Cyclometallated Imides as Templates for the H-Bond Directed Iridium-Catalyzed Asymmetric Hydrogenation of N-Methyl, N-Alkyl and N-Aryl Imines.

A combined computational and experimental approach allowed us to develop the most selective catalysts for the direct hydrogenation of N-methyl and N-alkyl imines described to date. Iridium catalysts with a cyclometallated cyclic imide group provide selectivity of up to 99% enantiomeric excess. Computational studies show that the selectivity results from the combined effect of H-bonding of the imide C=O with the substrate iminium ion and a stabilizing π-π interaction with the cyclometallated ligand. The cyclometallated ligand thus exhibits a unique mode of action, serving as a template for the H-bond directed approach of the substrate which results in enhanced selectivity. The catalyst (2) has been synthesized and isolated as a crystalline air-stable solid. X-ray analysis of 2 confirmed the structure of the catalyst and the correct position of the imide C=O groups to engage in an H-bond with the substrate. 19F-NMR real-time monitoring showed the hydrogenation of N-methyl imines catalyzed by 2 is very fast, with a TOF of approx. 3500 h-1.

Dithienylethene-Based Photoswitchable Phosphines for the Palladium-Catalyzed Stille Coupling Reaction.

Homogeneous transition metal catalysis is a constantly developing field in chemical sciences. A growing interest in this area is photoswitchable catalysis, which pursues in situ modulation of catalyst activity through noninvasive light irradiation. Phosphorus ligands are excellent targets to accomplish this goal by introducing photoswitchable moieties; however, only a limited number of examples have been reported so far. In this work, we have developed a series of palladium complexes capable of catalyzing the Stille coupling reaction that contain photoisomerizable phosphine ligands based on dithienylethene switches. Incorporation of electron-withdrawing substituents into these dithienylethene moieties allows variation of the electron density on the phosphorus atom of the ligands upon light irradiation, which in turn leads to a modulation of the catalytic properties of the formed complexes and their activity in a model Stille coupling reaction. These results are supported by theoretical computations, which show that the energy barriers for the rate-determining steps of the catalytic cycle decrease when the photoswitchable phosphine ligands are converted to their closed state.

Amplified photomodulation of a bis(dithienylethene)-substituted phosphine.

Phosphine ligands play a crucial role in homogeneous catalysis, allowing fine-tuning of the catalytic activity of various metals by modifying their structure. An ultimate challenge in this field is to reach controlled modulation of catalysis in situ, for which the development of phosphines capable of photoswitching between states with differential electronic properties has been proposed. To magnify this light-induced behavior, in this work we describe a novel phosphine ligand incorporating two dithienylethene photoswitchable moieties tethered to the same phosphorus atom. Double photoisomerization was observed for this ligand, which remains unhindered upon gold(I) complexation. As a result, the preparation of a fully ring-closed phosphine isomer was accomplished, for which amplified variation of phosphorus electron density was verified both experimentally and by computational calculations. Accordingly, the presented molecular design based on multiphotochromic phosphines could open new ways for preparing enhanced photoswitchable catalytic systems.

Single electron reduction of NHC-CO2-borane compounds.

The carbon dioxide radical anion [CO2˙-] is a highly reactive species of fundamental and synthetic interest. However, the direct one-electron reduction of CO2 to generate [CO2˙-] occurs at very negative reduction potentials, which is often a limiting factor for applications. Here, we show that NHC-CO2-BR3 species - generated from the Frustrated Lewis Pair (FLP)-type activation of CO2 by N-heterocyclic carbenes (NHCs) and boranes (BR3) - undergo single electron reduction at a less negative potential than free CO2. A net gain of more than one volt was notably measured with a CAAC-CO2-B(C6F5)3 adduct, which was chemically reduced to afford [CAAC-CO2-B(C6F5)3˙-]. This room temperature stable radical anion was characterized by EPR spectroscopy and by single-crystal X-ray diffraction analysis. Of particular interest, DFT calculations showed that, thanks to the electron withdrawing properties of the Lewis acid, significant unpaired spin density is localised on the carbon atom of the CO2 moiety. Finally, these species were shown to exhibit analogous reactivity to the carbon dioxide radical anion [CO2˙-] toward DMPO. This work demonstrates the advantage provided by FLP systems in the generation and stabilization of [CO2˙-]-like species.

Carboranylphosphines: B9-Substituted Derivatives with Enhanced Reactivity for Anchoring to Dendrimers.

