Turnover-limiting Step Research Articles

N-Heterocyclic Carbene-Catalyzed Synthesis of Ynones via C–H Alkynylation of Aldehydes with Alkynyliodonium Salts—Evidence for Alkynyl Transfer via Direct Substitution at Acetylenic Carbon

Alkynylation of aldehydes with alkynyl(aryl)iodonium salts catalyzed by an N-heterocyclic carbene (NHC) has been developed. The application of the organocatalyst and the hypervalent iodine group transfer reagent allowed for metal-free C–H functionalization and C–C bond formation. The reaction proceeds under mild conditions, at −40 °C and in the presence of an amine base, providing access to an array of heteroaryl-propargyl ketones containing various substituents in good to excellent yields. The mechanism of the reaction was investigated by means of both experiments and density functional theory calculations. 13C-labeling and computations determined that the key alkynyl transfer step occurs via an unusual direct substitution at an acetylenic carbon, wherein an iodine-based leaving group is exchanged by a Breslow intermediate nucleophile. Moreover, kinetic studies revealed that the turnover-limiting step of the catalytic cycle is the generation of the Breslow intermediate, whereas the subsequent C–C bond fo...

Cross-Coupling of Aryl Trifluoromethyl Sulfones with Arylboronates by Cooperative Palladium/Rhodium Catalysis.

The Suzuki-Miyaura arylation of aryl trifluoromethyl sulfones via C-SO2 bond cleavage has been developed by means of cooperative palladium/rhodium catalysis. A series of aryl trifluoromethyl sulfones and arylboronic acid neopentylglycol esters are converted to the corresponding biaryls. Mechanistic investigations suggest that (1) the rhodium catalyst mediates the transfer of the aryl ring from arylboronate to palladium, resulting in the acceleration of the transmetalation step, and (2) the C-C bond-forming reductive elimination step is the turnover-limiting step.

Mechanism of Ni-Catalyzed Reductive 1,2-Dicarbofunctionalization of Alkenes.

Ni-catalyzed cross-electrophile coupling reactions have emerged as appealing methods to construct organic molecules without the use of stoichiometric organometallic reagents. The mechanisms are complex: plausible pathways, such as "radical chain" and "sequential reduction" mechanisms, are dependent on the sequence of the activation of electrophiles. A combination of kinetic, spectroscopic, and organometallic studies reveals that a Ni-catalyzed, reductive 1,2-dicarbofunctionalization of alkenes proceeds through a "sequential reduction" pathway. The reduction of Ni by Zn is the turnover-limiting step, consistent with Ni(II) intermediates as the catalyst resting-state. Zn is only sufficient to reduce (phen)Ni(II) to a Ni(I) species. As a result, commonly proposed Ni(0) intermediates are absent under these conditions. (Phen)Ni(I)-Br selectively activates aryl bromides via two-electron oxidation addition, whereas alkyl bromides are activated by (phen)Ni(I)-Ar through single-electron activation to afford radicals. These findings could provide insight into achieving selectivity between different electrophiles.

Suzuki-Miyaura Coupling of (Hetero)Aryl Sulfones: Complementary Reactivity Enables Iterative Polyaryl Synthesis.

Ideal organic syntheses involve the rapid construction of C-C bonds, with minimal use of functional group interconversions. The Suzuki-Miyaura cross-coupling (SMC) is a powerful way to form biaryl linkages, but the relatively similar reactivity of electrophilic partners makes iterative syntheses involving more than two sequential coupling events difficult to achieve without additional manipulations. Here we introduce (hetero)aryl sulfones as electrophilic coupling partners for the SMC reaction, which display an intermediate reactivity between those of typical aryl (pseudo)halides and nitroarenes. The new complementary reactivity allows for rapid sequential cross-coupling of arenes bearing chloride, sulfone and nitro leaving groups, affording non-symmetric ter- and quateraryls in only 2 or 3 steps, respectively. The SMC reactivity of (hetero)aryl sulfones is demonstrated in over 30 examples. Mechanistic experiments and DFT calculations are consistent with oxidative addition into the sulfone C-S bond as the turnover-limiting step. The further development of electrophilic cross-coupling partners with complementary reactivity may open new possibilities for divergent iterative synthesis starting from small pools of polyfunctionalized arenes.

