Magnetisation transfer NMR spectroscopy in a kinetic and mechanistic study of fluoride transfer from tetra-n-butylammonium difluorotriphenylsilicate (TBAT)

Tetra-n-butylammonium difluorotriphenylsilicate (ⁿBu₄NPh₃SiF₂, known as TBAT) is a pentacoordinate silicon-based fluoride source, commonly used in nucleophilic fluorinations and as an anionic initiator. The mechanism via which TBAT transfers the fluoride is not understood, but prior studies have shown that the process is rapid with respect to standard in situ NMR spectroscopic measurements. We used two ¹⁹F magnetisation transfer NMR techniques to interrogate the process directly: ¹⁹F chemical exchange saturation transfer (CEST) to examine whether TBAT dissociates into fluorotriphenylsilane (Ph₃SiF, FTPS) and tetra-n-butylammonium fluoride (ⁿBu₄NF, TBAF) in solution; and ¹⁹F inversion transfer to interrogate the kinetics and mechanism of fluoride transfer from TBAT. We first derived analytical solutions which describe the kinetics of ¹⁹F magnetisation transfer in mixtures of TBAT and the appropriate fluoride acceptors, in the inversion transfer experiments. These kinetic models enabled the interrogation of the transfer pathways in the systems, as the dependence of the magnetisation transfer rate between the spins on concentrations of the involved species varies between the proposed mechanisms in each system. CEST experiments showed that in THF and MeCN, TBAT dissociates reversibly into FTPS and TBAF. The degree of dissociation is low and the spins exchange rapidly at 300 K. Depending on the amount of adventitious water, TBAF may be involved in further equilibria or decompose. Tetra-n-butylammonium bifluoride (ⁿBu₄NF₂, TBABF) is likely formed in either case. Preliminary inversion transfer experiments showed a very rapid exchange between TBAT and FTPS in their equilibrium mixture in THF. An inherent temporal instability was observed, whereby the rate of exchange between the spins increased over time in closed systems (under N2 atmosphere). Upon screening of potential stabilising conditions, it was found that two additives, 2,6-di-tert-butylpyridine and 3 ̊Å̱ molecular sieves, reversed the trend when used concurrently, slowing down the reaction until temporal stability of exchange rate in the system was reached. The effect of concentration of FTPS under these conditions (at a constant concentration of TBAT) showed that both dissociative and direct pathways proceed in parallel. The dissociative pathway was also confirmed in the non-stabilised system by observing an initial decrease of the inversion transfer rate in a rapid titration of a concentrated solution of TBAT with small aliquots of FTPS. Inversion transfer between TBAT and 2-naphthalenyl fluorosulfate (ArOSO2F, ARSF) was detected in MeCN at 300 K, and inhibited to below the detection limit upon addition of exogeneous FTPS (~4 mM). At 335 K, progressive inhibition of the exchange was observed in solutions of TBAT and ARSF in MeCN due to decomposition of TBAT and hence formation of FTPS. Overall, we postulate that the fluoride transfer from TBAT occurs via both dissociative and direct transfer pathways proceeding in parallel, and that the contributions of these pathways are dependent upon the conditions (solvent, temperature, adventitious water, nature and concentration of the fluoride acceptor etc.). Moreover, ¹H diffusion analysis of TBAT in THF-d₈ and MeCN-d₃ indicated strong ion pairing, confirmed by the observation of nuclear Overhauser effect (NOE) between the ¹H spins of ⁿBu₄N⁺ and Ph₃SiF₂₋.

Speciation and kinetics of fluoride transfer from tetra-n-butylammonium difluorotriphenylsilicate (‘TBAT’)

Authors thank CRITICAT-EPSRC-CDT (scholarship to MMK) and the EPSRC Programme Grant “Boron: Beyond the Reagent” (EP/W007517) for support.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.Publisher PDFPeer reviewe

Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study

Background Results from retrospective studies suggest that use of neuromuscular blocking agents during general anaesthesia might be linked to postoperative pulmonary complications. We therefore aimed to assess whether the use of neuromuscular blocking agents is associated with postoperative pulmonary complications. Methods We did a multicentre, prospective observational cohort study. Patients were recruited from 211 hospitals in 28 European countries. We included patients (aged ≥18 years) who received general anaesthesia for any in-hospital procedure except cardiac surgery. Patient characteristics, surgical and anaesthetic details, and chart review at discharge were prospectively collected over 2 weeks. Additionally, each patient underwent postoperative physical examination within 3 days of surgery to check for adverse pulmonary events. The study outcome was the incidence of postoperative pulmonary complications from the end of surgery up to postoperative day 28. Logistic regression analyses were adjusted for surgical factors and patients’ preoperative physical status, providing adjusted odds ratios (ORadj) and adjusted absolute risk reduction (ARRadj). This study is registered with ClinicalTrials.gov, number NCT01865513. Findings Between June 16, 2014, and April 29, 2015, data from 22803 patients were collected. The use of neuromuscular blocking agents was associated with an increased incidence of postoperative pulmonary complications in patients who had undergone general anaesthesia (1658 [7·6%] of 21694); ORadj 1·86, 95% CI 1·53–2·26; ARRadj –4·4%, 95% CI –5·5 to –3·2). Only 2·3% of high-risk surgical patients and those with adverse respiratory profiles were anaesthetised without neuromuscular blocking agents. The use of neuromuscular monitoring (ORadj 1·31, 95% CI 1·15–1·49; ARRadj –2·6%, 95% CI –3·9 to –1·4) and the administration of reversal agents (1·23, 1·07–1·41; –1·9%, –3·2 to –0·7) were not associated with a decreased risk of postoperative pulmonary complications. Neither the choice of sugammadex instead of neostigmine for reversal (ORadj 1·03, 95% CI 0·85–1·25; ARRadj –0·3%, 95% CI –2·4 to 1·5) nor extubation at a train-of-four ratio of 0·9 or more (1·03, 0·82–1·31; –0·4%, –3·5 to 2·2) was associated with better pulmonary outcomes. Interpretation We showed that the use of neuromuscular blocking drugs in general anaesthesia is associated with an increased risk of postoperative pulmonary complications. Anaesthetists must balance the potential benefits of neuromuscular blockade against the increased risk of postoperative pulmonary complications

Outcomes in Newly Diagnosed Atrial Fibrillation and History of Acute Coronary Syndromes: Insights from GARFIELD-AF

BACKGROUND: Many patients with atrial fibrillation have concomitant coronary artery disease with or without acute coronary syndromes and are in need of additional antithrombotic therapy. There are few data on the long-term clinical outcome of atrial fibrillation patients with a history of acute coronary syndrome. This is a 2-year study of atrial fibrillation patients with or without a history of acute coronary syndromes

Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation A Report From the GARFIELD-AF Registry

IMPORTANCE Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes