Evidence for Suzuki–Miyaura cross-couplings catalyzed by ligated Pd3-clusters: from cradle to grave

Pdn clusters offer unique selectivity and exploitable reactivity in catalysis. Understanding the behavior of Pdn clusters is thus critical for catalysis, applied synthetic organic chemistry and greener outcomes for precious Pd. The Pd3 cluster, [Pd3(μ-Cl)(μ-PPh2)2(PPh3)3][Cl] (denoted as Pd3Cl2), which exhibits distinctive reactivity, was synthesized and immobilized on a phosphine-functionalized polystyrene resin (denoted as immob-Pd3Cl2). The resultant material served as a tool to study closely the role of Pd3 clusters in a prototypical Suzuki–Miyaura cross-coupling of 4-fluoro-1-bromobenzene and 4-methoxyphenyl boronic acid at varying low Pd ppm concentrations (24, 45, and 68 ppm). Advanced heterogeneity tests such as Hg poisoning and the three-phase test showed that leached mononuclear or nanoparticulate Pd are unlikely to be the major active catalyst species under the reaction conditions tested. EXAFS/XANES analysis from (pre)catalyst and filtered catalysts during and after catalysis has shown the intactness of the triangular structure of the Pd3X2 cluster, with exchange of chloride (X) by bromide during catalytic turnover of bromoarene substrate. This finding is further corroborated by treatment of immob-Pd3Cl2 after catalyzing the Suzuki–Miyaura reaction with excess PPh3, which releases the cluster from the polymer support and so permits direct observation of [Pd3(μ-Br)(μ-PPh2)2(PPh3)3]+ ions by ESI-MS. No evidence is seen for a proposed intermediate in which the bridging halogen on the Pd3 motif is replaced by an aryl group from the organoboronic acid, i.e. formed by a transmetallation-first process. Our findings taken together indicate that the ‘Pd3X2’ motif is an active catalyst species, which is stabilized by being immobilized, providing a more robust Pd3 cluster catalyst system. Non-immobilized Pd3Cl2 is less stable, as is followed by stepwise XAFS of the non-immobilized Pd3Cl2, which gradually changes to a species consistent with ‘Pdx(PPh3)y’ type material. Our findings have far-reaching future implications for Pd3 cluster involvement in catalysis, showing that immobilization of Pd3 cluster species offers advantages for rigorous mechanistic examination and applied chemistries

Direct Cyclopalladation of Fluorinated Benzyl Amines by Pd3(OAc)6 : The Coexistence of Multinuclear PdnReaction Pathways Highlights the Importance of Pd Speciation in C-H Bond Activation

Palladacycles are key intermediates in catalytic C-H bond functionalization reactions and important precatalysts for cross-couplings. It is commonly believed that palladacycle formation occurs through the reaction of a substrate bearing a C-H bond ortho to a suitable metal-directing group for interaction with, typically, mononuclear "Pd(OAc)2"species, with cyclopalladation liberating acetic acid as the side product. In this study, we show that N,N-dimethyl-fluoro-benzyl amines, which can be cyclopalladated either ortho or para to fluorine affording two regioisomeric products, can occur by a direct reaction of Pd3(OAc)6, proceeding via higher-order cyclopalladated intermediates. Regioselectivity is altered subtly depending on the ratio of substrate:Pd3(OAc)6 and the solvent used. Our findings are important when considering mechanisms of Pd-mediated reactions involving the intermediacy of palladacycles, of particular relevance in catalytic C-H bond functionalization chemistry

Access to Some C5-Cyclised 2-Pyrones and 2-Pyridones via Direct Arylation; Retention of Chloride as a Synthetic Handle

The synthetic effort towards the functionalisation of C–H bonds on 2-pyrones and 2-pyridones has been enabled by the preferential reactivity of the C-3 position. Herein, we report a direct arylation protocol for the intramolecular coupling of 2-pyrones and 2-pyridones, allowing access to a previously unavailable class of C-5 cyclised products with an unstudied biological profile. A C–Cl bond was retained at C-3 during the direct arylation process allowing further derivatisation at C-3, using a Suzuki–Miyaura cross-coupling reaction