Base-free Enantioselective C(1)-Ammonium Enolate Catalysis Exploiting Aryloxides: A Synthetic and Mechanistic Study.

An isothiourea-catalyzed enantioselective Michael addition of aryl ester pronucleophiles to vinyl bis-sulfones via C(1)-ammonium enolate intermediates has been developed. This operationally simple method allows the base-free functionalization of aryl esters to form α-functionalized products containing two contiguous tertiary stereogenic centres in excellent yield and stereoselectivity (all ≥99:1 er). Key to the success of this methodology is the multifunctional role of the aryloxide, which operates as a leaving group, Brønsted base, Brønsted acid and Lewis base within the catalytic cycle. Comprehensive mechanistic studies, including variable time normalization analysis (VTNA) and isotopologue competition experiments, have been carried out. These studies have identified (i) orders of all reactants; (ii) a turnover-limiting Michael addition step, (iii) product inhibition, (iv) the catalyst resting state and (v) catalyst deactivation through protonation.

In search of alkene-diazene cross metathesis

Aside from alkene cross metathesis, involving two different alkene units, cross metathesis reactions of two functionally different unsaturated units - heterofunctional cross metathesis - are virtually unknown. We report here on our efforts to realize alkene-diazene cross metathesis to produce imines. The proven alkene-metathesis catalyst (Cy3P)2Cl2Ru = CHPh (1) reacts with aryl diazenes at room temperature to produce imines derived from coupling of the alkylidene unit of 1 with the nitrene fragment of the diazene. Attempts to induce catalytic alkene-diazene cross metathesis by 1 or (NHC)(PCy3)Cl2Ru = CHR (NHC = N-heterocyclic carbene, 2) result only in the transfer of the alkylidene unit from 1 without reaction of the alkene. 1H- and 31P NMR monitoring and other characterizational probes are consistent with the formation of an unreactive imido- or aza-metallacycle intermediate. DFT computational modeling of a potential catalytic pathway for diazene-alkene metathesis with (PMe3)2Cl2RuCH2 (4) has revealed viable intermediates and transition states, involving metal-carbene, metal-nitrene (imido) and derived azametallacyclobutanes. The turnover-limiting steps are calculated to occur during combination of the intermediate imido-complex (PMe3)2Cl2Ru = NMe (4) with alkene via a transition state for retrocyclization of an aza-ruthenacyclobutane (J) with a large energetic span of 47.8 kcal/mol. Modeling of the same reaction step with the experimental complex 1 reacting with PhN = NPh and PhCH = CHPh finds an even larger energetic span, accounting for the experimentally observed stoichiometric production of imine PhCH = NPh. In contrast, the corresponding energy profile for alkene-diazene metathesis promoted by phosphite-carbene complex [(MeO)3P]2Cl2RuCH2 (5) finds a much lower energetic span of 26.4 kcal/mol for conversion of imido complex G′ to imine via the aza-ruthenacyclobutane (J′) and that the turnover-limiting step would involve retrocyclization of the first stage diaza-metallacyclobutane C′ with an energetic span of 29.7 kcal/mol.

Regioselective Single-Electron Tsuji-Trost Reaction of Allylic Alcohols: A Photoredox/Nickel Dual Catalytic Approach.

A radical-mediated functionalization of allyl alcohol derived partners with a variety of alkyl 1,4-dihydropyridines via photoredox/nickel dual catalysis is described. This transformation transpires with high linear and E-selectivity, avoiding the requirement of harsh conditions (e.g., strong base, elevated temperature). Additionally, using aryl sulfinate salts as radical precursors, allyl sulfones can also be obtained. Kinetic isotope effect experiments implicated oxidative addition of the nickel catalyst to the allylic electrophile as the turnover-limiting step, supporting previous computational studies.

Pd-Catalyzed Carbonylation of Acyl Azides.

Pd-catalyzed reactions of azides with CO to access an isocynate intermediate have been developed extensively in recent years. However, the catalytic carbonylation of sensitive acyl azides has not been reported. Herein, we report a simple Pd-catalyzed carbonylation reaction of acyl azides with broad substrate scope, high efficiency, and simple operation under mild conditions, which provides facile access to acyl ureas. In addition, a mechanistic study was carried out by both experiment and DFT calculation. Control experiments and kinetic study revealed that the real active palladium species were Pd(0). The result of kinetic study suggested that palladium catalyst, azide, and CO were all involved in the turnover-limiting step except for amine. Further DFT study suggested that an unprecedented five-membered palladacycle intermediate was the key intermediate in the carbonylation reaction.

