Multi-channel ZULF NMR spectrometer using optically pumped magnetometers

Abstract

A nuclear magnetic resonance (NMR) spectrometer includes an array of distinct, separate samples to be tested, a set of optically pumped magnetometers (OPM), an inhomogeneous magnet having a bore configured to accept the array of samples, a zero-to- ultra-low field detection center, a field cycler stage to transport the array of samples between the inhomogeneous magnet and the detection center along a path, the path having a guiding field solenoid; and a computer to control operation of the spectrometer.

Description

MULTI-CHANNEL ZULF NMR SPECTROMETER USING OPTICALLY PUMPED MAGNETOMETERSSTATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0001] This invention was made with Government support under grants number 2141083 and 2231634 awarded by the National Science Foundation. The Government has certain rights in this invention.TECHNICAL FIELD

[0002] This disclosure relates to nuclear magnetic resonance (NMR), more particularly to NMR using optically pumped magnetometers.BACKGROUND

[0003] Nuclear Magnetic Resonance (NMR) is one of the most universal tools in synthetic chemistry due to the highly specific kinetic and structural information one obtains in a nondestructive and noninvasive way. Although NMR can study a wide array of solid- and liquid-state analytes due to the abundance of NMR active nuclei in nature, it suffers notable drawbacks in throughput due to the sequential way in which samples are measured. This is solely because of the high degree of magnetic field homogeneity needed during detection, which is only achieved in a small, sample-sized volume in commercial systems and is one of the largest contributors to the magnet’s cost.

[0004] New magnetic resonance techniques must be developed to meet the growing throughput demands of emerging fields such as robotic chemistry as well as existing fields such as chemical manufacturing, agriculture, and the pharmaceutical industry. Zero-to-ultra- low field (ZULF) NMR is an emerging technique that offers similarly extensive chemical information as conventional NMR but detects analyte NMR signals at zero-to-ultra-low magnetic field following polarization from a strong magnetic field. Since magnetic field homogeneity is necessary only during readout, one can polarize the sample with cheap, inhomogeneous magnets.

[0005] Meanwhile, a cheap, mu metal magnetic shield easily produces an arbitrarily large homogeneous region where optically pumped magnetometers (OPMs), which have recentlybecome available in palm-sized form, optically detect signals via rubidium sensing media. The rapid advancement of these compact optically pumped magnetometers (OPMs) has propelled this field greatly in the last decade, allowing ZULF NMR instruments to be easily constructed without the need for technical expertise in OPMs or even optics.

[0006] In contrast to the high-field regime, ZULF NMR additionally characterizes heterogeneous samples, such as analytes in porous media, and can be used to study heterogeneous catalysis. ZULF NMR spectra also contain rich information, exhibiting substantial changes even among similar molecules. However, the low sensitivity and the 0PM’ s susceptibility to noise has hindered its widespread adoption and limited its use to expensive13C enriched compounds, since only heteronuclear spin systems are observable in ZULF NMR such as CHx, phosphorus and fluorine containing compounds, or hyperpolarized spin systems.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1 shows an embodiment of a high-throughput zero-to-ultra-low field (ZULF) nuclear magnetic resonance (NMR) system.

[0008] FIG. 2 shows an embodiment of a ZULF NMR system.

[0009] FIG. 3 shows an embodiment of an array of samples and a set of optically pumped magnetometers (OPMs).

[0010] FIG. 4A shows a schematic representation of an embodiment of a process of performing ZULF NMR analysis of a sample.

[0011] FIGs.4B-4E show results of ZULF NMR spectroscopy on various samples.

[0012] FIGs. 5 A-5D show results of ZULF NMR spectroscopy measurements of organic molecules.

[0013] FIG. 6 shows a comparison of performance of the embodiments to other types of NMR analysis.

[0014] FIGs. 7A-7B shows results and analysis of an embodiment of a multi-channel simultaneous measurement.

[0015] FIGs. 8A-8C show results of detection of naturally abundant carbon species using embodiments of ZULF NMR.

