Pioneering studies by Kuivila, published more than 50 years ago, suggested ipso protonation of the boronate as the mechanism for base-catalyzed protodeboronation of arylboronic acids. However, the study was limited to UV spectrophotometric analysis under acidic conditions, and the aqueous association constants (Ka) were estimated. By means of NMR, stopped-flow IR, and quenched-flow techniques, the kinetics of base-catalyzed protodeboronation of 30 different arylboronic acids has now been determined at pH > 13 in aqueous dioxane at 70 °C. Included in the study are all 20 isomers of C6HnF(5–n)B(OH)2 with half-lives spanning 9 orders of magnitude: <3 ms to 6.5 months. In combination with pH–rate profiles, pKa and ΔS⧧ values, kinetic isotope effects (2H, 10B, 13C), linear free-energy relationships, and density functional theory calculations, we have identified a mechanistic regime involving unimolecular heterolysis of the boronate competing with concerted ipso protonation/C–B cleavage. The relative Lewis acidities of arylboronic acids do not correlate with their protodeboronation rates, especially when ortho substituents are present. Notably, 3,5-dinitrophenylboronic acid is orders of magnitude more stable than tetra- and pentafluorophenylboronic acids but has a similar pKa.

We report a new pure-shift method, termed SHARPER (Sensitive, Homogeneous, And Resolved PEaks in Real time) designed for the analysis of reactions and equilibria by NMR. By focusing on a single selected signal, SHARPER removes all heteronuclear couplings of a selected nucleus without the need to pulse on X channels, thus overcoming hardware limitations of conventional spectrometers. A more versatile decoupling scheme, termed sel-SHARPER, removes all heteronuclear and homonuclear couplings of the selected signal. Both methods are characterized by a periodic inversion of the active spin during the real-time acquisition. In addition to decoupling, they also compensate for pulse imperfections and magnetic field inhomogeneity, generating an extremely narrow singlet with a linewidth approaching limits dictated by the spin–spin relaxation. The decoupling and line narrowing effected by (sel)-SHARPER provide significant increases in the signal-to-noise (S/N) ratio. Increases of 20-fold were routinely achieved for 19F detection. sel-SHARPER is also applicable to first- and higher-order 1H spectra. The sensitivity gains are substantially greater for inhomogeneous magnetic fields, including dynamic inhomogeneity caused by gas sparging. The parameters of the pulse sequences have been analyzed in detail to provide guidelines for their most effective application. The considerable reduction in the detection threshold induced by (sel)-SHARPER make the technique particularly suited for in situ monitoring of reaction kinetics. The approach is illustrated by a 19F NMR study of the protodeboronation of an aryl boronic acid. Here, the high S/N allowed reliable determination of the net protodeoboronation kinetics, and the excess line broadening of 19F singlets was utilized to characterize the boronic acid/boronate equilibrium kinetics. Oxidation of diphenylphosphine, monitored by 31P NMR under optimized gas-flow conditions, demonstrated the high tolerance of SHARPER to dynamic inhomogeneity. The principles of the (sel)-SHARPER sequences are expected to find numerous applications in the design of new NMR experiments.

A mechanistic study of the isothiourea-catalyzed enantioselective [2,3]-rearrangement of allylic ammonium ylides is described. Reaction kinetic analyses using 19F NMR and density functional theory computations have elucidated a reaction profile and allowed identification of the catalyst resting state and turnover-rate limiting step. A catalytically relevant catalyst–substrate adduct has been observed, and its constitution elucidated unambiguously by 13C and 15N isotopic labeling. Isotopic entrainment has shown the observed catalyst–substrate adduct to be a genuine intermediate on the productive cycle toward catalysis. The influence of HOBt as an additive upon the reaction, catalyst resting state, and turnover-rate limiting step has been examined. Crossover experiments have probed the reversibility of each of the proposed steps of the catalytic cycle. Computations were also used to elucidate the origins of stereocontrol, with a 1,5-S···O interaction and the catalyst stereodirecting group providing transition structure rigidification and enantioselectivity, while preference for cation−π interactions over C–H···π is responsible for diastereoselectivity.

A concise formal synthesis of racemic allocolchicine has been developed, centred on three principal transformations: a retro-Brook alkylation reaction to generate an arylsilane, a gold-catalysed arylative cyclisation to generate the B-ring via biaryl linkage, and a palladium-catalysed carbonylation of an aryl chloride to generate an ester. 1H NMR monitoring of the key gold-catalysed cyclisation step reveals that a powerful catalyst deactivation process progressively attenuates the rate of catalyst turnover. The origins of the catalyst deactivation have been investigated, with an uncatalysed side-reaction, involving the substrate and the iodine(III) oxidant, identified as the source of a potent catalyst poison. The side reaction generates 1–4% of a diaryliodonium salt, and whilst this moiety is shown not to be an innate catalyst deactivator, when it is tethered to the arylsilane reactant, the inhibition becomes powerful. Kinetic modelling of processes run at two different catalyst concentrations allows extraction of the partitioning of the gold catalyst between the substrate and its diaryliodonium salt, with a rate of diaryliodonium salt generation consistent with that independently determined in the absence of catalyst. The high partition ratio between substrate and diaryliodonium salt (5/1) results in very efficient, and ultimately complete, diversion of the catalyst off-cycle.

