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Application of new 400 MHz high temperature superconducting (HTS) power-driven magnet NMR technology for online reaction monitoring: Proof of concept with a ring closing metathesis (RCM) reaction
Abstract
Monitoring chemical reactions by NMR is an established and valuable approach for process understanding, robustness, scalability, and control in the pharmaceutical industry. Understanding speciation, reaction rates, and reaction completion times provides information on how to improve a chemical process, leading to increased quality and quantity of the desired product. An important consideration for online monitoring is to have an NMR instrument co-located with a chemical reactor. Standard commercial medium-to-high field NMR instruments are normally installed in isolated locations due to facility and safety restrictions. Low field NMR instruments suffer from low resolution and sensitivity, requiring chemometric analysis for medium to complex chemical structures. Reactions are typically monitored using NMR tubes and deuterated solvents. Therefore, reaction analysis may not provide the same kinetic information as when the reaction occurs in a reactor at a larger scale. To overcome these factors, we have tested a prototype NMR instrument with a 400 MHz cryogen-free power-driven high temperature superconducting (HTS) magnet installed in a chemistry laboratory fume hood for online monitoring of reactions. We have tested the HTS NMR system with a ring-closing metathesis (RCM) reaction of diethyldiallyl malonate with Grubbs 2nd Gen catalyst in a reactor with protonated solvent. The reaction was monitored online with a Bruker InsightMRTM flow cell and data was acquired in automation, yielding a kinetic time-course of the transformation and reaction rate values. This work demonstrates that NMR instruments with HTS magnets can be integrated in the chemistry laboratory with other equipment and are a valuable tool for reaction monitoring under typical reaction conditions and in protonated solvents.
... [5,6] In this approach, the reaction is carried out in a reactor outside the magnet, and a fraction of the reaction mixture is continuously circulated through the NMR probe for analysis and then back to the reactor. [2,[7][8][9][10] Applications have also been reported that range from biological systems to batteries. [11][12][13] Flow NMR is also powerful for efficiently analysing the outcome of a reaction or process, with a strong potential for automation and active feedback. ...
... The design of custom and commercial flow cells that are compatible with standard high-field instrumentation has expanded the application of flow NMR, allowing the analysis of a broad range of chemical reactions. [9,10,12,15,17,18] Standard NMR monitoring approaches typically rely on 1D 1 H spectra, which are fast to acquire and provide good sensitivity. [19][20][21] However, these spectra are often complex, due to signal overlap, which can prevent compound identification and the accurate measurement of integrals. ...
Flow NMR is an expanding analytical approach with applications that include in‐line analysis for process control and optimisation, and real‐time reaction monitoring. The samples monitored by flow NMR are typically mixtures that yield complex 1D ¹H spectra. “Pure shift” NMR is a powerful approach to simplifying ¹H NMR spectra, but its standard implementation is not compatible with continuous flow because of interference between sample motion and the position‐dependent spin manipulations that are required in pure shift NMR. Here we show that pure shift NMR spectra can be successfully collected for continuously flowing samples, thanks to an adapted acquisition scheme, robust solvent suppression, and a velocity‐compensation strategy. The resulting method is used to collect ultrahigh resolution reaction monitoring data. Pure shift NMR spectra are expected to benefit many applications of flow NMR.
... benchtop NMR spectrometers are more appropriate in targeted studies. An interesting alternative to low-field instruments in reaction monitoring was reported by Silva-Elipe and co-workers [103]. These authors resorted to a medium-field (400 MHz) NMR spectrometer fitted with a high-temperature superconducting (HTS) magnet as the detector. ...
... Partially seen underneath the table is the BCU-II preconditioner unit and the Julabo chiller to control the temperature of the sample transfer tubing (black) of the Bruker InsightMR flow cell [104]. The 5 G line of the magnet is delineated by a black and yellow tape on the cart of the magnet.Adapted from ref. Silva Elipe et al.[103] with permission, copyright # 2020, American Chemical Society. ...
