Simple Parameters and Data Processing for Better Signal-to-Noise and Temporal Resolution in 1D NMR Reaction Monitoring.

1D NMR spectroscopic reaction monitoring allows detailed investigation of chemical kinetics and mechanism. Concentration versus time data are derived from a time series of NMR spectra. Each spectrum in the series is obtained by Fourier transform of the corresponding FID.

Kinetics and Mechanism of PPh/Ni-Catalyzed, Zn-Mediated, Aryl Chloride Homocoupling: Antagonistic Effects of ZnCl/Cl.

The Ni/PPh-catalyzed homocoupling of aryl chlorides in DMF using Zn as the stochiometric reducing agent is one of a general class of Ni-catalyzed processes, where the mechanism has been a matter of long-standing debate. This study re-evaluates prior conclusions and insights. NMR spectroscopy is used to identify [(PPh)Ni(Ar)Cl] as a key intermediate and to explore the indirect roles of using Zn as the reductant.

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 (CpTiS, CpTiSCMe, CpTi(SAr), CpTiCl(SAr)) to sulfenyl chlorides (SCl, 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, a sequence of two S-S bond-forming steps ( , ). The archetypical polysulfides CpTiS (1a) and CpTiSC(Me) (2a) react with disulfur dichloride (SCl) through rate-limiting intermolecular S-S bond formation ( ) followed by a rapid intramolecular cyclization ( , with ≫ [RSCl]).

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.

Mechanistic Basis of the Cu(OAc) 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.

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

Tetra--butylammonium difluorotriphenylsilicate (TBAT) is a conveniently handled anhydrous fluoride source, commonly used as a surrogate for tetra--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.

-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.

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

As reported by Zhao, the TBAT ([PhSiF][BuN])-initiated reaction of ethyl salicylate with TMSCF in THF generates α,α-difluoro-3-coumaranones via the corresponding -silylated ethoxy ketals. The mechanism has been investigated by in situ F and Si NMR spectroscopy, CF-trapping, competition, titration, and comparison of the kinetics with the 3-, 4-, 5-, and 6-fluoro ethyl salicylate analogues and their -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.

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 and stopped-flow H/F NMR spectroscopy, kinetics, isotopic labeling, H DOSY, and electronic structure calculations, we have investigated azole-catalyzed aminolysis of -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.

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

Since its discovery in mid-20 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.

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 Pd is not affected by the addition of HCl, palladium oxide in nanoparticles readily reacts with HCl to form the ionic species [PdCl], 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 ArNi(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 LED-F 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)SiH], [RBr]) independently control the product selectivity, but not the rate. A major resting state of nickel has been identified as ArNi(L)Br, and C-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.

Studies of Arylboronic Acids/Esters and RSiCF Reagents: Kinetics, Speciation, and Dysfunction at the Carbanion-Ate Interface.

Reagent instability reduces the efficiency of chemical processes, and while much effort is devoted to reaction optimization, less attention is paid to the mechanistic causes of reagent decomposition. Indeed, the response is often to simply use an excess of the reagent. Two reaction classes with ubiquitous examples of this are the Suzuki-Miyaura cross-coupling of boronic acids/esters and the transfer of CF or CF from the Ruppert-Prakash reagent, TMSCF.

Mechanistic analysis by NMR spectroscopy: A users guide.

A 'principles and practice' tutorial-style review of the application of solution-phase NMR in the analysis of the mechanisms of homogeneous organic and organometallic reactions and processes. This review of 345 references summarises why solution-phase NMR spectroscopy is uniquely effective in such studies, allowing non-destructive, quantitative analysis of a wide range of nuclei common to organic and organometallic reactions, providing exquisite structural detail, and using instrumentation that is routinely available in most chemistry research facilities. The review is in two parts.

Inverse Isotope Effects in Single-Crystal to Single-Crystal Reactivity and the Isolation of a Rhodium Cyclooctane σ-Alkane Complex.

The sequential solid/gas single-crystal to single-crystal reaction of [Rh(CyP(CH)PCy)(COD)][BAr ] (COD = cyclooctadiene) with H or D was followed in situ by solid-state P{H} NMR spectroscopy (SSNMR) and ex situ by solution quenching and GC-MS. This was quantified using a two-step Johnson-Mehl-Avrami-Kologoromov (JMAK) model that revealed an inverse isotope effect for the second addition of H, that forms a σ-alkane complex [Rh(CyP(CH)PCy)(COA)][BAr ]. Using D, a temporal window is determined in which a structural solution for this σ-alkane complex is possible, which reveals an η,η-binding mode to the Rh(I) center, as supported by periodic density functional theory (DFT) calculations.

Asymmetric Azidation under Hydrogen Bonding Phase-Transfer Catalysis: A Combined Experimental and Computational Study.

Asymmetric catalytic azidation has increased in importance to access enantioenriched nitrogen containing molecules, but methods that employ inexpensive sodium azide remain scarce. This encouraged us to undertake a detailed study on the application of hydrogen bonding phase-transfer catalysis (HB-PTC) to enantioselective azidation with sodium azide. So far, this phase-transfer manifold has been applied exclusively to insoluble metal alkali fluorides for carbon-fluorine bond formation.

A Lewis Base Nucleofugality Parameter, , and Its Application in an Analysis of MIDA-Boronate Hydrolysis Kinetics.