The intramolecular gold-catalyzed arylation of arenes by aryl-trimethylsilanes has been investigated from both mechanistic and preparative aspects. The reaction generates 5- to 9-membered rings, and of the 44 examples studied, 10 include a heteroatom (N, O). Tethering of the arene to the arylsilane provides not only a tool to probe the impact of the conformational flexibility of Ar–Au–Ar intermediates, via systematic modulation of the length of aryl–aryl linkage, but also the ability to arylate neutral and electron-poor arenes—substrates that do not react at all in the intermolecular process. Rendering the arylation intramolecular also results in phenomenologically simpler reaction kinetics, and overall these features have facilitated a detailed study of linear free energy relationships, kinetic isotope effects, and the first quantitative experimental data on the effects of aryl electron demand and conformational freedom on the rate of reductive elimination from diaryl-gold(III) species. The turnover-limiting step for the formation of a series of fluorene derivatives is sensitive to the reactivity of the arene and changes from reductive elimination to π-complexation for arenes bearing strongly electron-withdrawing substituents (σ > 0.43). Reductive elimination is accelerated by electron-donating substituents (ρ = −2.0) on one or both rings, with the individual σ-values being additive in nature. Longer and more flexible tethers between the two aryl rings result in faster reductive elimination from Ar–Au(X)–Ar and lead to the π-complexation of the arene by Ar–AuX2 becoming the turnover-limiting step.

pH–rate profiles for aqueous–organic protodeboronation of 18 boronic acids, many widely viewed as unstable, have been studied by NMR and DFT. Rates were pH-dependent, and varied substantially between the boronic acids, with rate maxima that varied over 6 orders of magnitude. A mechanistic model containing five general pathways (k1–k5) has been developed, and together with input of [B]tot, KW, Ka, and KaH, the protodeboronation kinetics can be correlated as a function of pH (1–13) for all 18 species. Cyclopropyl and vinyl boronic acids undergo very slow protodeboronation, as do 3- and 4-pyridyl boronic acids (t0.5 > 1 week, pH 12, 70 °C). In contrast, 2-pyridyl and 5-thiazolyl boronic acids undergo rapid protodeboronation (t0.5 ≈ 25–50 s, pH 7, 70 °C), via fragmentation of zwitterionic intermediates. Lewis acid additives (e.g., Cu, Zn salts) can attenuate (2-pyridyl) or accelerate (5-thiazolyl and 5-pyrazolyl) fragmentation. Two additional processes compete when the boronic acid and the boronate are present in sufficient proportions (pH = pKa ± 1.6): (i) self-/autocatalysis and (ii) sequential disproportionations of boronic acid to borinic acid and borane.

Under optimised conditions, the Trost modular ligand (TML) series induces high levels of asymmetric induction in an extraordinarily wide range of reactions involving palladium π-allyl intermediates. Prior mechanistic investigations into reactions involving Pd-η3-C6H9 intermediates have focussed on the monomeric 13-membered ring formed via P,P-chelation of the ligand to Pd. However, it is also recognised that ring-opening oligomerisation provides a pool of high nuclearity Pd-η3-C6H9 species that, by affording a low level, or even the opposite sense, of asymmetric induction relative to the mononuclear species, are responsible for a reduction in selectivity under non-optimised conditions. Herein we describe an investigation by NMR spectroscopy, molecular mechanics, molecular dynamics, and small-angle neutron scattering (SANS), of a Pd-η3-C6H9 cation bearing the 1,2-diaminocyclohexane TML ligand (2). Using both nondeuterated and perdeuterated (D47) isotopologues of the resulting complexes ([1]+), we show that a two-stage oligomerisation-aggregation process forms self assembled cylindrical aggregates of very high nuclearity (up to 56 Pd centres). We also investigate how concentration, solvent and counter-anion all modulate the extent of oligomerisation.

Suzuki–Miyaura (SM) cross-coupling is arguably the most widely-applied transition metal catalysed carbon–carbon bond forming reaction to date. Its success originates from a combination of exceptionally mild and functional group tolerant reaction conditions, with a relatively stable, readily prepared and generally environmentally benign organoboron reagent. A variety of such reagents have been developed for the process, with properties that have been tailored for application under specific SM coupling conditions. This review analyses the seven main classes of boron reagent that have been developed. The general physical and chemical properties of each class of reagent are evaluated with special emphasis on the currently understood mechanisms of transmetalation. The methods to prepare each reagent are outlined, followed by example applications in SM coupling.

