Several formal heteroborylative cyclization reactions have been recently reported, but little physical–organic and mechanistic data are known. We now investigate the catalyst-free formal thioboration reaction of alkynes to gain mechanistic insight into B-chlorocatecholborane (ClBcat) in its new role as an alkynophilic Lewis acid in electrophilic cyclization/dealkylation reactions. In kinetic studies, the reaction is second-order globally and first-order with respect to both the 2-alkynylthioanisole substrate and the ClBcat electrophile, with activation parameters of ΔG‡ = 27.1 ± 0.1 kcal mol–1 at 90 °C, ΔH‡ = 13.8 ± 1.0 kcal mol–1, and ΔS‡ = −37 ± 3 cal mol–1 K–1, measured over the range 70–90 °C. Carbon kinetic isotope effects supported a rate-determining AdE3 mechanism wherein alkyne activation by neutral ClBcat is concerted with cyclative attack by nucleophilic sulfur. A Hammett study found a ρ+ of −1.7, suggesting cationic charge buildup during the cyclization and supporting rate-determining concerted cyclization. Studies of the reaction with tris(pentafluorophenyl)borane (B(C6F5)3), an activating agent capable of cyclization but not dealkylation, resulted in the isolation of a postcyclization zwitterionic intermediate. Kinetic studies via UV–vis spectroscopy with this boron reagent found second-order kinetics, supporting the likely relevancy of intermediates in this system to the ClBcat system. Computational studies comparing ClBcat with BCl3 as an activating agent showed why BCl3, in contrast to ClBcat, failed to mediate the complete the cyclization/demethylation reaction sequence by itself. Overall, the results support a mechanism in which the ClBcat reagent serves a bifunctional role by sequentially activating the alkyne, despite being less electrophilic than other known alkyne-activating reagents and then providing chloride for post-rate-determining demethylation/neutralization of the resulting zwitterionic intermediate.

AbstractMultiple active individual molecular ruthenium catalysts have been pinpointed within growing polynorbornene, thereby revealing information on the reaction dynamics and location that is unavailable through traditional ensemble experiments. This is the first single-turnover imaging of a molecular catalyst by fluorescence microscopy and allows detection of individual monomer reactions at an industrially important molecular ruthenium ring-opening metathesis polymerization (ROMP) catalyst under synthetically relevant conditions (e.g. unmodified industrial catalyst, ambient pressure, condensed phase, ca. 0.03 m monomer). These results further establish the key fundamentals of this imaging technique for characterizing the reactivity and location of active molecular catalysts even when they are the minor components.

The sensitivity provided by fluorescence microscopy enabled the observation of surface intermediates in the synthesis of soluble organozinc reagents by direct insertion of alkyl iodides to commercial zinc powder. Five hypotheses were examined for the mechanistic role of lithium chloride in enabling this direct insertion. The data are consistent with lithium chloride solubilizing organozinc reagents from the surface of the zinc after oxidative addition.

A catalyst-free oxyboration reaction of alkynes is developed. The resulting borylated isocoumarins and 2-pyrones are isolated as boronic acids, pinacolboronate esters, or potassium organotrifluoroborate salts, providing a variety of bench-stable organoboron building blocks for downstream functionalization. This method has functional group compatibility, is scalable, and proceeds with readily available materials: B-chlorocatecholborane and methyl esters. Mechanistic studies indicate that the B-chlorocatecholborane acts as a carbophilic Lewis acid toward the alkyne, providing a mechanistically distinct pathway for oxyboration that avoids B–O σ bond formation and enables this catalyst-free route.

Herein we report an oxyboration reaction with activated substrates that employs B–O σ bond additions to C–C π bonds to form borylated isoxazoles, which are potential building blocks for drug discovery. Although this reaction can be effectively catalyzed by gold, it is the first example of uncatalyzed oxyboration of C–C π bonds by B–O σ bonds—and only the second example that is catalyzed. This oxyboration reaction is tolerant of groups incompatible with alternative lithiation/borylation and palladium-catalyzed C–H activation/borylation technologies for the synthesis of borylated isoxazoles.

In the present study, the oxyboration reaction catalyzed by IPrAuTFA in the presence and absence of NaTFA has been examined with kinetic studies, mass spectrometry, and 1H NMR and 11B NMR spectroscopy. Data from monitoring the reactions over the temperature range from 30 to 70 °C, the catalyst range from 1.3 to 7.5 mol %, and the NaTFA additive range from 2.5 to 30 mol % suggests a mechanism that involves rate-determining catalyst generation. Data from additive studies that replaced NaTFA with NaBARF (BARF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) or Bu4NTFA as an alternative additive suggest that catalyst quenching from residual NaCl remaining from a one-pot substrate synthesis/reaction method is the cause of this effect, despite the low solubility of this NaCl byproduct in toluene. Material produced through an alternative, sodium chloride-free substrate synthesis exhibited faster reaction rates, consistent with a change in rate-determining step that depended on the substrate synthesis route.