Flow NMR, where samples are continuously loaded (on-flow) into the probe, provides rich structural information of purified fractions when the NMR spectrometer is coupled (hyphenated) to liquid chromatography (LC) or another separation technique, or in reaction monitoring, where no previous separation takes place. The main features of NMR spectrometers as detectors in separation instruments working in continuous, on-flow mode are briefed. Emphasis is made on alternative modes of operation of these so-constituted LC-NMR platforms, and on newer, improved instrumental designs, all of them aiming to overcome, or at least ameliorate, those weaknesses intrinsic of on-flow LC-NMR setups when conventional NMR experiments are used. These shortcomings are the limited time for detection (NMR acquisition) in continuous flow regimes and the comparatively small amount of sample entering the NMR detection probe (low sensitivity). This work is structured in three parts. First, some modes of operation, alternative to on-flow regimes, are revised. In the second part, some improvements in hardware design that boost the sensitivity of the detector, notably miniaturized NMR probes amenable to be coupled to separation techniques, are presented. In the third part, novel NMR methodologies aimed at reducing experiment time and suitable for on-flow work are considered. Representative examples are given for each scenario. Finally, future prospects of flow NMR protocols, either hyphenated to a separation technique or not, are discussed.
Flow nuclear magnetic resonance (NMR) at high field is a powerful approach for the online monitoring of chemical reactions, which provides real‐time quantitative and structural information. While 1D ¹H spectra are commonly collected for NMR monitoring applications, their information content is limited because of peak overlap and assignment ambiguity. 2D NMR methods provide an opportunity to resolve peaks that overlap in 1D spectra and obtain correlation information that helps assignment. Their fast implementations additionally have durations (from sub‐second to minute) that remain compatible with a large range of online reaction monitoring applications. They are also expected to benefit flow synthesis applications in which a flow reactor is hyphenated with a high‐field NMR spectrometer. Herein, a selection of fast 2D NMR methods that are compatible with flow NMR applications is described: ultrafast 2D NMR and fast diffusion‐ordered NMR spectroscopy. After a description of an experimental setup and current best practices, the principle behind each method and the way in which it can be implemented for continuously flowing samples are described. Also, the flow effects that are specific to these methods, for different settings, are described. These fast 2D NMR methods should be useful to users of flow NMR with an interest in reaction monitoring.
In situ 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. When the spectrometer outputs FIDs recorded from multiple scans, the spectra benefit from an increase in signal-to-noise (S/N). However, this reduces the number of FIDs and, thus, kinetic data points. We report a simple alternative in which the same number of scans is acquired by the spectrometer, but each scan is saved independently. Signal averaging is then conducted by postacquisition processing. This leads to an increase in both the S/N and the number of kinetic data points and can avoid “overaveraging” effects. The entire series of single-scan FIDs spanning the reaction lifetime can be summed to yield a “total reaction spectrum” in which intermediates can be identified. The method can be applied in coherence with phase cycling to minimize spectral distortion during solvent signal suppression. Overall, the approach simplifies the preacquisition parameters to the estimation of the reaction duration and T1max and then the selection of the pulse angle, θ, and scan repetition time, τR, without the need to set the signal averaging before the experiment.
This book details the latest research and development in the use of magnetic resonance imaging and spectroscopy as tools to give quantitative insights concerning late stage pharmaceutical formulation, tablet manufacturing and drug dissolution behaviour. The book combines different facets of magnetic resonance and highlights the use of spatial resolution (MRI) and how this adds to the knowledge base to further our understanding of the microscopic physicochemical processes occurring during drug release from solid dosage forms. New topics, that have not been thoroughly reviewed elsewhere, are covered including the applications of solution state magnetic resonance in process scale up, reaction monitoring/understanding and process analytical technologies (PAT); dissolution testing; and counterfeit analysis. Solid state NMR and its role in understanding phase separation in dispersions, polymorphism and crystallography is included and magnetic resonance imaging and its use in assessing tablet dissolution performance, mass transport and mixing in hot melt extrusion (HME) are covered.Focusing on late stage development rather than molecular drug discovery provides a unique approach and the book will appeal to a diversity of disciplines using spectroscopy for study. Aimed at researchers in drug development, manufacture and formulation in both industry (pharmaceutical companies) and academia (pharmacy program), it includes examples, where appropriate, of studies on commercially available pharmaceutical products.
