Perspectives for Hyperpolarisation in Compact NMR

Nuclear magnetic resonance (NMR) is one of the most powerful analytical techniques currently available, with applications in fields ranging from synthetic chemistry to clinical diagnosis. Due to the size and cost of high-field spectrometers, NMR is generally considered to be ill-suited for industrial environments and field work. This conventional wisdom is currently being challenged through the development of NMR systems that are smaller, cheaper, more robust and portable. Despite remarkable progress in this area, potential applications are often limited by low sensitivity. Hyperpolarisation techniques have the potential to overcome this limitation and revolutionise the use of compact NMR. This review describes the state-of-the-art in NMR hyperpolarisation and presents promising examples of its application to compact NMR. Both the benefits and challenges associated with the different hyperpolarisation approaches are discussed and applications where these technologies have the potential to make a significant impact are highlighted

Multi-Acquisition and Multi-Dimensional Earth's Field Nuclear Magnetic Resonance Spectroscopy

In this thesis we investigate the ways in which the sensitivity, resolution and overall performance of an Earth's field NMR system can be improved without significantly compromising its simplicity, portability or affordability. We investigate the limits of the information obtainable using this device and present a range of methods for calculating and analyzing NMR spectroscopy experiments detected in the Earth's magnetic field. We demonstrate significant improvements in the performance of a commercial Earth's field NMR device, the Terranova-MRI, through several apparatus developments. First-order shimming is added to the system in order to counter any local inhomogeneity of the Earth's field. The spectral resolution of the instrument is further improved through the introduction of a field locking system to counter the natural temporal drift in the magnitude of the Earth's magnetic field. External noise interference is reduced through the use of Faraday screening, effectively increasing the signal-to-noise ratio (SNR) performance of the device. We explore three signal enhancement methodologies for optimizing the SNR performance of the system. Prepolarization, with an electromagnet as well as a permanent magnet array, is considered and compared to dynamic nuclear polarization (DNP) and hyperpolarization via optical pumping. We present a detailed theoretical discussion of DNP in low-fields and demonstrate the application of this technique for signal enhancement in EFNMR. An apparatus for performing DNP in the Earth's field is presented and optimized. A density matrix approach to simulating one- and two-dimensional Earth's field NMR experiments is presented. These numerical simulations, along with a perturbation theory approach to calculating one-dimensional EFNMR spectra of tightly coupled heteronuclear systems, are explored and compared to experimental spectra of the tetrahydroborate and ammonium ions. These systems are of particular interest for NMR detected in the Earth's field because they contain strongly coupled nuclei of differing spin, a situation previously unexplored in the literature. Multi-dimensional Earth's field NMR spectroscopy methods, in particular the correlation spectroscopy (COSY) experiment, are implemented and optimized through the use of shimming, field stabilization and noise screening. The 2D COSY spectrum of monofluorobenzene is analyzed and compared to calculated spectra in order to determine the indirect spin-spin coupling constants of this molecule in the Earth's magnetic field. A 2D COSY spectrum of 1,4-difluorobenzene is also presented and compared to simulation. The SNR performance of COSY in the Earth's field is greatly improved through the use of DNP for signal enhancement. A high-quality, 2D COSY EFNMR spectrum with DNP acquired from 2,2,2- trifluoroethanol is presented and compared to simulation. The particular features of this spectrum, which result from the use of DNP for signal enhancement, are discussed with reference to a density matrix simulation and to a one-dimensional spectrum calculated using perturbation theory. The strong indirect spin-spin coupling regime in fields weaker than the Earth's magnetic field is explored through exact calculations and density matrix simulations of a 13C-enriched methyl group. A novel multi-dimensional EFNMR method for observing such spectra is discussed. This experiment allows for the resolution of strongly coupled NMR spectra both in the Earth's magnetic field, in the directly detected domain, and in weaker fields, in the indirectly detected domain. In the final section of this thesis, residual dipolar coupling is observed by EFNMR for the first time in a system of poly-[gamma]-benzyl-L-glutamate (PBLG) in dichloromethane. The form of the EFNMR spectrum of this liquid crystalline system is discussed and compared to equivalent high-field (9.4T) spectra

Hyperpolarised 1H-13C benchtop NMR spectroscopy

Benchtop NMR spectrometers with sub-ppm spectral resolution have opened up new opportunities for performing NMR outside of the standard laboratory environment. However, the relatively weak magnetic fields of these devices (1 - 2 T) results in low sensitivity and significant peak overlap in 1H NMR spectra. Here we use hyperpolarised 13C{1H} NMR to overcome these challenges. Specifically, we demonstrate the use of the signal amplification by reversible exchange (SABRE) parahydrogen-based hyperpolarisation technique to enhance the sensitivity of natural abundance 1D and 2D 13C{1H} benchtop NMR spectra. We compare two detection methods for SABRE-enhanced 13C NMR and observe an optimal 13C{1H} signal-to-noise ratio (SNR) for a refocused INEPT approach, where hyperpolarisation is transferred from 1H to 13C. In addition, we exemplify SABRE-enhanced 2D 13C benchtop NMR through the acquisition of a 2D HETCOR spectrum of 260 mM of 4-methylpyridine at natural isotopic abundance in a total experiment time of 69 mins. In theory, signal averaging for over 300 days would be required to achieve a comparable SNR for a thermally polarised benchtop NMR spectrum acquired of a sample of the same concentration at natural abundanc