This communication demonstrates the first catalytic aminoboration of C–C π bonds by B–N σ bonds and its application to the synthesis of 3-borylated indoles. The regiochemistry and broad functional group compatibility of this addition reaction enable substitution patterns that are incompatible with major competing technologies. This aminoboration reaction effects the formation of C–B and C–N bonds in a single step from aminoboronic esters, which are simple starting materials available on the gram scale. This reaction generates synthetically valuable N-heterocyclic organoboron compounds as potential building blocks for drug discovery. The working mechanistic hypothesis involves a bifunctional Lewis acid/base catalysis strategy involving the combination of a carbophilic gold cation and a trifluoroacetate anion that activate the C–C π bond and the B–N σ bond simultaneously.

A supported ruthenium metathesis catalyst misleadingly appears efficient on the basis of ensemble rate data. Nonaveraged single-particle microscopy studies described herein reveal a significant interparticle and intraparticle reactivity heterogeneity and a potential of increasing catalytic efficiency. These SEM, EDS, and optical microscopy studies of ring-opening metathesis polymerization establish a mechanism for this spatial distribution in which most of the molecular ruthenium centers are catalytically inactive. Further, the morphology of the growing polynorbornene arises from its synthesis at individual catalytically active regions. These results suggest an expanded role for single-particle microscopy in detecting spatial reactivity heterogeneity and mechanisms of polymer morphology formation, even in such “large” systems of ∼1015 immobilized molecular complexes, and in employing this detected heterogeneity to identify and implement specific methods for improving catalysts.Keywords: catalysis; microscopy; polymerization; single particle; spatial heterogeneity

Electronic effects in the transmetalation of an aryl group from gold to boron were investigated by NMR spectroscopy. The transmetalation reaction is more facile for increasingly electrophilic boron reagents and is in equilibrium under certain conditions. Observed tetracoordinate boronate compounds suggest a two-step, associative transmetalation reaction mechanism in which the organogold complex first delivers a nucleophilic phenyl group to the empty p orbital of boron. For certain substrates, this tetracoordinate intermediate decomposes to the tricordinate, final transmetallation product, and in others this tricordinate species remains in equilibrium with a tetracoordinate anionic boron compound. Experimental and theoretical investigations into the extension of this transmetalation reaction from a mechanistic step in our previously reported intramolecular gold-catalyzed addition of boron–oxygen σ bonds across alkynes to an intermolecular variant are discussed.

For nearly 70 years, the addition of boron–X σ bonds to carbon–carbon multiple bonds has been employed in the preparation of organoboron reagents. However, the significantly higher strength of boron–oxygen bonds has thus far precluded their activation for addition, preventing a direct route to access a potentially valuable class of oxygen-containing organoboron reagents for divergent synthesis. We herein report the realization of an alkoxyboration reaction, the addition of boron–oxygen σ bonds to alkynes. Functionalized O-heterocyclic boronic acid derivatives are produced using this transformation, which is mild and exhibits broad functional group compatibility. Our results demonstrate activation of this boron–O σ bond using a gold catalysis strategy that is fundamentally different from that used previously for other boron addition reactions.

Double-label crossover, modified substrate, and catalyst comparison experiments in the gold and palladium dual-catalytic rearrangement/cross-coupling of allenoates were performed in order to probe the mechanism of this reaction. The results are consistent with a cooperative catalysis mechanism whereby (1) gold activates the substrate prior to oxidative addition by palladium, (2) gold acts as a carbophilic rather than oxophilic Lewis acid, (3) competing olefin isomerization is avoided, (4) gold participates beyond the first turnover and therefore does not serve simply to generate the active palladium catalyst, and (5) single-electron transfer is not involved. These experiments further demonstrate that the cooperativity of both gold and palladium in the reaction is essential because significantly lower to zero conversion is achieved with either metal alone in comparison studies that examined multiple potential gold, palladium, and silver catalysts and precatalysts. Notably, employment of the optimized cocatalysts, PPh3AuOTf and Pd2dba3, separately (i.e., only Au or only Pd) results in zero conversion to product at all monitored time points compared to quantitative conversion to product when both are present in cocatalytic reactions.Keywords: cooperative catalysis; cross-coupling; crossover; dual catalysis; gold; intermediates; mechanism; palladium

The chemo- and regioselectivity and functional group compatibility in gold and palladium cooperatively catalyzed cross-coupling reactions were determined in the synthesis of lactones; the selectivity in the gold and palladium dual-metal catalysis system was distinct from that available for the same class of substrates in systems with only gold catalysis or only palladium catalysis rather than dual catalysis. The dual-catalytic rearrangement reaction selectively promoted oxidative addition at the C–O bond over the C–Br bond, providing a useful C–Br bond handle for downstream functionalization showcased via Suzuki–Miyaura and Sonogashira coupling reactions. Product classes were expanded from isocoumarins to three previously unpublished ring classes: pyrone, indolepyrone, and furopyrone.