[0016] FIG. 9 shows an embodiment of ZULF NMR in a closed transport mechanism environment.

[0017] FIG. 10 shows a comparison of a simulation and experimental results for detection of benzene.

[0018] FIG. 11 shows results for detection of a compound before and after changing the sign demonstrating the sensitivity of the ZULF NMR system.DETAILED DESCRIPTION OF THE EMBODIMENTS

[0019] Zero-to-ultra-low field (ZULF) NMR has gained recent popularity due to the advancement of optically pumped magnetometers (0PM) which have become commercially available in a compact form-factor. This has enabled easy construction of such apparatuses without technical expertise in OPMs or optics. Despite its initial promise and growth, ZULF NMR suffers in scope due to its low sensitivity and susceptibility to noise, making it impossible to detect most organic molecules without resorting to hyperpolarization or13C enrichment. The embodiments described herein greatly improve state-of-the art ZULF NMR to distinguish this technique as a novel chemical analysis tool, leveraging its unique advantages to increase the throughput of NMR to an unprecedented scale.

[0020] The embodiments remedy sensitivity concerns, which lead to the first reported detection of organic molecules in natural isotopic abundance with sensitivity comparable to current commercial benchtop NMR spectrometers. The embodiments involve the first multichannel ZULF NMR spectrometer capable of measuring three distinct chemical samples simultaneously. In this way, ZULF NMR has been proven to be a reliable and extensible framework for high-throughput, parallel NMR detection.

[0021] The embodiments involve a ZULF NMR spectrometer that leverages the large homogeneous detection volume afforded by the mu metal shield as well as the magnet’s spacious bore to parallelize NMR detection in arrayed fashion for chemical analysis. The embodiment of a ZULF NMR spectrometer 10 shown in FIG. 1 comprises a high-throughput ZULF NMR platform. The arrayed detection 12 resides inside a magnetic shield 36, and a large, inhomogeneous magnet 14 enable this platform. As used here, the term “inhomogeneous magnet” means a magnet generating a field that can be as high as IT / cm, and a “large” magnet has a bore in the range of 1-15 cm. In comparison, typical magnets used in NMR have <100 ppb T / l cm, which requires expensive magnets and restricts the size ofthe region to which the field can be applied. An embodiment of the platform is shown at 16. The compact form factor for the optically pumped magnetometer 18. The inner view 20 shows optically pumped electrons in a sensing medium, with the sample magnetization at 22.

[0022] FIG. 2 shows another embodiment of the ZULF NMR instrument 30. The instrument includes an inhomogeneous 10 T magnet 32 in the Reaction Center or pre-polarization region. The Field Cycling Stage 32, or transport mechanism, allows for rapid, controlled motion of the sample array between the Zero-to-Ultralow-Field Detection Center, referred to here as the ZULF or Low Field Detection Center, and the Reaction Center 34. The Low Field Detection center 36 comprises a shielded region and accommodates zero-field conditions and steady, ultralow fields, either applied, or just the Earth’s field, which exists but is not “applied.” The discussion may refer to the cycling stage as being high-speed, which means the shuttle moves at speeds in the range of l-10000cm / s. The control computer 38 manages the process. In one embodiment, a frame 40 contains the system.

[0023] In the embodiments in FIGs. 1 and 2, the transport mechanism comprises the shuttle. The shuttle comprises a mechanism that physically moves the samples from the bore of the magnet to the shielded region. As will be discussed in further embodiments, the transport mechanism may comprise flowing liquid. The samples, or set of samples, may comprise an array of discrete individual samples as shown in FIGs. 1 and 2. As will be discussed in more detail below, the set of samples may also comprise samples contained in a liquid.

[0024] FIG. 3 shows a view of an embodiment of the array of optically pumped magnetometers 18 below the samples. The exploded view 42 shows an OPM as a standalone unit with a rubidium cell sensor 44 and optical components for sensor initialization and readout, such as laser 46. The rubidium and laser comprise examples, other materials and optical pumping devices may be used. The array of the OPMs shown in FIG. 3 comprises one array size and can extend to larger array sizes. The set of OPMs used may comprise multiple OPMs or a set having only one OPM that has multiple detection regions.