Global climate change is the most important challenge humankind is facing in the modern era. One of the main scientific concerns is the monitoring of contaminants in the environment, which require the right environmental remediation strategies. In this context, nuclear magnetic resonance (NMR) techniques have a very important role in enabling the discovery of how pollutants are transformed, how they can move and how they can affect human health.
This book discusses the present and the future perspectives of NMR techniques for environmental evaluations. It covers, amongst other topics, the importance of NMR as a contamination discovery tool, how to improve sensitivity in environmental NMR, and multiphase NMR for measurement of samples in their natural state. Samples include lubricant oils, soils and porous media. Due to the direct relationship between the environment and human health, there is information dedicated to the use of magnetic resonance imaging (MRI) to monitor human health as related to environmental pollution. There is also a chapter on how NMR is used in cultural heritage to measure artefacts directly affected by environmental pollution.
Filling a gap in the literature, the book is for researchers explaining how to apply their knowledge of NMR techniques to solve environmental problems, and for students who want to deepen their understanding of this topic.
The discovery of new ceramic materials containing Ba‐La‐Cu oxides in 1986 that exhibited superconducting properties at high temperatures in the range of 35 K or higher, recognized with the Nobel Prize in Physics in 1987, opened a new world of opportunities for nuclear magnetic resonance (NMRs) and magnetic resonance imaging (MRIs) to move away from liquid cryogens. This discovery expands the application of high temperature superconducting (HTS) materials to fields beyond the chemical and medical industries, including electrical power grids, energy, and aerospace. The prototype 400‐MHz cryofree HTS NMR spectrometer installed at Amgen's chemistry laboratory has been vital for a variety of applications such as structure analysis, reaction monitoring, and CASE‐3D studies with RDCs. The spectrometer has been integrated with Amgen's chemistry and analytical workflows, providing pipeline project support in tandem with other Kinetic Analysis Platform technologies. The 400‐MHz cryofree HTS NMR spectrometer, as the name implies, does not require liquid cryogens refills and has smaller footprint that facilitates installation into a chemistry laboratory fume hood, sharing the hood with a process chemistry reactor. Our evaluation of its performance for structural analysis with CASE‐3D protocol and for reaction monitoring of Amgen's pipeline chemistry was successful. We envision that the HTS magnets would become part of the standard NMR and MRI spectrometers in the future. We believe that while the technology is being developed, there is room for all magnet options, including HTS, low temperature superconducting (LTS) magnets, and low field benchtop NMRs with permanent magnets, where utilization will be dependent on application type and costs.
The performance of six newly synthesized benzo[h]quinoline‐derived acetonitrilo pentamethylcyclopentadienyl iridium(III) tetrakis(3,5‐bis‐trifluoromethylphenyl)borate salts bearing different substituents −X (−OMe, −H, −Cl, −Br, −NO2 and −(NO2)2) on the heterochelating ligand were evaluated in the dehydro‐O‐silylation of benzyl alcohol and the monohydrosilylation of 4‐methoxybenzonitrile by Et3SiH, two reactions involving the electrophilic activation of the Si−H bond. The benchmark shows a direct dependence of the catalytic efficiency with the electronic effect of −X, which is confirmed by theoretical assessment of the intrinsic silylicities Π of hydridoiridium(III)‐silylium adducts and by the theoretical evaluation of the propensity of hydridospecies to transfer the hydrido ligand to the activated substrate. The revisited analysis of the Ir−Si−H interactions shows that the most cohesive bond in hydridoiridium(III)‐silylium adducts is the Ir−H one, while the Ir−Si is a weak donor‐acceptor dative bond. The Si…H interaction in all the cases is noncovalent in nature and dominated by electrostatics confirming the heterolytic cleavage of the hydrosilane's Si−H bond in this key catalytically relevant species.