Photochemical Pump and NMR Probe to monitor the formation and kinetics of hyperpolarized metal dihydrides

On reaction of IrI(CO)(PPh 3) 21with para-hydrogen(p-H 2),Ir(H) 2I(CO)(PPh 3) 22 is formed which exhibits strongly enhanced 1H NMR signals for its hydride resonances. Complex 2 also shows similar enhancement of its NMR spectra when it is irradiated under p-H 2. We report the use of this photochemical reactivity to measure the kinetics of H 2 addition by laser-synchronized reactions in conjunction with NMR. The single laser pulse promotes the reductive elimination of H 2 from Ir(H) 2I(CO)(PPh 3) 22 in C 6D 6 solution to form the 16-electron precursor 1, back reaction with p-H 2 then reforms 2 in a well-defined nuclear spin-state. The build up of this product can be followed by incrementing a precisely controlled delay (τ), in millisecond steps, between the laser and the NMR pulse. The resulting signal vs. time profile shows a dependence on p-H 2 pressure. The plot of k obs against p-H 2 pressure is linear and yields the second order rate constant, k 2, for H 2 addition to 1 of (3.26 ± 0.42) × 10 2 M −1 s −1. Validation was achieved by transient-UV-vis absorption spectroscopy which gives k 2 of (3.06 ± 0.40) × 10 2 M −1 s −1. Furthermore, irradiation of a C 6D 6 solution of 2 with multiple laser shots, in conjunction with p-H 2 derived hyperpolarization, allows the detection and characterisation of two minor reaction products, 2a and 3, which are produced in such low yields that they are not detected without hyperpolarization. Complex 2a is a configurational isomer of 2, while 3 is formed by substitution of CO by PPh

Reaction monitoring using SABRE-hyperpolarized benchtop (1 T) NMR spectroscopy

The conversion of [IrCl(COD)(IMes)] (COD = cis,cis-1,5-cyclooctadiene, IMes = 1,3-bis(2,4,6-trimethyl-phenyl)imidazole-2-ylidene) in the presence of an excess of p-H2 and a substrate (4-aminopyridine (4-AP) or 4-methylpyridine (4-MP)) into [Ir(H)2(IMes)(substrate)3]Cl is monitored by 1H NMR spectroscopy using a benchtop (1 T) spectrometer in conjunction with the parahydrogen (p-H2) based hyperpolarization technique signal amplification by reversible exchange (SABRE). A series of single-shot 1H NMR measurements are used to monitor the chemical changes that take place in solution through the lifetime of the hyperpolarized response. Non-hyperpolarized high-field 1H NMR control measurements were also undertaken to confirm that the observed time dependent changes relate directly to the underlying chemical evolution. The formation of [Ir(H)2(IMes)(substrate)3]Cl is further linked to the hydrogen isotope exchange reaction (HIE) which leads to the incorporation of deuterium into the ortho positions of 4-AP, where the source of deuterium is the solvent, methanol-d4. Comparable reaction monitoring results are achieved at both high-field (9.4 T) and low-field (1 T). It is notable, that the low sensitivity of the benchtop (1 T) NMR enables the use of protio solvents, which is harnessed here to separate the effects of catalyst formation and substrate deuteration. Collectively, these methods illustrate how low-cost low-field NMR measurements provide unique insight into a complex catalytic process through a combination of hyperpolarization and relaxation data

Towards measuring reactivity on micro-to-millisecond timescales with laser pump, NMR probe spectroscopy

We present a quantitative analysis of the timescales of reactivity that are accessible to a laser pump, NMR probe spectroscopy method using parahydrogen induced polarisation (PHIP) and identify three kinetics regimes: fast, intermediate and slow. These regimes are defined by the relative rate of reaction, k, compared to δω, the frequency of the NMR signal oscillations associated with the coherent evolution of the hyperpolarised 1H NMR signals created after parahydrogen (p-H2) addition during the pump-probe delay. The kinetic regimes are quantitatively defined by a NMR dephasing parameter, ε = δω/k. For the fast regime, where k >> δω and ε tends to zero, the observed NMR signals are not affected by the chemical evolution of the system and so only an upper bound on k can be determined. In the slow regime, where k << δω and ε tends to infinity, destructive interference leads to the complete dephasing of the coherent NMR signal intensity oscillations. As a result, the observed NMR signal evolution during the pump-probe delay reflects only the chemical change of the system and NMR relaxation. Finally, in the intermediate regime, where k ~ δω, characteristic partial dephasing of the NMR signal oscillations is predicted. In the limit where the dephasing parameter is small but non-zero, chemical evolution manifests itself as a phase shift in the NMR signal oscillation that is equal to the dephasing parameter. As this phase shift is predicted to persist for pump-probe delays much longer than the timescale of the formation of the product molecules it provides a route to measure reactivity on micro-to-millisecond timescales through NMR detection. We predict that the most significant fundamental limitations on the accessible reaction timescales are the duration of the NMR excitation pulse (~ 1 µs) and the chemical shift difference (in Hz) between the p-H2-derived protons in the product molecule