Direct Evidence for Competitive C-H Activation by a Well-Defined Silver XPhos Complex in Palladium-Catalyzed C-H Functionalization

Increasing evidence indicates that silver salts can play a role in the C-H activation step of palladium-catalyzed C-H functionalization. Here we isolate a silver(I) complex by C-H bond activation and demonstrate its catalytic competence for C-H functionalization. We demonstrate how silver carbonate, a common but highly insoluble additive, reacts with pentafluorobenzene in the presence of a bulky phosphine, XPhos, to form the C-H bond activation product Ag(C6F5)(XPhos). By isolating and fully characterizing this complex and the related carbonate and iodide complexes, [Ag(XPhos)]2(μ-κ2,κ2-CO3) and [AgI(XPhos)]2, we show how well-defined Ag(I) complexes can operate in conjunction with palladium complexes to achieve C-H functionalization even at ambient temperature. Reactions are tested against the standard cross-coupling of C6F5H with 4-iodotoluene, catalyzed by palladium acetate at 60 °C in the presence of silver carbonate and Xphos. Key observations are that (a) PdI(C6H5)(XPhos) reacts stoichiometrically with Ag(C6F5)(XPhos) to form Ph-C6F5 instantly at room temperature; (b) catalytic cross coupling can be achieved using 5% Ag(C6F5)(XPhos) as the sole silver source; and (c) palladium acetate (typical precatalyst) can be replaced for catalytic cross coupling by the expected oxidative addition compound PdI(C6H5)(XPhos). These investigations lead to a catalytic cycle in which Ag(I) plays the C-H bond activation role and palladium plays the coupling role. Moreover, we show how the phosphine can be exchanged between silver complexes, ensuring that it is recycled even though silver carbonate is consumed during catalytic cross-coupling

Broad Spectrum Enantioselective Amide Bond Synthetase from Streptoalloteichus hindustanus

The synthesis of amide bonds is one of the most frequently performed reactions in pharmaceutical synthesis, but the requirement for stoichiometric quantities of coupling agents and activated substrates in established methods has prompted interest in biocatalytic alternatives. Amide Bond Synthetases (ABSs) actively catalyze both the ATP-dependent adenylation of carboxylic acid substrates and their subsequent amidation using an amine nucleophile, both within the active site of the enzyme, enabling the use of only a small excess of the amine partner. We have assessed the ability of an ABS from Streptoalloteichus hindustanus (ShABS) to couple a range of carboxylic acid substrates and amines to form amine products. ShABS displayed superior activity to a previously studied ABS, McbA, and a remarkable complementary substrate specificity that included the enantioselective formation of a library of amides from racemic acid and amine coupling partners. The X-ray crystallographic structure of ShABS has permitted mutational mapping of the carboxylic acid and amine binding sites, revealing key roles for L207 and F246 in determining the enantioselectivity of the enzyme with respect to chiral acid and amine substrates. ShABS was applied to the synthesis of pharmaceutical amides, including ilepcimide, lazabemide, trimethobenzamide, and cinepazide, the last with 99% conversion and 95% isolated yield. These findings provide a blueprint for enabling a contemporary pharmaceutical synthesis of one of the most significant classes of small molecule drugs using biocatalysis

Reactivity of a Dinuclear PdIComplex [Pd2(μ-PPh2)(μ2-OAc)(PPh3)2] with PPh3 : Implications for Cross-Coupling Catalysis Using the Ubiquitous Pd(OAc)2/nPPh3Catalyst System

[PdI2(μ-PPh2)(μ2-OAc)(PPh3)2] is the reduction product of PdII(OAc)2(PPh3)2, generated by reaction of ‘Pd(OAc)2’ with two equivalents of PPh3. Here, we report that the reaction of [PdI2(μ-PPh2)(μ2-OAc)(PPh3)2] with PPh3results in a nuanced disproportionation reaction, forming [Pd0(PPh3)3] and a phosphinito-bridged PdI-dinuclear complex, namely [PdI2(μ-PPh2){κ2-P,O-μ-P(O)Ph2}(κ-PPh3)2]. The latter complex is proposed to form by abstraction of an oxygen atom from an acetate ligand at Pd. A mechanism for the formal reduction of a putative PdIIdisproportionation species to the observed PdIcomplex is postulated. Upon reaction of the mixture of [Pd0(PPh)3] and [PdI2(μ-PPh2){κ2-P,O-μ-P(O)Ph2}(κ-PPh3)2] with 2-bromopyridine, the former Pd0complex undergoes a fast oxidative addition reaction, while the latter dinuclear PdIcomplex converts slowly to a tripalladium cluster, of the type [Pd3(μ-X)(μ-PPh2)2(PPh3)3]X, with an overall 4/3 oxidation stateperPd. Our findings reveal complexity associated with the precatalyst activation step for the ubiquitous ‘Pd(OAc)2’/nPPh3catalyst system, with implications for cross-coupling catalysis