[0025] To realize a multichannel NMR platform for chemical analysis, an embodiment of a robust “pulse-free” procedure was developed as shown in FIG. 4A. This procedure eliminates the need to construct and calibrate pulsing coils for every distinct channel and decreases the risk of magnetizing the shield through strong pulses. In addition, current state of the art ZULF NMR methods needs greater sensitivity to expand the scope beyond13C labeled as is standard in the literature since only heteronuclear spin systems are observed at ZULF. In the“pulse-free” procedure, the sample first undergoes polarization inside a magnet, in one embodiment a 9.4 T magnet, for a given period. The range of the magnetic field strength may be from IT to 20T, the 9.4T magnet comprises one example. In one embodiment, if the sample is formic acid, the period was 19 seconds, to generate nuclear spin polarization. Next, the first guiding field (GF) is turned on immediately before shuttling. The first guiding field is produced by a solenoid that spans the shuttling path joining the magnet and the shield. During shuttling, a second GF is turned on inside the shield along the sensitive axis of the OPM before the sample arrives. Once inside the shield, the first GF is adiabatically turned off in the presence of the second GF, causing the nuclear spins to reorient themselves along the sensitive axis of the OPM. This reorients all spins non-selectively, assuming the adiabatic condition is met for all spin species expressed by gyromagnetic ratios in the sample. Lastly the second guiding field is suddenly turned off, and the nonadiabatic change to ZULF initiates the dynamics subsequently captured by the OPM. The nature of these dynamics at ZULF and the interactions that give rise to them are known.

[0026] To perform such a procedure, the embodiments used a prototype NMRduino based on a Teensy 3.5 microcontroller equipped with digital and analog outputs for producing GFs with smooth decay profiles as well as an analog to digital converter for signal acquisition in the kHz range. Since ZULF spectra are typically on the order of the J coupling values found between heteronuclei within the molecule, the measurement bandwidth is typically 0-500 Hz, a region plagued with electrical, 60 Hz and harmonics in the US, and vibrational noise. To combat this, the inventors powered the electronics using an uninterruptable power supply (UPS) to supply clean battery power to the system as well as operated the experiment on a laptop computer. In some embodiments, the one or more processors in the computer are configured to execute code. The code causes the one or more processors to operate the inhomogeneous magnet to apply a polarization field to the array of samples, turning on a first guide field before turning off the polarization field, prior to transport of the array of samples, turning on a second guide field inside the shield, turning off the first guide field after the array of samples enter the shield, turning off the second guide field, and reading out spectra of the samples from the optically pumped magnetometers.

[0027] In addition, one embodiment fitted the shield housing with Sorbothane vibration dampening feet and mounted the chemical sample on a flexible carbon fiber rod to lessen vibration from the shuttier. As a result, most noise artifacts in the spectrum have been suppressed in minimal scans, as shown FIG. 4B with13C enriched formic acid in 20 scans.This enables extremely sensitive measurements, even achieving a one-shot SNR of 1250 in the case of13C enriched formic acid, shown in FIG. 4B(i), and suggesting the possibility of detection in (1%) natural abundance (NA). This level of sensitivity additionally eliminates the need to remove oxygen from solution by performing degassing procedures such as freezepump-thaw which is normally standard in the ZULF literature to maximize signal.

