Kinetics of sulfur-transfer from titanocene (poly)sulfides to sulfenyl chlorides: rapid metal-assisted concerted substitution.

The kinetics of sulfur transfer from titanocene (poly)sulfides (RCp2TiS5, Cp2TiS4CMe2, Cp2Ti(SAr)2, Cp2TiCl(SAr)) to sulfenyl chlorides (S2Cl2, RSCl) have been investigated by a combination of stopped-flow UV-Vis/NMR reaction monitoring, titration assays, numerical kinetic modelling and KS-DFT calculations. The reactions are rapid, proceeding to completion over timescales of milliseconds to minutes, via a sequence of two S-S bond-forming steps (k 1, k 2). The archetypical polysulfides Cp2TiS5 (1a) and Cp2TiS4C(Me2) (2a) react with disulfur dichloride (S2Cl2) through rate-limiting intermolecular S-S bond formation (k 1) followed by a rapid intramolecular cyclization (k 2, with k 2 ≫ k 1 [RSCl]). The monofunctional sulfenyl chlorides (RSCl) studied herein react in two intermolecular S-S bond forming steps proceeding at similar rates (k 1 ≈ k 2). Reactions of titanocene bisthiophenolates, Cp2Ti(SAr)2 (5), with both mono- and di-functional sulfenyl chlorides result in rapid accumulation of the monothiophenolate, Cp2TiCl(SAr) (6) (k 1 > k 2). Across the range of reactants studied, the rates are relatively insensitive to changes in temperature and in the electronics of the sulfenyl chloride, moderately sensitive to the electronics of the titanocene (poly)sulfide (ρ (Ti-(SAr)) ≈ -2.0), and highly sensitive to the solvent polarity, with non-polar solvents (CS2, CCl4) leading to the slowest rates. The combined sensitivities are the result of a concerted, polarized and late transition state for the rate-limiting S-S bond forming step, accompanied by a large entropic penalty. Each substitution step {[Ti]-SR' + Cl-SR → [Ti]-Cl + RS-SR'} proceeds via titanium-assisted Cl-S cleavage to generate a transient pentacoordinate complex, Cl-[Cp2TiX]-S(R')-SR, which then undergoes rapid Ti-S dissociation.

Origins of High-Activity Cage-Catalyzed Michael Addition.

Cage catalysis continues to create significant interest, yet catalyst function remains poorly understood. Herein, we report mechanistic insights into coordination-cage-catalyzed Michael addition using kinetic and computational methods. The study has been enabled by the detection of identifiable catalyst intermediates, which allow the evolution of different cage species to be monitored and modeled alongside reactants and products. The investigations show that the overall acceleration results from two distinct effects. First, the cage reaction shows a thousand-fold increase in the rate constant for the turnover-limiting C-C bond-forming step compared to a reference state. Computational modeling and experimental analysis of activation parameters indicate that this stems from a significant reduction in entropy, suggesting substrate coencapsulation. Second, the cage markedly acidifies the bound pronucleophile, shifting this equilibrium by up to 6 orders of magnitude. The combination of these two factors results in accelerations up to 109 relative to bulk-phase reference reactions. We also show that the catalyst can fundamentally alter the reaction mechanism, leading to intermediates and products that are not observable outside of the cage. Collectively, the results show that cage catalysis can proceed with very high activity and unique selectivity by harnessing a series of individually weak noncovalent interactions.

Mechanistic Basis of the Cu(OAc)2 Catalyzed Azide-Ynamine (3 + 2) Cycloaddition Reaction.

The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is used as a ligation tool throughout chemical and biological sciences. Despite the pervasiveness of CuAAC, there is a need to develop more efficient methods to form 1,4-triazole ligated products with low loadings of Cu. In this paper, we disclose a mechanistic model for the ynamine-azide (3 + 2) cycloadditions catalyzed by copper(II) acetate. Using multinuclear nuclear magnetic resonance spectroscopy, electron paramagnetic resonance spectroscopy, and high-performance liquid chromatography analyses, a dual catalytic cycle is identified. First, the formation of a diyne species via Glaser-Hay coupling of a terminal ynamine forms a Cu(I) species competent to catalyze an ynamine-azide (3 + 2) cycloaddition. Second, the benzimidazole unit of the ynamine structure has multiple roles: assisting C-H activation, Cu coordination, and the formation of a postreaction resting state Cu complex after completion of the (3 + 2) cycloaddition. Finally, reactivation of the Cu resting state complex is shown by the addition of isotopically labeled ynamine and azide substrates to form a labeled 1,4-triazole product. This work provides a mechanistic basis for the use of mixed valency binuclear catalytic Cu species in conjunction with Cu-coordinating alkynes to afford superior reactivity in CuAAC reactions. Additionally, these data show how the CuAAC reaction kinetics can be modulated by changes to the alkyne substrate, which then has a predictable effect on the reaction mechanism.