Complex mixtures are ubiquitous in many branches of chemistry, be it a complex pharmaceutical formulation, a collection of biofluids analysed in a metabolomics workflow, or a flowing mixture in a reaction monitoring setting. The accurate quantitative determination of mixture components is one of the toughest challenges posed to analytical chemists, requiring the determination of often heavily overlapped signals from compounds in very diverse concentrations. NMR spectroscopists have developed an impressive variety of approaches to deal with such challenges, including the development of innovative pulse sequences, hyperpolarization methods and processing tools. We describe the most recent advances in the field of quantitative NMR, and the many subsequent application perspectives in fields where the sample complexity is a daily challenge, such as pharmaceutical science, metabolomics, isotopic analysis, and monitoring.
According to UV-vis spectroscopy (0.10 mM, CH2Cl2 at 25 °C), the catalyst transformation (which could possibly include ligand dissociation with active catalyst formation, dimer formation, and decomposition) rate constants (k obs) of Grubbs' first (1) and second (2) generation catalysts are 7.48 × 10-5 and 1.52 × 10-4 s-1, respectively. From 31P NMR (0.1 M, CD2Cl2, at 25 °C), the catalyst transformation was 5.1% for 1 and 16.5% for 2 after 72 h. However, due to the larger concentrations of the NMR samples compared to the UV-vis samples, the extent of transformation did not correspond. The oxidation potential of the RuII/RuIII couple of 2 (E°' = 27.5 mV at v = 200 mV s-1) was considerably lower than that of 1 (E°' = 167 mV at v = 200 mV s-1). In the case of 1, a second reduction peak appeared at slow scan rates. This may probably be ascribed to an electrochemically active compound that was formed from the intermediate cation 1 •+ and the subsequent reduction of the latter. The oxidation/reduction of 1 proceeds according to an ErCi electrochemical mechanism (Er = electrochemically reversible step, Ci = chemically irreversible step), whereas 2 proceeds according to an ErCr electrochemical mechanism (Er = electrochemically reversible step, Ci = chemically reversible step).
In this article we review some fundamental engineering concepts and evaluate components and materials required to assemble and operate safe and effective FlowNMR setups that reliably generate meaningful results.
High-throughput experimentation (HTE) is a well-established technique used in the pharmaceutical industry to accelerate compound synthesis and route optimization through automated chemical processes. A key part of any HTE workflow is the analytical component, through which the reaction outcome can be determined. The development of new analytical techniques capable of high-throughput data generation from nanoscale chemical reactions has been required to streamline the HTE process and address challenges generated through the recent move to miniaturize synthesis. In this Perspective, we review the currently available state-of-the-art analytical methods, discuss the challenges encountered in high-throughput analysis - with a particular focus on the analysis of nanoscale reactions, and provide a future outlook on potential developments in the field.
Nuclear magnetic resonance (NMR) is a powerful technique for the structure elucidation of organic molecules and significantly important in the pharmaceutical industry supporting the discovery and development of drug substances or active pharmaceutical ingredients (APIs). Following an initial study and assessment of a prototype NMR instrument with a high-temperature superconducting (HTS) power-driven magnet of 9.4 T (400 MHz for ¹H observation) operating with standard commercial electronics and probes, we tested the instrument with three compounds representing typical pharmaceutical drugs. We compared results from two probes and shimstacks with different geometries (broadband fluorine observe (BBFO) with Bruker orthogonal shim system-3 (BOSS3) and Bruker quattro nucleus probe (QNP) with BOSS1 shims) testing standard one-dimensional (1D) NMR experiments including selective excitation experiments, and two-dimensional (2D) homonuclear and heteronuclear experiments for the purposes of evaluating the equipment for structure elucidation capabilities. In our initial study on cinacalcet HCl, only the 1D ¹H experiment showed a loss of resolution when using the longer coiled BBFO probe with the BOSS3 shims compared to the shorter coiled QNP probe with BOSS1 shims. The selective excitation experiments using the cinacalcet HCl were successful. Our characterization of 1D (¹H, ¹³C, ¹⁹F) and 2D (¹H-¹H and ¹H-¹³C) NMR experiments for compounds I and II with the two probes and shimstacks indicated no significance differences. Overall, these results are satisfactory with the HTS magnet at the field of 9.4 T for the structural elucidation work of standard pharmaceutical compounds. This new technology has the advantage of being able to locate the HTS NMR magnet system in any chemistry or analytical laboratory where the samples are produced, facilitating rapid analysis with minor needs from the facilities and without cryogenic liquids.