Phase separation polymerization of dicyclopentadiene has been characterized from initiation to bulk material formation for the first time via in operando fluorescence microscopy imaging. The morphology of the precipitated polymers at early reaction stages persists in the bulk polymer after completion of the reaction. Two-fluorophore experiments revealed the mechanistic origin of the “dumbbell” morphology as physical strand aggregation/precipitation rather than chemical attachment and revealed that strand aggregation was slow and irreversible relative to precipitation. These data highlight the complementary information available through the single-particle sensitivity and in operando microscopy nature of this technique.

The single-particle resolution of in operando bright-field optical microscopy revealed that only a small fraction of (salph)Co crystals showed high initial catalytic activity with EO. In addition, each active particle displayed individual loci of reactivity rather than uniform reactivity distributed over the entire particle. Growth kinetics at an individual locus showed stepwise periods of higher and lower activity. This reactivity distribution data and single-locus kinetics data would not be available through a traditional ensemble technique that examined bulk material properties.Keywords: bright-field imaging; epoxide; heterogeneous catalysis; kinetics; microscopy; polymerization; single-crystal; single-particle

A vinyl aziridine activation strategy cocatalyzed by palladium(0) and a gold(I) Lewis acid has been developed. This rearrangement installs a C–C and a C–N bond in one synthetic step to form pyrrolizidine and indolizidine products. Two proposed mechanistic roles for the gold cocatalyst were considered: (1) carbophilic gold catalysis or (2) azaphilic gold catalysis. Mechanistic studies support an azaphilic Lewis acid activation of the aziridine over a carbophilic Lewis acid activation of the alkene.

A new method for the synthesis of stereodefined organogold(I) compounds has been developed using an alkyne hydrozirconation and Zr to Au transmetalation sequence to prepare a series of functionally diverse (E)-alkenylgold(I) compounds that were inaccessible or unreported using other synthetic methods. This facile reaction sequence is complete in 4 h at ambient temperature and can employ commercially available starting materials. As part of this synthetic study, we also discovered an organogold compound that underwent an E to Z isomerization consistent with progression through a novel carbenoid pathway.

Using two transition metals to simultaneously catalyze a reaction can offer distinct opportunities for reactivity and selectivity when compared to using single-metal catalyst systems. Creating dual transition metal catalytic systems is complicated, however, by challenges in predicting compatible reactivities and designing turnover pathways for both metals. In this Account, we describe our development of dual-metal catalysis reactions involving gold and a second transition metal.The unique rearrangement intermediates accessible through gold-only catalysis, which exploits the soft Lewis acidity of Au(I), make gold an attractive partner for dual-metal catalysis reactions. Because of the complexity of achieving simultaneous turnover of two catalysts and predicting compatibilities, our approach has been to first gain a fundamental understanding of the reactivity of the two metals with each other, both in stoichiometric and monocatalyzed reactions. To this end, we have investigated the combined reactivity of organogold compounds with palladium, nickel, and rhodium.We narrate the intricacies of turning over two catalysts simultaneously and thereby illuminate the valuable role of fundamental studies in identifying the optimal conditions to promote desirable two-metal reactivity and compatibility. Transmetalation, redox reactivity, and new mechanisms for dual-metal catalytic turnover were probed from this standpoint. We have applied the knowledge gained through these studies to the development of reactions that are dual-catalyzed by gold and palladium, as well as nickel- and rhodium-catalyzed reactions of organogold compounds. More broadly, these new reactions expand the reactivity available to catalytic organogold intermediates via trapping and functionalization reactions with other transition metals.Our investigations reveal strategies useful for designing dual-metal reactions with gold. First, the versatility of gold as a transmetalation partner suggests that many potential methods may exist to intercept catalytic organogold intermediates with a second transition metal. Second, ligands on both metals should be selected carefully in order to prevent catalyst deactivation. Finally, reactions must be designed such that any oxidative steps involving the second metal outcompete undesired reactions with redox-active organogold compounds. We believe that the application of these principles will allow for the design of a diverse set of dual-catalyzed functionalizations befitting the wide variety of gold-catalyzed transformations already established.

A high-sensitivity and high-resolution single-particle fluorescence microscopy technique differentiated between homogeneous and heterogeneous metathesis polymerization catalysis by imaging the location of the early stages of polymerization. By imaging single polymers and single crystals of Grubbs II, polymerization catalysis was revealed to be solely homogeneous rather than heterogeneous or both.