[0028] Another attractive feature of the apparatus of the embodiments lies in its remarkable magnetic field homogeneity achievable in the shield with minimal effort. Thanks to the pulse- free nature of the experiment, the magnetic shield integrity and homogeneity is maintained as long as the shield is not opened. If opened, degaussing is required once more upon reassembly. Occasionally, DC magnetic “shimming” fields must be applied as cancellation fields if degaussing is insufficient, although these values need not be changed once set unless the shield is opened again. As a result, inhomogeneous broadening is greatly suppressed, as seen in FIG. 4C where sub-Hz linewidths can be observed in complex spectra. These narrow linewidths are remarkably stable, and no adjustment to the shield is needed to maintain its integrity. This contrasts with conventional NMR systems in which linewidths degrade over time as seen in FIG. 4D. Lastly, stable shield conditions allow for precise ultralow field control as demonstrated with water at 12 nT and 244 nT as shown in FIG. 4E. This is useful in cases where controlled Zeeman fields are reintroduced to provide chemical resolution or to perform relaxometry at ultralow field. As used here, an ultralow field has a range of 10 nT to 250 pT.

[0029] Leveraging the sensitivity of the sensitivity of the apparatus allows a report the first organic molecules measured at ZULF in natural isotopic abundance (NA). For molecules with a single carbon such as formic acid, the results attained a 100 times reduction in SNR in agreement with13C’s prevalence in nature (1%) as shown in FIG. 5 A. Similarly, methanol, shown in FIG. 5B, and benzene, shown in FIG. 5C are observed, taking advantage of the high degree of symmetry found in the latter which provides 6% NA since each of the six equivalent carbons have an equal chance (1%) of being naturally enriched. Given the stability of the detection apparatus, the inventors observed an SNR scaling of 1V with N scans implying uncorrelated, Gaussian noise. This idealized noise scaling is crucial for detecting NA samples in low concentrations for chemical analysis contexts. FIG. 5D shows various formic acid spectra taken at different numbers of scans.

[0030] As a metric of sensitivity, one can compare the apparatus of the embodiments to various13C NMR experiments performed on a Spinsolve® 80 Carbon benchtop spectrometer as summarized in FIG. 6, using an identical neat NA formic acid solution for each study. This shows the first ZULF NMR measurements within an order of magnitude of benchtop NMR, having achieved within two orders of magnitude in the case of the most sensitive benchtop experiment. The ability of ZULF NMR to achieve sensitivity comparable to commercial benchtop NMR systems without the need for routine shimming combined with the ability to extend this framework to an arrayed multichannel NMR spectrometer distinguishes ZULF NMR as an analytical analysis tool in a class all its own.

[0031] FIG. 7A showcases a simultaneous three-channel measurement with the setup configured as in FIG. 7A (iv). Leveraging the large homogeneous volume within the shield allowed detection of multiple samples at different positions in the shield at once. FIG. 7A (i)- (iii) shows three distinct signals, alongside the acquisition of three unique free induction decay signals simultaneously as seen in FIG. 7A (v).

[0032] However, a potential concern that arises from parallel measurements is the ’’crosstalk” between channels, which refers to the phenomenon of a spectrum ’’bleeding” into another due to correlations at short distances, be it through the interference of the sensors or the sample’s magnetization / signal being sensed by adjacent sensors. To study and quantify this behavior, the apparatus was configured as described in FIG. 7B.

[0033] In this configuration, two OPMs are separated at a specified distance, with a sample containing enriched formic acid placed in front of one 0PM only. The process then obtains the signal from both the 0PM directly facing sample and the adjacent 0PM. The ratio of the magnitudes of the signal are expressed as a percent and denoted ’Crosstalk %.’ The distance between OPMs is then varied to measure its effect on crosstalk. As observed in FIG. 7B (iii), one can see that the crosstalk even at the closest possible distance (5.4 mm) is less than 10% and decreases rapidly at larger distances. This promising result demonstrates the feasibility of arrayed 0PM detection at a larger scale making ZULF NMR an extensible framework limited solely by the size of the magnetic shield, which defines the detection region, that one can fabricate or buy.

[0034] FIGs. 8A-8C shows results of applying ZULF NMR to a few representative molecules at natural abundance13C, meaning without isotopic enrichment. FIG. 8A shows detection of cyclopentane, FIG. 8B shows detection of acetone, where the peaks refer to different motifsof CH coupling networks. FIG. 8C shows detection of benzene, wherein each of the different isotopomers can be uniquely identified. The low frequency of the ZULF NMR allows for detection of materials even through metal structures such as pipes, and this work shows that this can be carried out at natural abundance of the molecules without isotopic enrichment.