Invited for the cover of this issue are the groups and colleagues of Anne-Marie Caminade at the CNRS and University of Toulouse, Evamarie Hey-Hawkins at Leipzig University, and Agustí Lledós from the Autonomous University of Barcelona. The image depicts birds crowned by a carborane competing for access to food, to illustrate the steric hindrance encountered when grafting carboranes to dendrimers (artwork by Dr. Christoph Selg). Read the full text of the article at 10.1002/chem.202303867.

Carboranylphosphines: B9-Substituted Derivatives with Enhanced Reactivity for the Anchoring to Dendrimers.

Several ortho-carboranes bearing a phenoxy or a phenylamino group in the B9 position were prepared employing various protection and deprotection strategies. Following established protocols, dendritic compounds were synthesized from a hexachlorocyclotriphosphazene or thiophosphoryl chloride core, and possible anchoring options for the B9-substituted ortho-carboranes were investigated experimentally and theoretically (DFT). Furthermore, 1- or 1,2-phosphanyl-substituted carborane derivatives were obtained. The resulting diethyl-, diisopropyl-, di-tert-butyl-, diphenyl- or diethoxyphosphines bearing a tunable ortho-carborane moiety are intriguing ligands for future applications in homogeneous catalysis or the medicinal sector.

Anti-Markovnikov Intermolecular Hydroamination of Alkenes and Alkynes: A Mechanistic View.

Hydroamination, the addition of an N-H bond across a C-C multiple bond, is a reaction with a great synthetic potential. Important advances have been made in the last decades concerning catalysis of these reactions. However, controlling the regioselectivity in the amine addition toward the formation of anti-Markovnikov products (addition to the less substituted carbon) still remains a challenge, particularly in intermolecular hydroaminations of alkenes and alkynes. The goal of this review is to collect the systems in which intermolecular hydroamination of terminal alkynes and alkenes with anti-Markovnikov regioselectivity has been achieved. The focus will be placed on the mechanistic aspects of such reactions, to discern the step at which regioselectivity is decided and to unravel the factors that favor the anti-Markovnikov regioselectivity. In addition to the processes entailing direct addition of the amine to the C-C multiple bond, alternative pathways, involving several reactions to accomplish anti-Markovnikov regioselectivity (formal hydroamination processes), will also be discussed in this review. The catalysts gathered embrace most of the metal groups of the Periodic Table. Finally, a section discussing radical-mediated and metal-free approaches, as well as heterogeneous catalyzed processes, is also included.

IrI(η4-diene) precatalyst activation by strong bases: formation of an anionic IrIII tetrahydride.

The reaction between [IrCl(COD)]2 and dppe in a 1 : 2 ratio was investigated in detail under three different conditions. [IrCl(COD)(dppe)], 1, is formed at room temperature in the absence of base. In the presence of a strong base at room temperature, hydride complexes that retain the carbocyclic ligand in the coordination sphere are generated. In isopropanol, 1 is converted into [IrH(1,2,5,6-η2:η2-COD)(dppe)] (2) on addition of KOtBu, with k12 = (1.11 ± 0.02) × 10-4 s-1, followed by reversible isomerisation to [IrH(1-κ-4,5,6-η3-C8H12)(dppe)] (3) with k23 = (3.4 ± 0.2) × 10-4 s-1 and k32 = (1.1 ± 0.3) × 10-5 s-1 to yield an equilibrium 5 : 95 mixture of 2 and 3. However, when no hydride source is present in the strong base (KOtBu in benzene or toluene), the COD ligand in 1 is deprotonated, followed by ß-H elimination of an IrI-C8H11 intermediate, which leads to complex [IrH(1-κ-4,5,6-η3-C8H10)(dppe)] (4) selectively. This is followed by its reversible isomerisation to 5, which features a different relative orientation of the same ligands (k45 = (3.92 ± 0.11) × 10-4 s-1; k5-4 = (1.39 ± 0.12) × 10-4 s-1 in C6D6), to yield an equilibrated 32 : 68 mixture of 4 and 5. DFT calculations assisted in the full rationalization of the selectivity and mechanism of the reactions, yielding thermodynamic (equilibrium) and kinetic (isomerization barriers) parameters in excellent agreement with the experimental values. Finally, in the presence of KOtBu and isopropanol at 80 °C, 1 is transformed selectively to K[IrH4(dppe)] (6), a salt of an anionic tetrahydride complex of IrIII. This product is also selectively generated from 2, 3, 4 and 5 and H2 at room temperature, but only when a strong base is present. These results provide an insight into the catalytic action of [IrCl(COD)(LL)] complexes in the hydrogenation of polar substrates in the presence of a base.