Operando Spectroscopic and Kinetic Characterization of Aerobic Allylic C-H Acetoxylation Catalyzed by Pd(OAc)2/4,5-Diazafluoren-9-one.

Allylic C-H acetoxylations are among the most widely studied palladium(II)-catalyzed C-H oxidation reactions. While the principal reaction steps are well established, key features of the catalytic mechanisms are poorly characterized, including the identity of the turnover-limiting step and the catalyst resting state. Here, we report a mechanistic study of aerobic allylic acetoxylation of allylbenzene with a catalyst system composed of Pd(OAc)2 and 4,5-diazafluoren-9-one (DAF). The DAF ligand is unique in its ability to support aerobic catalytic turnover, even in the absence of benzoquinone or other co-catalysts. Herein, we describe operando spectroscopic analysis of the catalytic reaction using X-ray absorption and NMR spectroscopic methods that allow direct observation of the formation and decay of a palladium(I) species during the reaction. Kinetic studies reveal the presence of two distinct kinetic phases: (1) a burst phase, involving rapid formation of the allylic acetoxylation product and formation of the dimeric PdI complex [PdI(DAF)(OAc)]2, followed by (2) a post-burst phase that coincides with evolution of the catalyst resting state from the PdI dimer into a π-allyl-PdII species. The data provide unprecedented insights into the role of ancillary ligands in supporting catalytic turnover with O2 as the stoichiometric oxidant and establish an important foundation for the development of improved catalysts for allylic oxidation reactions.

Rhodium-Catalyzed 1,1-Hydroacylation of Thioacyl Carbenes with Alkynyl Aldehydes and Subsequent Cyclization.

A rhodium-catalyzed 1,1-hydroacylation of thioacyl carbenes with alkynyl and alkenyl aldehydes and subsequent 6- endo-trig/dig cyclization are realized, giving structurally diverse 4 H-thiopyran-4-ones and 2,3-dihydro-4 H-thiopyran-4-ones in moderate to good yields. The oxidative addition of Rh(I) to aldehydes is proposed to be the turnover-limiting step. Manipulations of estrones demonstrate the applications of our formal (3 + 3) transannulations in the structural modifications of natural products.

Pd-Catalyzed C-N Coupling Reactions Facilitated by Organic Bases: Mechanistic Investigation Leads to Enhanced Reactivity in the Arylation of Weakly Binding Amines.

The ability to use soluble organic amine bases in Pd-catalyzed C-N cross-coupling reactions has provided a long-awaited solution to the many issues associated with employing traditional, heterogeneous reaction conditions. However, little is known about the precise function of these bases in the catalytic cycle and about the effect of variations in base structure on catalyst reactivity. We used 19F NMR to analyze the kinetic behavior of C-N coupling reactions facilitated by different organic bases. In the case of aniline coupling reactions employing DBU, the resting state was a DBU-bound oxidative addition complex, LPd(DBU)(Ar)X, and the reaction was found to be inhibited by base. In general, however, depending on the binding properties of the chosen organic base, increased concentration of the base can have a positive or negative influence on the reaction rate. Furthermore, the electronic nature of the aryl triflate employed in the reaction directly affects the reaction rate. The fastest reaction rates were observed with electronically neutral aryl triflates, while the slowest were observed with highly electron-rich and -deficient substrates. We propose a model in which the turnover-limiting step of the catalytic cycle depends on the relative nucleophilicity of the base compared to that of the amine. This hypothesis guided the discovery of new reaction conditions for the coupling of weakly binding amines, including secondary aryl amines, which were unreactive nucleophiles in our original protocol.

Investigation of a Weak Temperature-Rate Relationship in the Carbamoylation of a Barbituric Acid Pharmaceutical Intermediate.

The rate of reaction between N, N'-dicyclohexylbarbituric acid 1 and ethyl 2-isocyanatoacetate 2 is invariant with temperature. Positive orders in each reactant and dissociation of triethylammonium salts of 1 and product 3 at elevated temperature indicate that reaction occurs via a catalytic mechanism where changes to the positions of equilibria negate changes in the rate of the turnover-limiting step. A model for the consumption of 1 in a flow reactor accurately predicted the outcome of a laboratory-scale multivariate study.