[0035] FIG. 9 shows an embodiment of a ZULF NMR system in a “closed” environment, meaning that magnetic and shielded regions in which the samples reside are closed. In these types of embodiments, the transport mechanism comprises a fluid flow through a pipe 50. The samples comprise materials in the fluid. As the samples flow through the pipe, they flow through a pre-polarization region 52, comprises a magnetic field caused by a magnet having its bore configured around the pipe. The samples then flow through the shielded measurement region 54, with the shield configured around the pipe some distance away from the polarization region. The OPMs from FIGs. 1-3 reside inside the shielded region. One could monitor the spectrometers remotely, if desired, because the samples do not have to be physically loaded into a magnetic bore and then shuttled.

[0036] FIG. 10 shows a simulation of detection of benzene in through metal but a ZULF NMR. The simulated results are shown on the bottom, and the top shows the experimental results. The results indicate the ZULF NMR detected the spectrum of benzene experimentally at a level higher than the simulation suggested.

[0037] As an example of an application of these embodiments would be monitoring the outflow of hazardous or potentially hazardous materials. Because the ZULF NMR spectrometers have such high sensitivity, no need exists to directly access the samples such as opening the pipe. In conventional ZULF NMR spectrometers, the spectrometers must operate through thin, NMR grade glass.

[0038] As a specific example, without limitation, one can consider the plutonium purification process, commonly referred to as “purex.” The purex process exploits small differences in solubility between uranium and plutonium in a solvent, typically tributyl phosphate (TBP). Repeating this process several times allows for separation of the two materials. Over time, radiation in the form of beta emissions from the waste will degrade the solvent, causing it to lose butyl groups as it degrades. As the solvent degrades, the separation process fails, resulting in no more separation between the two materials. This can result in higher toxicity in the waste and reduces the efficiency of the process.

[0039] Because ZULF NMR spectrometers of the embodiments can “see” through many materials, including pipes, it presents a solution to monitor the solvent composition. This allows the process users to know when the solvent needs to be replenished without having to directly sample the hazardous materials. The ZULF NMR spectrometer can differentiate between the solvent and its decomposition products, allowing detection of when to replace or replenish the solvent.

[0040] In another example, a ZULF NMR spectrometer can detect the presence of tritium, a radioactive isotope of hydrogen that has a nucleus comprised of one proton and two neutrons. Tritium emits low levels of beta radiation, which can cause harm if ingested in large quantities as may occur if contained in a water source. FIG. 11 shows a molecule with a tritiated group 60, with the top graph being the simulated results of detection of that group. The bottom graph shows the results with a change of the sign of the frequency. The bottom graph is significantly different from the top graph, demonstrating the sensitivity of the ZULF NMR spectrometers of the embodiments.

[0041] The embodiments have made significant milestones in terms of sensitivity enabling the detection of organic chemical samples in NA and demonstrated the first multichannel ZULF NMR measurement. These show that ZULF MNR comprises an emerging chemical analysis tool In addition, the ability to use lower quality, inhomogeneous magnets for polarization as well as the affordability of magnetic shields and 0PM sensors in general could enable such a tool with an appreciable number of channels at a significantly lower cost compared to conventional high-field NMR systems.

[0042] Additionally, recent advances in high temperature superconducting technology promise appreciable field-strengths in extremely compact and even “wristwatch” sized formfactors. Since homogeneity and magnetic field stability are only necessary to a high degree during detection, ZULF NMR stands to enjoy these advances in superconducting technology much more readily than conventional NMR systems which requires detection at high field as well as polarization, rather than detection at zero-to-ultra-low fields.