Palladium-Catalyzed Ortho C-H Arylation of Unprotected Anilines: Chemo- and Regioselectivity Enabled by the Cooperating Ligand [2,2'-Bipyridin]-6(1H)-one.

Metal-catalyzed C-H functionalizations on the aryl ring of anilines usually need cumbersome N-protection-deprotection strategies to ensure chemoselectivity. We describe here the Pd-catalyzed direct C-H arylation of unprotected anilines with no competition of the N-arylation product. The ligand [2,2'-bipyridin]-6(1H)-one drives the chemoselectivity by kinetic differentiation in the product-forming step, while playing a cooperating role in the C-H cleavage step. The latter is favored in an anionic intermediate where the NH moiety is deprotonated, driving the regioselectivity of the reaction toward ortho substitution.

Getting Deeper into the Molecular Events of Heme Binding Mechanisms: A Comparative Multi-level Computational Study of HasAsm and HasAyp Hemophores.

Many biological systems obtain their activity by the inclusion of metalloporphyrins into one or several binding pockets. However, decoding the molecular mechanism under which these compounds bind to their receptors is something that has not been widely explored and is a field with open questions. In the present work, we apply computational techniques to unravel and compare the mechanisms of two heme-binding systems, concretely the HasA hemophores from Gram negative bacteria Serratiamarcescens (HasAsm) and Yersinia pestis (HasAyp). Despite the high sequence identity between both systems, the comparison between the X-ray structures of their apo and holo forms suggests different heme-binding mechanisms. HasAyp has extremely similar structures for heme-free and heme-bound forms, while HasAsm presents a very large displacement of a loop that ultimately leads to an additional coordination to the metal with respect to HasAyp. We combined Gaussian accelerated molecular dynamics simulations (GaMDs) in explicit solvent and protein-ligand docking optimized for metalloligands. GaMDs were first carried out on heme-free forms of both hemophores. Then, protein-ligand dockings of the heme were performed on cluster representatives of these simulations and the best poses were then subjected to a new series of GaMDs. A series of analyses reveal the following: (1) HasAyp has a conformational landscape extremely similar between heme-bound and unbound states with no to limited impact on the binding of the cofactor, (2) HasAsm presents as a slightly broader conformational landscape in its apo state but can only visit conformations similar to the X-ray of the holo form when the heme has been bound. Such behavior results from a complex cascade of changes in interactions that spread from the heme-binding pocket to the flexible loop previously mentioned. This study sheds light on the diversity of molecular mechanisms of heme-binding and discusses the weight between the pre-organization of the receptor as well as the induced motions resulting in association.

Direct Benzene Hydroxylation with Dioxygen Induced by Copper Complexes: Uncovering the Active Species by DFT Calculations.

The direct oxidation of benzene into phenol using molecular oxygen at very mild temperatures can be promoted in the presence of the copper complex TpBr3Cu(NCMe) in the homogeneous phase in the presence of ascorbic acid as the source of protons and electrons. The stoichiometric nature, relative to copper, of this transformation prompted a thorough DFT study in order to understand the reaction pathway. As a result, the dinuclear species TpBr3CuII(µ-O•)(µ-OH)CuIITpBr3 is proposed as the relevant structure which is responsible for activating the arene C-H bond leading to phenol formation.

Copper(I) activation of C-X bonds: bimolecular vs. unimolecular reaction mechanism.

Experimental kinetic studies and DFT calculations show that the oxidative addition of aryl halides (Ar-X) to complexes [Cu(NHC)R] follow different paths depending on the nature of X. For X = Br a concerted addition leads to cis-[Cu(NHC)XRAr] from which the usual C-C coupled product Ar-R eliminates. However, for X = I trans-[Cu(NHC)IRAr] is formed instead, leading to the elimination of R-I in a metathesis reaction. This behaviour is accounted for by a change in the reaction mechanism for Ar-I, which involves two molecules of copper(I) complex, the second one stabilising the incipient iodide formed in the C-I breaking (oxidative addition) and C-I forming (reductive elimination) processes.

Successes and challenges in multiscale modelling of artificial metalloenzymes: the case study of POP-Rh2 cyclopropanase.