Revealing the Hidden Complexity and Reactivity of Palladacyclic Precatalysts:The P(o-tolyl)3 Ligand Enables a Cocktail of Active Species Utilizing the Pd(II)/Pd(IV) and Pd(0)/Pd(II) Pathways for Efficient Catalysis

The ligand, P(o-tolyl)3, is ubiquitous in applied synthetic chemistry and catalysis, particularly in Pd-catalyzed processes, which typically include Pd(OAc)2 (most commonly used as Pd3(OAc)6) as a precatalyst. The Herrmann-Beller palladacycle [Pd(C^P)(μ2-OAc)]2 (where C^P = monocyclopalladated P(o-tolyl)3) is easily formed from reaction of Pd(OAc)2 with P(o-tolyl)3. The mechanisms by which this precatalyst system operates are inherently complex, with studies previously implicating Pd nanoparticles (PdNPs) as reservoirs for active Pd(0) species in arylative cross-coupling reactions. In this study, we reveal the fascinating, complex, and nontrivial behavior of the palladacyclic group. First, in the presence of hydroxide base, [Pd(C^P)(μ2-OAc)]2 is readily converted into an activated form, [Pd(C^P)(μ2-OH)]2, which serves as a conduit for activation to catalytically relevant species. Second, palladacyclization imparts unique stability for catalytic species under reaction conditions, bringing into play a Pd(II)/Pd(IV) cross-coupling mechanism. For a benchmark Suzuki-Miyaura cross-coupling (SMCC) reaction, there is a shift from a mononuclear Pd catalytic pathway to a PdNP-controlled catalytic pathway during the reaction. The activation pathway of [Pd(C^P)(μ2-OH)]2 has been studied using an arylphosphine-stabilized boronic acid and low-temperature NMR spectroscopic analysis, which sheds light on the preactivation step, with water and/or acid being critical for the formation of active Pd(0) and Pd(II) species. In situ reaction monitoring has demonstrated that there is a sensitivity to the structure of the arylboron species in the presence of pinacol. This work, taken together, highlights the mechanistic complexity accompanying the use of palladacyclic precatalyst systems. It builds on recent findings involving related Pd(OAc)2/PPh3 precatalyst systems which readily form higher order Pdn clusters and PdNPs under cross-coupling reaction conditions. Thus, generally, one needs to be cautious with the assumption that Pd(OAc)2/tertiary phosphine mixtures cleanly deliver mononuclear “Pd(0)Ln” species and that any assessment of individual phosphine ligands may need to be taken on a case-by-case basis

Mechanically Robust Hybrid Gel Beads Loaded with “Naked” Palladium Nanoparticles as Efficient, Reusable, and Sustainable Catalysts for the Suzuki–Miyaura Reaction

The increase in demand for Pd and its low abundance pose a significant threat to its future availability, rendering research into more sustainable Pd-based technologies essential. Herein, we report Pd scavenging mechanically robust hybrid gel beads composed of agarose, a polymer gelator (PG), and an active low-molecular-weight gelator (LMWG) based on 1,3:2,4-dibenzylidenesorbitol (DBS), DBS-CONHNH2. The robustness of the PG and the ability of the LMWG to reduce Pd(II) in situ to generate naked Pd(0) nanoparticles (PdNPs) combine within these gel beads to give them potential as practical catalysts for Suzuki–Miyaura cross-coupling reactions. The optimized gel beads demonstrate good reusability, green metrics, and most importantly the ability to sustain stirring, improving reaction times and energy consumption compared to previous examples. In contrast to previous reports, the leaching of palladium from these next-generation beads is almost completely eliminated. Additionally, for the first time, a detailed investigation of these Pd-loaded gel beads explains precisely how the nanoparticles are formed in situ without a stabilizing ligand. Further, detailed catalytic investigations demonstrate that catalysis occurs within the gel beads. Hence, these beads can essentially be considered as robust “nonligated” heterogeneous PdNP catalysts. Given the challenges in developing ligand-free, naked Pd nanoparticles as stable catalysts, these gel beads may have future potential for the development of easily used systems to perform chemical reactions in “kit” form