The kinetics of quinuclidine displacement of BH from a wide range of Lewis base borane adducts have been measured. Parameterization of these rates has enabled the development of a nucleofugality scale (), shown to quantify and predict the leaving group ability of a range of other Lewis bases. Additivity observed across a number of series R'RX (X = P, N; R' = aryl, alkyl) has allowed the formulation of related substituent parameters (, ), providing a means of calculating values for a range of Lewis bases that extends far beyond those experimentally derived.

Heavy-Atom Kinetic Isotope Effects: Primary Interest or Zero Point?

Chemists have many options for elucidating reaction mechanisms. Global kinetic analysis and classic transition-state probes (e.g.

Controlled Synthesis of Well-Defined Polyaminoboranes on Scale Using a Robust and Efficient Catalyst.

The air tolerant precatalyst, [Rh(L)(NBD)]Cl () [L = κ-(PrPCHCH)NH, NBD = norbornadiene], mediates the selective synthesis of -methylpolyaminoborane, (HBNMeH), by dehydropolymerization of HB·NMeH. Kinetic, speciation, and DFT studies show an induction period in which the active catalyst, Rh(L)H (), forms, which sits as an outer-sphere adduct as the resting state. At the end of catalysis, dormant Rh(L)HCl () is formed.

Protodeboronation of (Hetero)Arylboronic Esters: Direct versus Prehydrolytic Pathways and Self-/Auto-Catalysis.

The kinetics and mechanism of the base-catalyzed hydrolysis (ArB(OR) → ArB(OH)) and protodeboronation (ArB(OR) → ArH) of a series of boronic esters, encompassing eight different polyols and 10 polyfluoroaryl and heteroaryl moieties, have been investigated by in situ and stopped-flow NMR spectroscopy (F, H, and B), pH-rate dependence, isotope entrainment, H KIEs, and KS-DFT computations. The study reveals the phenomenological stability of boronic esters under basic aqueous-organic conditions to be highly nuanced. In contrast to common assumption, esterification does not necessarily impart greater stability compared to the corresponding boronic acid.

Rapid Estimation of for Quantitative NMR.

Quantitative NMR spectroscopy (qNMR) is an essential tool in organic chemistry, with applications including reaction monitoring, mechanistic analysis, and purity determination. Establishing the correct acquisition rate for consecutive qNMR scans requires knowledge of the longitudinal relaxation time constants () for all of the nuclei being monitored. We report a simple method that is about 10-fold faster than the conventional inversion recovery technique for the estimation of .

Systematic Evaluation of 1,2-Migratory Aptitude in Alkylidene Carbenes.

Alkylidene carbenes undergo rapid inter- and intramolecular reactions and rearrangements, including 1,2-migrations of β-substituents to generate alkynes. Their propensity for substituent migration exerts profound influence over the broader utility of alkylidene carbene intermediates, yet prior efforts to categorize 1,2-migratory aptitude in these elusive species have been hampered by disparate modes of carbene generation, ultrashort carbene lifetimes, mechanistic ambiguities, and the need to individually prepare a series of C-labeled precursors. Herein we report on the rearrangement of C-alkylidene carbenes generated by the homologation of carbonyl compounds with [C]-Li-TMS-diazomethane, an approach that obviates the need for isotopically labeled substrates and has expedited a systematic investigation (C{H} NMR, DLPNO-CCSD(T)) of migratory aptitudes in an unprecedented range of more than 30 alkylidene carbenes.

Unexpected Nickel Complex Speciation Unlocks Alternative Pathways for the Reactions of Alkyl Halides with dppf-Nickel(0).

The mechanism of the reactions between dppf-Ni complexes and alkyl halides has been investigated using kinetic and mechanistic experiments and DFT calculations. The active species is [Ni(κ-dppf)(κ-dppf)], which undergoes a halide abstraction reaction with alkyl halides and rapidly captures the alkyl radical that is formed. The rates of the reactions of [Ni(COD)(dppf)] with alkyl halides and the yields of prototypical nickel-catalyzed Kumada cross-coupling reactions of alkyl halides are shown to be significantly improved by the addition of free dppf ligand.

Difluorocarbene Generation from TMSCF: Kinetics and Mechanism of NaI-Mediated and Si-Induced Anionic Chain Reactions.

The mechanism of CF transfer from TMSCF (), mediated by TBAT (2-12 mol %) or by NaI (5-20 mol %), has been investigated by in situ/stopped-flow F NMR spectroscopic analysis of the kinetics of alkene difluorocyclopropanation and competing TFE/CF/homologous perfluoroanion generation, C/H KIEs, LFERs, CF transfer efficiency and selectivity, the effect of inhibitors, and density functional theory (DFT) calculations. The reactions evolve with profoundly different kinetics, undergoing autoinhibition (TBAT) or quasi-stochastic autoacceleration (NaI) and cogenerating perfluoroalkene side products. An overarching mechanism involving direct and indirect fluoride transfer from a CF anionoid to TMSCF () has been elucidated.

Kinetics and Mechanism of the Arase-Hoshi RBH-Catalyzed Alkyne Hydroboration: Alkenylboronate Generation via B-H/C-B Metathesis.

The mechanism of RBH-catalyzed hydroboration of alkynes by 1,3,2-dioxaborolanes has been investigated by in situ F NMR spectroscopy, kinetic simulation, isotope entrainment, single-turnover labeling (B/H), and density functional theory (DFT) calculations. For the CyBH-catalyzed hydroboration 4-fluorophenylacetylene by pinacolborane, the resting state is the anti-Markovnikov addition product ArCH = CHBCy. Irreversible and turnover-rate limiting reaction with pinacolborane ( ≈ 7 × 10 M s) regenerates CyBH and releases -Ar-CH═CHBpin.