After years towards higher field strength magnets, NMR technology in commercial instruments in the past decade has expanded at low and high magnetic fields to take advantage of new opportunities. At lower field strengths, permanent magnets are well‐established, whereas for mid‐range and high field, developments utilize superconducting magnets cooled with cryogenic liquids. Recently, the desire to locate NMR spectrometers in non‐typical NMR laboratories has created interest in the development of cryogen‐free magnets. These magnets require no cryogenic maintenance, eliminating routine filling and large cryogen dewars in the facility. Risks of spontaneous quenches and safety concerns when working with cryogenic liquids are eliminated. The highest field commercially available cryogen‐free NMR magnet previously reported was at 4.7 T in 2013. Here we tested a prototype cryogen‐free 9.4 T power‐driven high temperature superconducting (HTS) magnet mated to commercial NMR spectrometer electronics. We chose cinacalcet HCL, a typical pharmaceutical API, to evaluate its performance towards structure elucidation. Satisfactory standard 1D and 2D homonuclear and heteronuclear NMR results were obtained and compared to that from a standard 9.4 T cryogenically cooled superconducting NMR instrument. The results were similar between both systems with minor differences. Further comparison with different shims and probes in the HTS magnet system confirmed that the magnet homogeneity profile could be matched with commercially available NMR equipment for optimal results. We conclude that HTS magnet technology works well providing comparable results to standard instruments leading us to investigate additional applications for this magnet technology outside a traditional NMR facility.
We report findings from the qualitative evaluation of nuclear magnetic resonance (NMR) reaction monitoring techniques of how each relates to the kinetic profile of a reaction process. The study highlights key reaction rate differences observed between the various NMR reaction monitoring methods investigated: online NMR, static NMR tubes, and periodic inversion of NMR tubes. The analysis of three reaction processes reveals that rates derived from NMR analysis are highly dependent on monitoring method. These findings indicate that users must be aware of the effect of their monitoring method upon the kinetic rate data derived from NMR analysis. Copyright © 2015 John Wiley & Sons, Ltd.
Copyright © 2015 John Wiley & Sons, Ltd.
This study centers on the use of in situ FTIR spectroscopy and online NMR to study the nucleophilic addition of benzimidazole analogues to an N-methylpyridinium salt. The reaction consists of two stages. First, the protected benzimidazole was lithiated with LDA to form the C-2 lithiated benzimidazole. The lithiated benzimidazole was then added to the pyridinium salt to generate the coupled product. The lithiated benzimidazole was not thermally stable, so offline sampling was challenging. A good understanding of the reaction completion of the lithiation was needed for process understanding as well as to provide a basis to determine the fate of the lithiated benzimidazole through the entire addition sequence. In situ FTIR and flow NMR provided online methods for monitoring the reaction sequence and studying the temperature-dependent stability of the lithiated benzimidazole.