A detailed catalytic, stoichiometric, and mechanistic study on the dehydrocoupling of H3B·NMe2H and dehydropolymerization of H3B·NMeH2 using the [Rh(Xantphos)]+ fragment is reported. At 0.2 mol % catalyst loadings, dehydrocoupling produces dimeric [H2B−NMe2]2 and poly(methylaminoborane) (Mn = 22 700 g mol–1, PDI = 2.1), respectively. The stoichiometric and catalytic kinetic data obtained suggest that similar mechanisms operate for both substrates, in which a key feature is an induction period that generates the active catalyst, proposed to be a Rh–amido–borane, that reversibly binds additional amine–borane so that saturation kinetics (Michaelis–Menten type steady-state approximation) operate during catalysis. B–N bond formation (with H3B·NMeH2) or elimination of amino–borane (with H3B·NMe2H) follows, in which N–H activation is proposed to be turnover limiting (KIE = 2.1 ± 0.2), with suggested mechanisms that only differ in that B–N bond formation (and the resulting propagation of a polymer chain) is favored for H3B·NMeH2 but not H3B·NMe2H. Importantly, for the dehydropolymerization of H3B·NMeH2, polymer formation follows a chain growth process from the metal (relatively high degrees of polymerization at low conversions, increased catalyst loadings lead to lower-molecular-weight polymer), which is not living, and control of polymer molecular weight can be also achieved by using H2 (Mn = 2 800 g mol–1, PDI = 1.8) or THF solvent (Mn = 52 200 g mol–1, PDI = 1.4). Hydrogen is suggested to act as a chain transfer agent in a similar way to the polymerization of ethene, leading to low-molecular-weight polymer, while THF acts to attenuate chain transfer and accordingly longer polymer chains are formed. In situ studies on the likely active species present data that support a Rh–amido–borane intermediate as the active catalyst. An alternative Rh(III) hydrido–boryl complex, which has been independently synthesized and structurally characterized, is discounted as an intermediate by kinetic studies. A mechanism for dehydropolymerization is suggested in which the putative amido–borane species dehydrogenates an additional H3B·NMeH2 to form the “real monomer” amino–borane H2B═NMeH that undergoes insertion into the Rh—amido bond to propagate the growing polymer chain from the metal. Such a process is directly analogous to the chain growth mechanism for single-site olefin polymerization.

The mechanism of gold-catalyzed coupling of arenes with aryltrimethylsilanes has been investigated, employing an improved precatalyst (thtAuBr3) to facilitate kinetic analysis. In combination with linear free-energy relationships, kinetic isotope effects, and stoichiometric experiments, the data support a mechanism involving an Au(I)/Au(III) redox cycle in which sequential electrophilic aromatic substitution of the arylsilane and the arene by Au(III) precedes product-forming reductive elimination and subsequent cycle-closing reoxidation of the metal. Despite the fundamental mechanistic similarities between the two auration events, high selectivity is observed for heterocoupling (C–Si then C–H auration) over homocoupling of either the arylsilane or the arene (C–Si then C–Si, or C–H then C–H auration); this chemoselectivity originates from differences in the product-determining elementary steps of each electrophilic substitution. The turnover-limiting step of the reaction involves associative substitution en route to an arene π-complex. The ramifications of this insight for implementation of the methodology are discussed.

Suzuki–Miyaura (SM) cross-coupling is arguably the most widely-applied transition metal catalysed carbon–carbon bond forming reaction to date. Its success originates from a combination of exceptionally mild and functional group tolerant reaction conditions, with a relatively stable, readily prepared and generally environmentally benign organoboron reagent. A variety of such reagents have been developed for the process, with properties that have been tailored for application under specific SM coupling conditions. This review analyses the seven main classes of boron reagent that have been developed. The general physical and chemical properties of each class of reagent are evaluated with special emphasis on the currently understood mechanisms of transmetalation. The methods to prepare each reagent are outlined, followed by example applications in SM coupling.

Under optimised conditions, the Trost modular ligand (TML) series induces high levels of asymmetric induction in an extraordinarily wide range of reactions involving palladium π-allyl intermediates. Prior mechanistic investigations into reactions involving Pd-η3-C6H9 intermediates have focussed on the monomeric 13-membered ring formed via P,P-chelation of the ligand to Pd. However, it is also recognised that ring-opening oligomerisation provides a pool of high nuclearity Pd-η3-C6H9 species that, by affording a low level, or even the opposite sense, of asymmetric induction relative to the mononuclear species, are responsible for a reduction in selectivity under non-optimised conditions. Herein we describe an investigation by NMR spectroscopy, molecular mechanics, molecular dynamics, and small-angle neutron scattering (SANS), of a Pd-η3-C6H9 cation bearing the 1,2-diaminocyclohexane TML ligand (2). Using both nondeuterated and perdeuterated (D47) isotopologues of the resulting complexes ([1]+), we show that a two-stage oligomerisation-aggregation process forms self assembled cylindrical aggregates of very high nuclearity (up to 56 Pd centres). We also investigate how concentration, solvent and counter-anion all modulate the extent of oligomerisation.