Diarylborinic Acid-Catalyzed, Site-Selective Sulfation of Carbohydrate Derivatives.

Sulfated carbohydrates have been implicated in diverse biological processes, with the position and extent of sulfation of a glycoside often playing important roles in determining the affinity and specificity of its binding to a biomolecular partner. Methods for the site-selective introduction of sulfate groups to carbohydrates are thus of interest. Here, we describe the development of a diarylborinic acid-catalyzed protocol for selective sulfation of pyranoside derivatives at the equatorial position of a cis-1,2-diol group. This method, which employs the sulfur trioxide-trimethylamine complex as the electrophile, has been employed for installation of a sulfate group at the 3-position of a range of galacto- and mannopyranosides, including substrates having a free primary OH group. By using a full equivalent of the diarylborinic acid, selective syntheses of more complex monosulfated glycosides, namely, a 3'-sulfolactose derivative and 3'-sulfo-β-galactosylceramide, have been accomplished. Preliminary kinetics experiments suggested that the catalyst resting state is a tetracoordinate diarylborinic ester that reacts with the SO3 complex in the turnover-limiting step. Catalyst inhibition by the pyranoside sulfate product and trialkylamine byproduct of the reaction was demonstrated.

Ta-Catalyzed Hydroaminoalkylation of Alkenes: Insights into Ligand-Modified Reactivity Using DFT

Density functional theory (DFT) calculations were performed to probe the mechanism of tantalum-catalyzed hydroaminoalkylation, a reaction that affords Csp3–Csp3 bond formation via α-alkylation of a secondary amine with an alkene. Electronic effects in catalyst design were probed to reveal key features in the energy profile of the proposed mechanism, corroborating experimental trends in which electrophilic metal centers demonstrate enhanced reactivity. Modeling of the energy profile with an N,O-chelating amidate Ta catalyst (I) revealed profound differences in relative energetics, rationalizing improvements that have been observed using sterically and electronically varied ligands. N,O-Chelating ligands electronically promote preferential reactivity in the equatorial plane. The turnover-limiting step can be completely changed depending upon the ligand; for sterically bulky monoamidate complexes, the protonolysis of an intermediate metallacycle is the turnover-limiting step rather than C–H activation, as ha...

Arylation/Intramolecular Conjugate Addition of 1,6-Enynes Enabled by Manganese(I)-Catalyzed C-H Bond Activation.

An arylation/intramolecular conjugate addition of cyclohexadienone-containing 1,6-enynes has been established through initiation by manganese(I)-catalyzed C-H bond activation. This tandem reaction involved unusual E/ Z-isomerized alkenyl-Mn intermediates and proceeded smoothly with high chemoselectivities and perfect atom economy. The cyclization products could be further transformed to various structures. Mechanistic studies suggested that cleavage of the C-H bond was involved in the turnover-limiting step, and a manganese carbene anion intermediate was proposed to explain such an E/ Z isomerization process.

Mechanistic Study of a Re-Catalyzed Monoalkylation of Phenols

A mechanistic study of a rhenium catalyzed monoalkylation of phenols is described. Reaction kinetics reveals a zero-order dependence on both alkene and phenol and a half order dependence on catalyst. Isotopic labeling studies, competition experiments, kinetic isotope effects, and Hammett analysis together afford experimental data consistent with a reversible C–H activation step and an irreversible hydrometalation process. The turnover-limiting step is identified as catalyst deaggregation. NMR studies of binary mixtures of catalyst and a single substrate (alkene or phenol) as well as those of reaction mixtures identify potential intermediates and off-cycle species. Despite the numerous Re complexes formed in these mixtures, the overall reaction is both high yielding and highly selective for monoalkylation of phenols.

Electrochemical and Kinetic Insights into Molecular Water Oxidation Catalysts Derived from Cp*Ir(pyridine-alkoxide) Complexes.