Molecular modelling applications in metalloenzyme design are still scarce due to a series of challenges. On top of that, the simulations of metal-mediated binding and the identification of catalytic competent geometries require both large conformational exploration and simulation of fine electronic properties. Here, we demonstrate how the incorporation of new tools in multiscale strategies, namely substrate diffusion exploration, allows taking a step further. As a showcase, the enantioselective profiles of the most outstanding variants of an artificial Rh2-based cyclopropanase (GSH, HFF and RFY) developed by Lewis and co-workers (Nat. Commun., 2015, 6, 7789 and Nat. Chem., 2018, 10, 318-324) have been rationalized. DFT calculations on the free-cofactor-mediated process identify the carbene insertion and the cyclopropanoid formation as crucial events, the latter being the enantiodetermining step, which displays up to 8 competitive orientations easily altered by the protein environment. The key intermediates of the reaction were docked into the protein scaffold showing that some mutated residues have direct interaction with the cofactor and/or the co-substrate. These interactions take the form of a direct coordination of Rh in GSH and HFF and a strong hydrophobic patch with the carbene moiety in RFY. Posterior molecular dynamics sustain that the cofactor induces global re-arrangements of the protein. Finally, massive exploration of substrate diffusion, based on the GPathFinder approach, defines this event as the origin of the enantioselectivity in GSH and RFY. For HFF, fine molecular dockings suggest that it is likely related to local interactions upon diffusion. This work shows how modelling of long-range mutations on the catalytic profiles of metalloenzymes may be unavoidable and software simulating substrate diffusion should be applied.

Transmetalation Reactions Triggered by Electron Transfer between Organocopper Complexes.

[Cu(bipy)(C6F5)] reacts with most aryl iodides to form heterobiphenyls by cross-coupling, but when Rf-I is used (Rf = 3,5-dicholoro-2,4,6-trifluorophenyl), homocoupling products are also formed. Kinetic studies suggest that, for the homocoupling reaction, a mechanism based on transmetalation from [Cu(bipy)(C6F5)] to Cu(III) intermediates formed in the oxidative addition step is at work. Density functional theory calculations show that the interaction between these Cu(III) species and the starting Cu(I) complex involves a Cu(I)-Cu(III) electron transfer concerted with the formation of an iodine bridge between the metals and that a fast transmetalation takes place in a dimer in a triplet state between two Cu(II) units.

Computational Analysis on the Pd-Catalyzed C-N Coupling of Ammonia with Aryl Bromides Using a Chelate Phosphine Ligand.

The Buchwald-Hartwig amination of arylhalides with the Pd-Josiphos complex is a very useful process for the generation of primary amines using ammonia as a reactant. Density-functional theory (DFT) calculations are carried out to examine the reaction mechanism for this process. Although the general mechanism for the C-N cross-coupling reaction is known, there are still some open questions regarding the effect of a chelate phosphine ligand and the role of the base in the process. Reaction pathways involving the release of one of the arms of the phosphine ligand are compared with those where the chelate phosphine remains fully coordinated. Conformational analysis for the complex with the open chelate phosphine is required to properly evaluate the proposed pathways. The role played by the added base (t-BuO-) as a possible ligand or just as a base was also evaluated. The understanding of all of these aspects allowed us to propose a complete reaction mechanism for the Pd-catalyzed C-N coupling of arylhalides with ammonia using the chelate Josiphos ligand.

Aerobic intramolecular carbon-hydrogen bond oxidation promoted by Cu(I) complexes.

The oxidation of C-H bonds by copper centres in enzymes with molecular oxygen takes place in nature under ambient conditions. Herein we report a similar transformation in which under ambient pressure and temperature (1 atm, 25 °C) the complex TpMsCu(THF) (TpMs = hydrotris(3-mesityl-pyrazol-1-yl)borate) undergoes the intramolecular oxidation of an alkylic C-H bond with O2, leading to the formation of a trinuclear compound where alkoxy and hydroxyl ligands are bonded to the copper centres, as inferred from X-ray studies. The presence of adventitious Cu(0) derived from the partial decomposition of initial TpMsCu(THF) facilitates the formation of such a trinuclear compound. DFT studies support the reaction taking place through a Cu(iii) alkoxy-hydroxyl copper intermediate.

Dynamic PdII /CuI Multimetallic Assemblies as Molecular Models to Study Metal-Metal Cooperation in Sonogashira Coupling.

Cooperation between two different metals plays a crucial role in many synergistic catalytic reactions, such as the Sonogashira C-C cross-coupling reaction, where an interaction between the Pd and Cu centers is proposed in the transmetalation step. Although several heterobimetallic Pd/Cu complexes were proposed as structural models of the active species in Sonogashira coupling, the detailed understanding of the metal-metal cooperation in transmetalation is still lacking in current systems. In this work, we report a stepwise and systematic approach to building heteromultimetallic Pd/Cu assemblies as a tool to study metal-metal cooperativity. We obtained fully characterized Pd/Cu multimetallic assemblies that show reactivity in alkyne activation, formation of catalytically relevant aryl/acetylide species, and C-C elimination, serving as functional models for Sonogashira reaction intermediates. The combined experimental and DFT studies highlight the importance of ligand-controlled coordination geometry, metal-metal distances and dynamics of the multimetallic assembly for transmetalation step.

