryl/acyl C-B bonds using a bulky boryl fragment. The role of nucleophilic borylzinc reagents in the reduction of the PdII pre-catalysts to Pd0 active species has been demonstrated. The non-innocent behavior of the PPh3 ligands of the [Pd(PPh3 )2 Cl2 ] pre-catalyst under activation conditions has been probed both experimentally and computationally, revealing the formation of a trimetallic Pd species bearing bridging phosphide (PPh2- ) ligands. Our studies also reveal the monoligated formulation of the Pd0 active species, which led us to synthesize related (η3 -indenyl)Pd-monophosphine catalysts which show improved catalytic performances under mild conditions. A complete mechanistic proposal to aid future catalyst developments is provided.

How Solvent Dynamics Controls the Schlenk Equilibrium of Grignard Reagents: A Computational Study of CH3MgCl in Tetrahydrofuran.

The Schlenk equilibrium is a complex reaction governing the presence of multiple chemical species in solution of Grignard reagents. The full characterization at the molecular level of the transformation of CH3MgCl into MgCl2 and Mg(CH3)2 in tetrahydrofuran (THF) by means of ab initio molecular dynamics simulations with enhanced-sampling metadynamics is presented. The reaction occurs via formation of dinuclear species bridged by chlorine atoms. At room temperature, the different chemical species involved in the reaction accept multiple solvation structures, with two to four THF molecules that can coordinate the Mg atoms. The energy difference between all dinuclear solvated structures is lower than 5 kcal mol-1. The solvent is shown to be a direct key player driving the Schlenk mechanism. In particular, this study illustrates how the most stable symmetrically solvated dinuclear species, (THF)CH3Mg(µ-Cl)2MgCH3(THF) and (THF)CH3Mg(µ-Cl)(µ-CH3)MgCl(THF), need to evolve to less stable asymmetrically solvated species, (THF)CH3Mg(µ-Cl)2MgCH3(THF)2 and (THF)CH3Mg(µ-Cl)(µ-CH3)MgCl(THF)2, in order to yield ligand exchange or product dissociation. In addition, the transferred ligands are always departing from an axial position of a pentacoordinated Mg atom. Thus, solvent dynamics is key to successive Mg-Cl and Mg-CH3 bond cleavages because bond breaking occurs at the most solvated Mg atom and the formation of bonds takes place at the least solvated one. The dynamics of the solvent also contributes to keep relatively flat the free energy profile of the Schlenk equilibrium. These results shed light on one of the most used organometallic reagents whose structure in solvent remains experimentally unresolved. These results may also help to develop a more efficient catalyst for reactions involving these species.