SHARPER-enhanced benchtop NMR:improving SNR by removing couplings and approaching natural linewidths

We present a signal enhancement strategy for benchtop NMR that produces SNR increases on the order of 10 to 30 fold by collapsing the target resonance into an extremely narrow singlet. Importantly, the resultant signal is amenable to quantitative interpretation and therefore can be applied to analytical applications such as reaction monitoring

Enhancing 19F benchtop NMR spectroscopy by combining parahydrogen hyperpolarisation and multiplet refocusing

Benchtop NMR spectrometers provide a promising alternative to high-field NMR for applications that are limited by instrument size and/or cost. 19F benchtop NMR is attractive due to the larger chemical shift range of 19F relative to 1H and the lack of background signal in most applications. However, practical applications of benchtop 19F NMR are limited by its low sensitivity due to the relatively weak field strengths of benchtop NMR spectrometers. Here we present a sensitivity-enhancement strategy that combines SABRE (Signal Amplification By Reversible Exchange) hyperpolarisation with the multiplet refocusing method SHARPER (Sensitive, Homogeneous, And Resolved PEaks in Real time). When applied to a range of fluoropyridines, SABRE-SHARPER achieves overall signal enhancements of up to 5700-fold through the combined effects of hyperpolarisation and line-narrowing. This approach can be generalised to the analysis of mixtures through the use of a selective variant of the SHARPER sequence, selSHARPER. The ability of SABRE-selSHARPER to simultaneously boost sensitivity and discriminate between two components of a mixture is demonstrated, where selectivity is achieved through a combination of selective excitation and the choice of polarisation transfer field during the SABRE step

Quantitative In-situ Monitoring of Parahydrogen Fraction Using Raman Spectroscopy

Raman spectroscopy has been used to provide a rapid, noninvasive, and nondestructive quantification method for determining the parahydrogen fraction of hydrogen gas. The basis of the method is the measurement of the ratio of the first two rotational bands of hydrogen at 355 cm −1 and 586 cm −1 corresponding to parahydrogen and orthohydrogen, respectively. The method has been used to determine the parahydrogen content during a production process and a reaction. In the first example, the performance of an in-house liquid nitrogen cooled parahydrogen generator was monitored both at-line and on-line. The Raman measurements showed that it took several hours for the generator to reach steady state and, hence, for maximum parahydrogen production (50%) to be reached. The results obtained using Raman spectroscopy were compared to those obtained by at-line low-field nuclear magnetic resonance (NMR) spectroscopy. While the results were in good agreement, Raman analysis has several advantages over NMR for this application. The Raman method does not require a reference sample, as both spin isomers (ortho and para) of hydrogen can be directly detected, which simplifies the procedure and eliminates some sources of error. In the second example, the method was used to monitor the fast conversion of parahydrogen to orthohydrogen in situ. Here the ability to acquire Raman spectra every 30 s enabled a conversion process with a rate constant of 27:4 * 10 -4 s −1 to be monitored. The Raman method described here represents an improvement on previously reported work, in that it can be easily applied on-line and is approximately 500 times faster. This offers the potential of an industrially compatible method for determining parahydrogen content in applications that require the storage and usage of hydrogen

Quantification of hyperpolarisation efficiency in SABRE and SABRE-Relay enhanced NMR spectroscopy

para-Hydrogen (p-H 2) induced polarisation (PHIP) is an increasingly popular method for sensitivity enhancement in NMR spectroscopy. Its growing popularity is due in part to the introduction of the signal amplification by reversible exchange (SABRE) method that generates renewable hyperpolarisation in target analytes in seconds. A key benefit of PHIP and SABRE is that p-H 2 can be relatively easily and cheaply produced, with costs increasing with the desired level of p-H 2 purity. In this work, the efficiency of the SABRE polarisation transfer is explored by measuring the level of analyte hyperpolarisation as a function of the level of p-H 2 enrichment. A linear relationship was found between p-H 2 enrichment and analyte 1H hyperpolarisation for a range of molecules, polarisation transfer catalysts, NMR detection fields and for both the SABRE and SABRE-Relay transfer mechanisms over the range 29-99% p-H 2 purity. The gradient of these linear relationships were related to a simple theoretical model to define an overall efficiency parameter, E, that quantifies the net fraction of the available p-H 2 polarisation that is transferred to the target analyte. We find that the efficiency of SABRE is independent of the NMR detection field and exceeds E = 20% for methyl-4,6-d 2-nicotinate when using a previously optimised catalyst system. For the SABRE-Relay transfer mechanism, efficiencies of up to E = 1% were found for 1H polarisation of 1-propanol, when ammonia was used as the polarisation carrier