Molecular Modeling for Artificial Metalloenzyme Design and Optimization.

Artificial metalloenzymes (ArMs) are obtained by inserting homogeneous catalysts into biological scaffolds and are among the most promising strategies in the quest for new-to-nature biocatalysts. The quality of their design strongly depends on how three partners interact: the biological host, the "artificial cofactor," and the substrate. However, structural characterization of functional artificial metalloenzymes by X-ray or NMR is often partial, elusive, or absent. How the cofactor binds to the protein, how the receptor reorganizes upon the binding of the cofactor and the substrate, and which are the binding mode(s) of the substrate for the reaction to proceed are key questions that are frequently unresolved yet crucial for ArM design. Such questions may eventually be solved by molecular modeling but require a step change beyond the current state-of-the-art methodologies.Here, we summarize our efforts in the study of ArMs, presenting both the development of computational strategies and their application. We first focus on our integrative computational framework that incorporates a variety of methods such as protein-ligand docking, classical molecular dynamics (MD), and pure quantum mechanical (QM) methods, which, when properly combined, are able to depict questions that range from host-cofactor binding predictions to simulations of entire catalytic mechanisms. We also pay particular attention to the protein-ligand docking strategies that we have developed to accurately predict the binding of transition metal-containing molecules to proteins. While this aspect is fundamental to many bioinorganic fields beyond ArMs, it has been disregarded from the molecular modeling landscape until very recently.Next we describe how to apply this computational framework to particular ArMs including systems previously characterized experimentally as well as others where computation served to guide the design. We start with the prediction of the interactions between homogeneous catalysts and biological hosts. Protein-ligand docking is pivotal at that stage, but it needs to be combined with QM/MM or MD approaches when the binding of the cofactor implies significant conformational changes of the protein or involve changes of the electronic state of the metal.Then, we summarize molecular modeling studies aimed at identifying cofactor-substrate arrangements inside the ArM active pocket that are consistent with its reactivity. These calculations stand on "Theozyme"-like dockings, MD-refined or not, which provide molecular rationale of the catalytic profiles of the artificial systems.In the third section, we present case studies to decode the entire catalytic mechanism of two ArMs: (1) an iridium based asymmetric transfer hydrogenase obtained by insertion of Noyori's catalyst into streptavidin and (2) a metallohydrolase achieved by including a receptor. Transition states, second coordination sphere effects, as well as motions of the cofactors are identified as drivers of the enantiomeric profiles.Finally, we report computer-aided designs of ArMs to guide experiments toward chemical and mutational changes that improve their activity and/or enantioselective profiles and expand toward future directions.

Catalytic Regioselective Isomerization of 2,2-Disubstituted Oxetanes to Homoallylic Alcohols.

The selective isomerization of strained heterocyclic compounds is an important tool in organic synthesis. An unprecedented regioselective isomerization of 2,2-disubstituted oxetanes into homoallylic alcohols is described. The use of tris(pentafluorophenyl)borane (B(C6 F5 )3 ), a commercially available Lewis acid was key to obtaining good yields and selectivities since other Lewis acids afforded mixtures of isomers and substantial polymerization. The reaction took place under exceptionally mild reaction conditions and very low catalyst loading (0.5 mol %). DFT calculations disclose the mechanistic features of the isomerization and account for the high selectivity displayed by the B(C6 F5 )3 catalyst. The synthetic applicability of the new reaction is demonstrated by the preparation of γ-chiral alcohols using iridium-catalyzed asymmetric hydrogenation.

Skeletal diversity in Pt- and Au-catalyzed annulations of allenedienes: dissecting unconventional mechanistic pathways.

We describe the discovery of unprecedented annulation processes of 1,7-allenedienes, promoted by Pt or Au catalysts. These transformations revealed mechanistic pathways that had not been previously observed in reactions involving carbophilic catalysis. In particular, we have found that allenedienes bearing a silyl ether in the carbon tether connecting the diene and the allene divergently afford cyclopropane-embedded tricyclic derivatives, 6,6-fused bicarbocyclic products or 5,6-fused bicarbocyclic systems, depending on the type of Au or Pt catalyst used. We have carried out experimental and computational studies that shed light on the mechanistic reasons behind this rich and unusual skeletal divergence, and provide new lessons on the drastic influence of platinum ancillary ligands on the reaction outcome.