ABSTRACT
The Suzuki-Miyaura coupling is a widely used C-C bond forming reaction. Numerous mechanistic studies have enabled the use of low catalyst loadings and broad functional group tolerance. However, the dominant mode of transmetalation remains controversial and likely depends on the conditions employed. Herein we detail a mechanistic study of the palladium-catalyzed Suzuki-Miyaura coupling under biphasic conditions. The use of phase transfer catalysts results in a remarkable 12-fold rate enhancement in the targeted system. A shift from an oxo-palladium based transmetalation to a boronate-based pathway lies at the root of this activity. Furthermore, a study of the impact of different water loadings reveals reducing the proportion of the aqueous phase increases the reaction rate, contrary to reaction conditions typically employed in the literature. The importance of these findings is highlighted by achieving an exceptionally broad substrate scope with benzylic electrophiles using a 10-fold reduction in catalyst loading relative to literature precedent.
ABSTRACT
The ability for nuclear magnetic resonance (NMR) spectroscopy to provide quantitative, structurally rich information makes this spectroscopic technique an attractive reaction monitoring tool. The practicality of NMR for this type of analysis has only increased in the recent years with the influx of commercially available benchtop NMR instruments and compatible flow systems. In this study, we aim to compare 19F NMR reaction profiles acquired under both on-line continuous-flow and stopped-flow sampling methods, with modern benchtop NMR instrumentation, and two reaction systems: a homogeneous imination reaction and a biphasic activation of a carboxylic acid to acyl fluoride. Reaction trends with higher data density can be acquired with on-line continuous-flow analyses, and this work highlights that representative reaction trends can be acquired without any correction when monitoring resonances with a shorter spin-lattice relaxation time (T1), and with the used flow conditions. On-line stopped-flow analyses resulted in representative reaction trends in all cases, including the monitoring of resonances with a long T1, without the need of any correction factors. The benefit of easier data analysis, however, comes with the cost of time, as the fresh reaction solution must be flowed into the NMR system, halted, and time must be provided for spins to become polarized in the instrument's external magnetic field prior to spectral measurement. Results for one of the reactions were additionally compared with the use of a high-field NMR.
ABSTRACT
Nuclear magnetic resonance (NMR) spectroscopy is a powerful analytical technique with the ability to acquire both quantitative and structurally insightful data for multiple components in a test sample. This makes NMR spectroscopy a desirable tool to understand, monitor, and optimize chemical transformations. While quantitative NMR (qNMR) approaches relying on internal standards are well-established, using an absolute external calibration scheme is beneficial for reaction monitoring as resonance overlap complications from an added reference material to the sample can be avoided. Particularly, this type of qNMR technique is of interest with benchtop NMR spectrometers as the likelihood of resonance overlap is only enhanced with the lower magnetic field strengths of the used permanent magnets. The included study describes a simple yet robust methodology to determine concentration conversion factors for NMR systems using single- and multi-analyte linear regression models. This approach is leveraged to investigate a pharmaceutically relevant amide coupling batch reaction. An on-line stopped-flow (i.e., interrupted-flow or paused-flow) benchtop NMR system was used to monitor both the 1,1'-carbonyldiimidazole (CDI) promoted acid activation and the amide coupling. The results highlight how quantitative measurements in benchtop NMR systems can provide valuable information and enable analysts to make decisions in real time.
ABSTRACT
This study focused on fundamental data acquisition parameter selection for a benchtop nuclear magnetic resonance (NMR) system with continuous flow, applicable for reaction monitoring. The effect of flow rate on the mixing behaviors within a flow cell was observed, along with an exponential decay relationship between flow rate and the apparent spin-lattice relaxation time (T1*) of benzaldehyde. We also monitored sensitivity (as determined by signal-to-noise ratios; SNRs) under various flow rates, analyte concentrations, and temperatures of the analyte flask. Results suggest that a maximum SNR can be achieved with low to medium flow rates and higher analyte concentrations. This was consistent with data collected with parameters that promote either slow or fast data acquisition. We further consider the effect of these conditions on the analyte's residence time, T1*, and magnetic field inhomogeneity that is a product of continuous flow. Altogether, our results demonstrate how fundamental acquisition parameters can be manipulated to achieve optimal data acquisition in continuous-flow NMR systems.
ABSTRACT
PURPOSE: We investigate the potential of a common dietary supplement, methylsulfonylmethane (MSM), to act as a chemical shift reference for in vivo 1 H MR spectroscopy (MRS). The scope of the investigation is 2-fold: (1) We use high-resolution nuclear MR (NMR) measurements of the chemical shift values of MSM to establish the stability of MSM resonance across the ranges of pH and temperature, and (2) we demonstrate MR properties of MSM in the healthy human brain. METHODS: The relationship of chemical shift with temperature and pH is examined using high-resolution 1 H NMR (14.1T) spectra of MSM in aqueous solution. MSM concentration in human brain tissue was measured as a function of time, together with the relaxation properties in the brain using 1 H MRS at 3T. RESULTS: The chemical shift of MSM remains stable in the range of the biologically relevant temperatures and pH values. The chemical shift at pH = 7.2 and 37°C was measured to be 3.142 ppm (relative to DSS, a common water-soluble NMR reference compound). Time course in the brain tissue in vivo confirmed an observable MSM signal 10 minutes after oral intake and a stable signal intensity within a ~3-hour window. CONCLUSION: The chemical and biological properties of MSM-rapid crossing of the blood-brain barrier, water solubility, a singlet resonance resolved from metabolite resonances, chemical shift stability with respect to pH/temperature, and stable temporal presence in the brain-lead us to propose its use as a frequency reference for MRS.