Speciation and kinetics of fluoride transfer from tetra-n-butylammonium difluorotriphenylsilicate ('TBAT').

Tetra-n-butylammonium difluorotriphenylsilicate (TBAT) is a conveniently handled anhydrous fluoride source, commonly used as a surrogate for tetra-n-butylammonium fluoride (TBAF). While prior studies indicate that TBAT reacts rapidly with fluoride acceptors, little is known about the mechanism(s) of fluoride transfer. We report on the interrogation of the kinetics of three processes in which fluoride is transferred from TBAT, in THF and in MeCN, using a variety of NMR methods, including chemical exchange saturation transfer, magnetisation transfer, diffusion analysis, and 1D NOESY. These studies reveal ion-pairing between the tetra-n-butylammonium and difluorotriphenylsilicate moieties, and a very low but detectable degree of fluoride dissociation, which then undergoes further equilibria and/or induces decomposition, depending on the conditions. Degenerate exchange between TBAT and fluorotriphenylsilane (FTPS) is very rapid in THF, inherently increases in rate over time, and is profoundly sensitive to the presence of water. Addition of 2,6-di-tert-butylpyridine and 3 Å molecular sieves stabilises the exchange rate, and both dissociative and direct fluoride transfer are shown to proceed in parallel under these conditions. Degenerate exchange between TBAT and 2-naphthalenyl fluorosulfate (ARSF) is not detected at the NMR timescale in THF, and is slow in MeCN. For the latter, the exchange is near-fully inhibited by exogenous FTPS, indicating a predominantly dissociative character to this exchange process. Fluorination of benzyl bromide (BzBr) with TBAT in MeCN-d3 exhibits moderate progressive autoinhibition, and the initial rate of the reaction is supressed by the presence of exogenous FTPS. Overall, TBAT can act as a genuine surrogate for TBAF, as well as a reservoir for rapidly-reversible release of traces of it, with the relative contribution of the pathways depending, inter alia, on the identity of the fluoride acceptor, the solvent, and the concentration of endogenous or exogenous FTPS.

TMSCF3-Mediated Conversion of Salicylates into α,α-Difluoro-3-coumaranones: Chain Kinetics, Anion-Speciation, and Mechanism.

As reported by Zhao, the TBAT ([Ph3SiF2]-[Bu4N]+)-initiated reaction of ethyl salicylate with TMSCF3 in THF generates α,α-difluoro-3-coumaranones via the corresponding O-silylated ethoxy ketals. The mechanism has been investigated by in situ 19F and 29Si NMR spectroscopy, CF2-trapping, competition, titration, and comparison of the kinetics with the 3-, 4-, 5-, and 6-fluoro ethyl salicylate analogues and their O-silylated derivatives. The process evolves in five distinct stages, each arising from a discrete array of anion speciations that modulate a sequence of silyl-transfer chain reactions. The deconvolution of coupled equilibria between salicylate, [CF3]-, and siliconate [Me3Si(CF3)2]- anions allowed the development of a kinetic model that accounts for the first three stages. The model provides valuable practical insights. For example, it explains how the initial concentrations of the TMSCF3 and salicylate and the location of electron-withdrawing salicylate ring substituents profoundly impact the overall viability of the process, how stoichiometric CF3H generation can be bypassed by using the O-silylated salicylate, and how the very slow liberation of the α,α-difluoro-3-coumaranone can be rapidly accelerated by evaporative or aqueous workup.

Exo-cage catalysis and initiation derived from photo-activating host-guest encapsulation.

Coordination cage catalysis has commonly relied on the endogenous binding of substrates, exploiting the cavity microenvironment and spatial constraints to engender increased reactivity or interesting selectivity. Nonetheless, there are issues with this approach, such as the frequent occurrence of product inhibition or the limited applicability to a wide range of substrates and reactions. Here we describe a strategy in which the cage acts as an exogenous catalyst, wherein reactants, intermediates and products remain unbound throughout the course of the catalytic cycle. Instead, the cage is used to alter the properties of a cofactor guest, which then transfers reactivity to the bulk-phase. We have exemplified this approach using photocatalysis, showing that a photoactivated host-guest complex can mediate [4 + 2] cycloadditions and the aza-Henry reaction. Detailed in situ photolysis experiments show that the cage can both act as a photo-initiator and as an on-cycle catalyst where the quantum yield is less than unity.

Kinetics and Mechanism of Azole n-π*-Catalyzed Amine Acylation.

Azole anions are highly competent in the activation of weak acyl donors, but, unlike neutral (aprotic) Lewis bases, are not yet widely applied as acylation catalysts. Using a combination of in situ and stopped-flow 1H/19F NMR spectroscopy, kinetics, isotopic labeling, 1H DOSY, and electronic structure calculations, we have investigated azole-catalyzed aminolysis of p-fluorophenyl acetate. The global kinetics have been elucidated under four sets of conditions, and the key elementary steps underpinning catalysis deconvoluted using a range of intermediates and transition state probes. While all evidence points to an overarching mechanism involving n-π* catalysis via N-acylated azole intermediates, a diverse array of kinetic regimes emerges from this framework. Even seemingly minor changes to the solvent, auxiliary base, or azole catalyst can elicit profound changes in the temporal evolution, thermal sensitivity, and progressive inhibition of catalysis. These observations can only be rationalized by taking a holistic view of the mechanism and a set of limiting regimes for the kinetics. Overall, the analysis of 18 azole catalysts spanning nearly 10 orders of magnitude in acidity highlights the pitfall of pursuing ever more nucleophilic catalysts without regard for catalyst speciation.

SHARPER-DOSY: Sensitivity enhanced diffusion-ordered NMR spectroscopy.

Since its discovery in mid-20th century, the sensitivity of Nuclear Magnetic Resonance (NMR) has increased steadily, in part due to the design of new, sophisticated NMR experiments. Here we report on a liquid-state NMR methodology that significantly increases the sensitivity of diffusion coefficient measurements of pure compounds, allowing to estimate their sizes using a much reduced amount of material. In this method, the diffusion coefficients are being measured by analysing narrow and intense singlets, which are invariant to magnetic field inhomogeneities. The singlets are obtained through signal acquisition embedded in short (<0.5 ms) spin-echo intervals separated by non-selective 180° or 90° pulses, suppressing the chemical shift evolution of resonances and their splitting due to J couplings. The achieved 10-100 sensitivity enhancement results in a 100-10000-fold time saving. Using high field cryoprobe NMR spectrometers, this makes it possible to measure a diffusion coefficient of a medium-size organic molecule in a matter of minutes with as little as a few hundred nanograms of material.

Direct Observation of Palladium Leaching from Pd/C by a Simple Method: X-ray Absorption Spectroscopy of Heterogeneous Mixtures.

Herein, we show the detailed behavior of palladium leaching from palladium on charcoal by aqueous HCl, directly observed by X-ray absorption spectroscopy measurement employing a simplified reaction setup. While Pd0 is not affected by the addition of HCl, palladium oxide in nanoparticles readily reacts with HCl to form the ionic species [PdIICl4]2-, even though these ions mostly remain adsorbed on the surface of activated charcoal and can only be detected at a low level in the solution phase. This finding provides a new aspect for control of the leaching behavior and robust usage of palladium on charcoal in organic reactions.

Kinetics of a Ni/Ir-Photocatalyzed Coupling of ArBr with RBr: Intermediacy of ArNiII(L)Br and Rate/Selectivity Factors.

The Ni/Ir-photocatalyzed coupling of an aryl bromide (ArBr) with an alkyl bromide (RBr) has been analyzed using in situ LED-19F NMR spectroscopy. Four components (light, [ArBr], [Ni], [Ir]) are found to control the rate of ArBr consumption, but not the product selectivity, while two components ([(TMS)3SiH], [RBr]) independently control the product selectivity, but not the rate. A major resting state of nickel has been identified as ArNiII(L)Br, and 13C-isotopic entrainment is used to show that the complex undergoes Ir-photocatalyzed conversion to products (Ar-R, Ar-H, Ar-solvent) in competition with the release of ArBr. A range of competing absorption and quenching effects lead to complex correlations between the Ir and Ni catalyst loadings and the reaction rate. Differences in the Ir/Ni Beer-Lambert absorption profiles allow the rate to be increased by the use of a shorter-wavelength light source without compromising the selectivity. A minimal kinetic model for the process allows simulation of the reaction and provides insights for optimization of these processes in the laboratory.