This article describes the development of a 5 mm NMR flow-tube that can be used in a standard 5 mm NMR probe, enabling the user to conduct experiments on flowing samples; or more specifically, on flowing reaction mixtures. This enables reaction monitoring or kinetic experiments to be conducted by flowing reaction mixtures from a reaction vessel to detection in the coil area of the NMR, without the need for a specialized flow NMR probe. One of the key benefits of this flow-tube is that it provides flexibility to be used across a range of available spectrometers of varying magnetic field strengths with a standard 5 mm probe setup. The applicability of this flow-tube to reaction monitoring is demonstrated using the reaction of p-phenylenediamine and isobutyraldehyde to form the diimine product.
An optimized route to an iodo-imidazole intermediate in the synthesis of 4-ethynyl-2,5-dimethyl-1-aryl-1H-imidazoles (6) was devised. Important data for the optimization work was obtained by carrying out a DOE study to gain understanding of the parameters that affect the key intramolecular cyclization to build the imidazole ring. Additional information on the reaction mechanism of this step was obtained by carrying out a flow NMR experiment. In order to complete the proof of concept, the iodo-imidazole intermediate was converted to two ethynyl imidazoles (6a, b) using metal-catalyzed reactions.
This communication describes an in situ method for direct observation and quantitation of dissolved H2 at high pressure with concurrent monitoring and characterization of organic reactions. This capability also allows for direct measurement of kLa values and provides insight into reactions that was not previously attainable.
Detector response (in many spectroscopic methods) is not equivalent between detector or instruments types, and factors that impact detector response include molecular structure, instrument type and detection wavelength. In LC, UV is often the primary detector, however without determination of UV response factors for each analyte, chromatographic results are reported on an area percent rather than a weight percent. In extreme cases, response factors can differ by several orders of magnitude for structurally dissimilar compounds, making the data useless for quantitative applications. While impurity reference standards are normally used to calculate UV relative response factors (RRFs), these reference standards of reaction mixture components are typically not available during route scouting or in the early stages of process development. Here we describe an approach to establish RRFs from a single experiment using both online NMR and LC. NMR is used as a mass detector from which a UV response factor can be determined to correct the HPLC data [Note: this approach can easily be applied to calibrate other in-situ tools such as mid infrared spectrometers]. Online reaction monitoring using simultaneous NMR and HPLC provides a platform to expedite the development and understanding of pharmaceutical reaction processes. Ultimately, the knowledge provided by a structurally information rich technique such as NMR can be correlated with more prevalent and mobile instrumentation (e.g., LC, MIR) for additional routine process understanding and optimization.
The success of olefin metathesis has spurred the intense investigation of new catalysts for this transformation. With the development of many different catalysts, however, it becomes increasingly difficult to compare their efficiencies. In this article we introduce a set of six reactions with specific reaction conditions to establish a standard for catalyst comparison in olefin metathesis. The reactions were selected on the basis of their ability to provide a maximum amount of information describing catalyst activity, stability, and selectivity, while being operationally simple. Seven of the most widely used ruthenium-based olefin metathesis catalysts were evaluated with these standard screens. This standard is a useful tool for the comparison and evaluation of new metathesis catalysts.
On-flow ReactIR and (1)H NMR reaction monitoring, coupled with in situ intermediate characterization, was used to aid in the mechanistic elucidation of the N-chlorosuccinimide mediated transformation of an α-thioamide. Multiple intermediates in this reaction cascade are identified and characterized, and in particular, spectroscopic evidence for the intermediacy of the chlorosulfonium ion in the chlorination of α-thioamides is provided. Further to this, solvent effects on the outcome of the transformation are discussed. This work also demonstrates the utility of using a combination of ReactIR and flow NMR reaction monitoring (ReactNMR) for characterizing complex multicomponent reaction mixtures.
Reaction progress kinetic analysis to obtain a comprehensive picture of complex catalytic reaction behavior is described. This methodology employs in situ measurements and simple manipulations to construct a series of graphical rate equations that enable analysis of the reaction to be accomplished from a minimal number of experiments. Such an analysis helps to describe the driving forces of a reaction and may be used to help distinguish between different proposed mechanistic models. This Review describes the procedure for undertaking such analysis for any new reaction under study.