Understanding Precatalyst Activation and Speciation in Manganese-Catalyzed C-H Bond Functionalization Reactions

An investigation into species formed following precatalyst activation in Mn-catalyzed C-H bond functionalization reactions is reported. Time-resolved infrared spectroscopy demonstrates that light-induced CO dissociation from precatalysts [Mn(C^N)(CO)4] (C^N = cyclometalated 2-phenylpyridine (1a), cyclometalated 1,1-bis(4-methoxyphenyl)methanimine (1b)) in a toluene solution of 2-phenylpyridine (2a) or 1,1-bis(4-methoxyphenyl)methanimine (2b) results in the initial formation of solvent complexes fac-[Mn(C^N)(CO)3(toluene)]. Subsequent solvent substitution on a nanosecond time scale then yields fac-[Mn(C^N)(CO)3(κ1-(N)-2a)] and fac-[Mn(C^N)(CO)3(κ1-(N)-2b)], respectively. When the experiments are performed in the presence of phenylacetylene, the initial formation of fac-[Mn(C^N)(CO)3(toluene)] is followed by a competitive substitution reaction to give fac-[Mn(C^N)(CO)3(2)] and fac-[Mn(C^N)(CO)3(η2-PhC2H)]. The fate of the reaction mixture depends on the nature of the nitrogen-containing substrate used. In the case of 2-phenylpyridine, migratory insertion of the alkyne into the Mn-C bond occurs, and fac-[Mn(C^N)(CO)3(κ1-(N)-2a)] remains unchanged. In contrast, when 2b is used, substitution of the η2-bound phenylacetylene by 2b occurs on a microsecond time scale, and fac-[Mn(C^N)(CO)3(κ1-(N)-2b)] is the sole product from the reaction. Calculations with density functional theory indicate that this difference in behavior may be correlated with the different affinities of 2a and 2b for the manganese. This study therefore demonstrates that speciation immediately following precatalyst activation is a kinetically controlled event. The most dominant species in the reaction mixture (the solvent) initially binds to the metal. The subsequent substitution of the metal-bound solvent is also kinetically controlled (on a ns time scale) prior to the thermodynamic distribution of products being obtained

A comprehensive understanding of carbon-carbon bond formation by alkyne migratory insertion into manganacycles

Migratory insertion (MI) is one of the most important processes underpinning the transition metal-catalysed formation of C-C and C-X bonds. In this work, a comprehensive model of MI is presented, based on the direct observation of the states involved in the coupling of alkynes with cyclometallated ligands, augmented with insight from computational chemistry. Time-resolved spectroscopy demonstrates that photolysis of complexes [Mn(C^N)(CO)4] (C^N = cyclometalated ligand) results in ultra-fast dissociation of a CO ligand. Performing the experiment in a toluene solution of an alkyne results in the initial formation of a solvent complex fac-[Mn(C^N)(toluene)(CO)3]. Solvent substitution gives an η2-alkyne complex fac-[Mn(C^N)(η2-R1C2R2)(CO)3] which undergoes MI of the unsaturated ligand into the Mn-C bond. These data allowed for the dependence of second order rate constants for solvent substitution and first order rate constants for C-C bond formation to be determined. A systematic investigation into the influence of the alkyne and C^N ligand on this process is reported. The experimental data enabled the development of a computational model for the MI reaction which demonstrated that a synergic interaction between the metal and the nascent C-C bond controls both the rate and regiochemical outcome of the reaction. The time-resolved spectroscopic method enabled the observation of a multi-step reaction occurring over 8 orders of magnitude in time, including the formation of solvent complexes, ligand substitution and two sequential C-C bond formation steps