We report the solution‐phase electrochemistry of seven half‐sandwich iridium(III) complexes with varying pyridine‐alkoxide ligands to quantify electronic ligand effects that translate to their activity in catalytic water oxidation. Our results unify some previously reported electrochemical data of Cp*Ir complexes by showing how the solution speciation determines the electrochemical response: cationic complexes show over 1 V higher redox potentials that their neutral forms in a distinct demonstration of charge accumulation effects relevant to water oxidation. Building on previous work that analysed the activation behaviour of our pyalk‐ligated Cp*Ir complexes 1–7, we assess their catalytic oxygen evolution activity with sodium periodate (NaIO4) and ceric ammonium nitrate (CAN) in water and aqueous tBuOH solution. Mechanistic studies including H/D kinetic isotope effects and reaction progress kinetic analysis (RPKA) of oxygen evolution point to a dimer‐monomer equilibrium of the IrIV resting state preceding a proton‐coupled electron transfer (PCET) in the turnover‐limiting step (TLS). Finally, true electrochemically driven water oxidation is demonstrated for all catalysts, revealing surprising trends in activity that do not correlate with those obtained using chemical oxidants.

Discovery of a Photoinduced Dark Catalytic Cycle Using in Situ LED-NMR Spectroscopy.

We report the use of LED-NMR spectroscopy to study the reaction mechanism of a newly discovered photoinduced iron-catalyzed cycloisomerization of alkynols to cyclic enol ethers. By understanding on/off ligand binding to the catalyst, we were able to appropriately design reaction conditions to balance catalyst activity and stability. LED-NMR was demonstrated to be a powerful toolin elucidating reaction mechanisms of photochemical reactions. Temporal NMR spectroscopic data under visible light illumination (1) revealed the pre-catalyst activation mechanism, (2) proved that photon flux provides a unique external control of the equilibrium distribution between the pre-catalyst and active catalyst, and ultimately the rate of reaction, (3) provided information about the reaction driving forces and the turnover-limiting step, and (4) enabled both real-time structural and kinetic insights into elusive species (e.g., dissolved gases).

Hydrogen Transfer Catalysis beyond the Primary Coordination Sphere

In this Perspective, we outline recent examples of homogeneous transition-metal hydrogen transfer catalysts for which functionality within the complex’s outer coordination sphere influences the outcome of a reaction. Secondary-sphere groups are often applied to hydrogen transfer reactions, but their specific role during catalysis is not always well-understood. New experimental and theoretical work details the complexity associated with predicting secondary-sphere interactions and therefore designing improved catalysts. This Perspective highlights examples of catalysts containing secondary-sphere groups that (1) accelerate a key turnover-limiting step such as H2 heterolysis or hydride transfer, (2) limit competing catalytic cycles, (3) prevent catalyst decomposition, and/or (4) provide access to new catalysts through postmetalation modifications. The examples described herein emphasize numerous roles of the secondary sphere in hydrogen transfer catalysis and illustrate how the optimal use of these interact...

Supported Au Nanoparticles with N-Heterocyclic Carbene Ligands as Active and Stable Heterogeneous Catalysts for Lactonization

Attachment of N-heterocyclic carbenes (NHCs) on the surface of metal nanoparticle (NP) catalysts permits fine-tuning of catalytic activity and product selectivity. Yet, NHC-coated Au NPs have been seldom used in catalysis beyond hydrogenation chemistry. One challenge in this field has been to develop a platform that permits arbitrary ligand modification without having to compromise NP stability toward aggregation or leaching. Herein, we exploit the strategy of supported dendrimer-encapsulated metal clusters (DEMCs) to achieve aggregation-stable yet active heterogeneous Au NP catalysts with NHC ligands. Dendrimers function as aggregation-inhibitors during the NP synthesis, and NHCs, well-known for their strong attachment to the gold surface, provide a handle to modify the stereochemistry, stereoelectronics, and chemical functionality of the NP surface. Indeed, compared to "ligandless" Au NPs which are virtually inactive below 80 °C, the NHC-ligated Au NP catalysts enable a model lactonization reaction to proceed at 20 °C on the same time scale (hours). Based on Eyring analysis, proto-deauration is the turnover-limiting step accelerated by the NHC ligands. Furthermore, the use of chiral NHCs led to asymmetric induction (up to 16% enantiomeric excess) in the lactonization transformations, which demonstrates the potential of supported DEMCs with ancillary ligands in enantioselective catalysis.