The subensemble kinetics of a platinum–sulfur covalent chemical reaction at the solution/surface interface of a model industrial catalyst support was examined using single-molecule fluorescence microscopy (SMFM) and was found to exhibit biexponential first-order kinetic behavior. The observed kinetics was a convolution of the observation probability and chemical reaction rate. These results suggest that deconvolution strategies may be broadly important for obtaining accurate chemical reaction kinetics with SMFM.

A new Heck-type reaction accessed the migratory insertion chemistry of palladium from organogold complexes. Observation, isolation, and characterization of a palladium intermediate established the role of gold/palladium transmetalation in this reaction. Recent reports of combining the reactivity of organogold compounds with palladium in organic synthesis generally assume a gold-to-palladium transmetalation step, although this step had not been directly observed in these reactions. The results herein furnish experimental evidence for the mechanisms of reactions mediated or catalyzed by both gold and palladium and reveal a migratory insertion strategy for outcompeting homocoupling pathways.

A powerful fluorescence technique for imaging individual covalent-bond-forming events in diverse chemical reactions is reported. The generality originates from employing the fluorophore as a spectator rather than a chemical reaction partner. This spectator technique was used to image individual ligand exchange reactions between platinum complexes and sulfur in real time. The chemical reactions were imaged on a key industrial catalyst support, a siloxy-modified surface, providing insight about reactivity distribution on these surfaces. Such reactivity distribution information is not available via traditional solution ensemble techniques, which average the properties of billions of molecules, or via AFM measurements, which provide information about the topology of the surface. Using superlocalization techniques, the positions of individual chemical reactions on the surface were localized below the diffraction limit, with a positional accuracy of up to ±11 nm.

A transmetalation reaction between rhodium(III) and sp2- and sp3-hybridized organogold(I) compounds proceeds rapidly at ambient temperature (15 min to 6 h). Mechanistic experiments demonstrate that ligand dissociation on rhodium(III) precedes transmetalation; synthetic applications of the gold/rhodium transmetalation are highlighted by linking rhodium-mediated C−H activation, conjugate addition, and reductive elimination to transmetalation from organogold compounds.

Organogold compounds undergo nickel-catalyzed cross-coupling reactions with aryl and vinyl bromides in high yield under mild conditions. The reaction tolerates both electron-rich and electron-poor organogold complexes, and olefinic bromides undergo cross-coupling with high stereoselectivity. This novel transformation links well-established nickel catalysis with more recent developments in organogold transformations.

Single-molecule fluorescence microscopy provided information about the real-time distribution of chemical reactivity on silicon oxide supports at the solution−surface interface, at a level of detail which would be unavailable from a traditional ensemble technique or from a technique that imaged the static physical properties of the surface. Chemical reactions on the surface were found to be uncorrelated; that is, the chemical reaction of one metal complex did not influence the location of a future chemical reaction of another metal complex.

The relative kinetic basicities of a series of differentially substituted and hybridized neutral organogold compounds were examined through competitive protodeauration experiments and were found to span 2.2 orders of magnitude. The effect of electron-withdrawing and electron-donating substituents on the rate of protodeauration of alkenylgold and arylgold compounds was explored. An acid counterion effect indicated the presence of a gold-mediated substrate preequilibrium before protodemetalation, and hybridization effects and a Hammett correlation with ρ+ = −0.41 indicated the involvement of the C−C π system in the protodeauration of vinylgold, alkynylgold, and arylgold complexes.

A new strategy for gold and palladium dual-catalytic reactivity and turnover, called catalyzed catalysis, enhanced the synthetic usefulness of vinylgold intermediates by providing dual-catalytic carbon−carbon cross-coupling as an alternative to protodemetalation. This protocol enabled the synthesis of substituted butenolides and isocoumarins from allyl esters. Kinetic and spectroscopic experiments support a mechanism in which the Lewis acidic gold complex catalyzes both an initial rearrangement step and a subsequent Lewis basic palladium oxidative-addition step.

A two-fluorophore FRET system provided a more general approach than previously described fluorescence techniques to observing and quantifying organometallic complexes under reaction conditions. Over the concentration range of 3 × 10−7 to 5 × 10−6 M, this method provided quantification with faster time resolution and greater sensitivity than is possible with NMR spectroscopy.

A new palladium-catalyzed syn carboauration of alkynes proceeds in 2 h at ambient temperature with complete regioselectivity. The resulting α-ester vinyl−gold intermediates are resistant to rapid protodemetalation, permitting their participation in new one-pot palladium-and-gold cross-coupling reactions and electrophilic trapping reactions.

The single-molecule fluorescence microscopy imaging of individual palladium(II) complexes is reported and the requisite high-quantum-yield BODIPY fluorophore tags are synthesized and shown to act as spectators when bound to metal complexes. These combined experimental results lay the fundamental groundwork for studying organometallic reaction chemistry at the single-molecule level using fluorophore tags.