300 research outputs found
TMSCF<sub>3</sub>-Mediated Conversion of Salicylates into α,α-Difluoro-3-coumaranones: Chain Kinetics, Anion-Speciation, and Mechanism
SHARPER reaction monitoring: generation of a narrow linewidth NMR singlet, without X-pulses, in an inhomogeneous magnetic field
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 <i>sel</i>-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 spinâspin
relaxation. The decoupling and line narrowing effected by (<i>sel</i>)-SHARPER provide significant increases in the signal-to-noise
(S/N) ratio. Increases of 20-fold were routinely achieved for <sup>19</sup>F detection. <i>sel</i>-SHARPER is also applicable
to first- and higher-order <sup>1</sup>H 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 (<i>sel</i>)-SHARPER
make the technique particularly suited for <i>in situ</i> monitoring of reaction kinetics. The approach is illustrated by
a <sup>19</sup>F 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 <sup>19</sup>F singlets was utilized to characterize the boronic acid/boronate
equilibrium kinetics. Oxidation of diphenylphosphine, monitored by <sup>31</sup>P NMR under optimized gas-flow conditions, demonstrated the
high tolerance of SHARPER to dynamic inhomogeneity. The principles
of the (<i>sel</i>)-SHARPER sequences are expected to find
numerous applications in the design of new NMR experiments
Kinetics of a Ni/Ir-Photocatalyzed Coupling of ArBr with RBr: Intermediacy of ArNi<sup>II</sup>(L)Br and Rate/Selectivity Factors
[Image: see text] The Ni/Ir-photocatalyzed coupling of an aryl bromide (ArBr) with an alkyl bromide (RBr) has been analyzed using in situ LED-(19)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)(3)SiH], [RBr]) independently control the product selectivity, but not the rate. A major resting state of nickel has been identified as ArNi(II)(L)Br, and (13)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. 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 BeerâLambert 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
Formal Synthesis of (±)-Allocolchicine Via Gold-Catalysed Direct Arylation: Implication of Aryl Iodine(III) Oxidant in Catalyst Deactivation Pathways
Abstract
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 1â4% 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.
Graphical Abstract
</jats:sec
<i>In Situ </i>Studies of Arylboronic Acids/Esters and R<sub>3</sub>SiCF<sub>3</sub> Reagents: Kinetics, Speciation, and Dysfunction at the CarbanionâAte Interface
[Image: see text] 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 SuzukiâMiyaura cross-coupling of boronic acids/esters and the transfer of CF(3) or CF(2) from the RuppertâPrakash reagent, TMSCF(3). This Account describes some of the overarching features of our mechanistic investigations into their decomposition. In the first section we summarize how specific examples of (hetero)arylboronic acids can decompose via aqueous protodeboronation processes: ArâB(OH)(2) + H(2)O â ArH + B(OH)(3). Key to the analysis was the development of a kinetic model in which pH controls boron speciation and heterocycle protonation states. This method revealed six different protodeboronation pathways, including self-catalysis when the pH is close to the pK(a) of the boronic acid, and protodeboronation via a transient aryl anionoid pathway for highly electron-deficient arenes. The degree of âprotectionâ of boronic acids by diol-esterification is shown to be very dependent on the diol identity, with six-membered ring esters resulting in faster protodeboronation than the parent boronic acid. In the second section of the Account we describe (19)F NMR spectroscopic analysis of the kinetics of the reaction of TMSCF(3) with ketones, fluoroarenes, and alkenes. Processes initiated by substoichiometric âTBATâ ([Ph(3)SiF(2)][Bu(4)N]) involve anionic chain reactions in which low concentrations of [CF(3)](â) are rapidly and reversibly liberated from a siliconate reservoir, [TMS(CF(3))(2)][Bu(4)N]. Increased TMSCF(3) concentrations reduce the [CF(3)](â) concentration and thus inhibit the rates of CF(3) transfer. Computation and kinetics reveal that the TMSCF(3) intermolecularly abstracts fluoride from [CF(3)](â) to generate the CF(2), in what would otherwise be an endergonic α-fluoride elimination. Starting from [CF(3)](â) and CF(2), a cascade involving perfluoroalkene homologation results in the generation of a hindered perfluorocarbanion, [C(11)F(23)](â), and inhibition. The generation of CF(2) from TMSCF(3) is much more efficiently mediated by NaI, and in contrast to TBAT, the process undergoes autoacceleration. The process involves NaI-mediated α-fluoride elimination from [CF(3)][Na] to generate CF(2) and a [NaI·NaF] chain carrier. Chain-branching, by [(CF(2))(3)I][Na] generated in situ (CF(2) + TFE + NaI), causes autoacceleration. Alkenes that efficiently capture CF(2) attenuate the chain-branching, suppress autoacceleration, and lead to less rapid difluorocyclopropanation. The Account also highlights how a collaborative approach to experiment and computation enables mechanistic insight for control of processes
Taming Ambident Triazole Anions: Regioselective Ion-Pairing Catalyzes Direct N-Alkylation with Atypical Regioselectivity
Controlling the regioselectivity
of ambident nucleophiles toward
alkylating agents is a fundamental problem in heterocyclic chemistry.
Unsubstituted triazoles are particularly challenging, often requiring
inefficient stepwise protectionâdeprotection strategies and
prefunctionalization protocols. Herein we report on the alkylation
of archetypal ambident 1,2,4-triazole, 1,2,3-triazole, and their anions,
analyzed by in situ <sup>1</sup>H/<sup>19</sup>F NMR, kinetic modeling,
diffusion-ordered NMR spectroscopy, X-ray crystallography, highly
correlated coupled-cluster computations [CCSDÂ(T)-F12, DF-LCCSDÂ(T)-F12,
DLPNO-CCSDÂ(T)], and Marcus theory. The resulting mechanistic insights
allow design of an organocatalytic methodology for ambident control
in the <i>direct</i> N-alkylation of unsubstituted triazole
anions. Amidinium and guanidinium receptors are shown to act as strongly
coordinating phase-transfer organocatalysts, shuttling triazolate
anions into solution. The intimate ion pairs formed in solution retain
the reactivity of liberated triazole anions but, by virtue of highly
regioselective ion pairing, exhibit alkylation selectivities that
are completely inverted (1,2,4-triazole) or substantially enhanced
(1,2,3-triazole) compared to the parent anions. The methodology allows
direct access to 4-alkyl-1,2,4-triazoles (<i>rr</i> up to
94:6) and 1-alkyl-1,2,3-triazoles (<i>rr</i> up to 99:1)
in one step. Regioselective ion pairing acts in effect as a noncovalent
in situ protection mechanism, a concept that may have broader application
in the control of ambident systems
Au-Catalyzed Oxidative Arylation: Chelation-Induced Turnover of ortho-Substituted Arylsilanes
<i>ortho</i>-Substituted aryl silanes have previously
been found to undergo much slower Au-catalyzed intermolecular arylation
than their <i>m,p</i>-substituted isomers, with many examples
failing to undergo turnover at all. A method to indirectly quantify
the rates of CâSi auration of <i>o</i>-substituted
aryl silanes, under conditions of turnover, has been developed. All
examples are found to undergo very efficient CâSi auration,
indicative that it is the subsequent CâH auration that is inhibited
by the <i>ortho</i> substituent. A simple ArâAu conformational
model suggests that CâH auration can be accelerated by chelation.
A series of <i>ortho</i>-functionalized aryl silanes are
shown to undergo efficient arylation
Direct Observation of Palladium Leaching from Pd/C by a Simple Method: X-ray Absorption Spectroscopy of Heterogeneous Mixtures
- âŠ