[0043] Lastly, the typical bandwidth (0-500 Hz) of ZULF NMR spectra lead to high skin depth of these signals through conductive materials, allowing for NMR measurements inside metal containers. This is also permitted by the lack of an applied field during detection, eliminating the risk of magnetic susceptibility induced broadening in the sample. This could extend the scope of ZULF NMR beyond traditional chemical analysis into contexts whereconventional NMR is normally blind such as large scale in operando battery assays for quality control. Another application of ZULF NMR in this regime is the study of chemistry in high-pressure environments inside metal canisters at pressures unachievable in NMR-grade glass. In this way, ZULF NMR can extend the scope of NMR to new applications while maintaining an attractive price point.

[0044] All features disclosed in the specification, including the claims, abstract, and drawings, and all the steps in any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. Each feature disclosed in the specification, including the claims, abstract, and drawings, can be replaced by alternative features serving the same, equivalent, or similar purpose, unless expressly stated otherwise.

[0045] Additionally, this written description makes reference to particular features. It is to be understood that the disclosure in this specification includes all possible combinations of those particular features. For example, where a particular feature is disclosed in the context of a particular aspect, that feature can also be used, to the extent possible, in the context of other aspects.

[0046] Also, when reference is made in this application to a method having two or more defined steps or operations, the defined steps or operations can be carried out in any order or simultaneously, unless the context excludes those possibilities.

[0047] Although specific aspects of this disclosure have been illustrated and described for purposes of illustration, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention should not be limited except as by the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A nuclear magnetic resonance (NMR) spectrometer, comprising: a set samples to be tested; a shielded region; a set of optically pumped magnetometers (OPM) in the shielded region; an inhomogeneous magnet having a bore configured to accept the samples; a transport mechanism to transport the set of samples between the inhomogeneous magnet and the shielded region, the path having a guiding field solenoid; and a computer to control operation of the spectrometer.

2. The NMR spectrometer as claimed in claim 1, wherein the computer includes one or more processors configured to execute code to cause the one or more processors to: operate the inhomogeneous magnet to apply a polarization field to the set of samples; turning on a first guide field before turning off the polarization field, prior to transport of the array of samples; turning on a second guide field inside the shield inside the region; turning off the first guide field after the array of samples enter the shielded region; and turning off the second guide field; and reading out spectra of the samples from the optically pumped magnetometers.

3. The NMR spectrometer as claimed in claim 1, wherein the set of optically pumped magnetometers comprises one of multiple optically pumped magnetometers, or one optically pumped magnetometer having multiple detection regions.

4. The NMR spectrometer as claimed in claim 1, wherein the shielded region operates in both a zero-field condition and an ultralow field condition, the ultralow field condition has a magnetic strength in a range of 10 nT to 100 pT.

5. The NMR spectrometer as claimed in claim 1, wherein each optically pumped spectrometer in the array of optically pumped spectrometer comprises a cell sensor and a laser.

6. The NMR spectrometer as claimed in claim 1, wherein the optically pumped spectrometers are arranged in channels, providing the NMR spectrometer with multiple channels.

7. The NMR spectrometer as claimed in claim 6, wherein the cell sensor comprises a rubidium sensor.

9. The NMR spectrometer as claimed in claim 1, wherein each sample in the set samples are mounted on a rod to reduce vibration.

10. The NMR spectrometer as claimed in claim 1, wherein the transport mechanism comprises a shuttle to transport the set of samples between the bore of the inhomogeneous magnet and the shielded region.

11. The NMR spectrometer as claimed in claim 1, wherein the set of samples comprise samples in a liquid.

12. The NMR spectrometer as claimed in claim 11, wherein the transport mechanism comprises a flow of the liquid.

13. The NMR spectrometer as claimed in claim 11, wherein the magnet and the shielded regions are mounted to surround the pipe in two regions of the pipe separated by a distance.

14. A method of operating a NMR spectrometer, comprising: polarizing a set of samples using a large magnet having a field strength in the range of IT to 20T;turning on a first guiding field; transporting the set of samples to outside the large magnet along a path; turning on a second guiding field inside the shield; turning off the second guiding field; capturing a readout from each sample in the set of samples at a corresponding optically pumped spectrometer.

15. The method as claimed in claim 14, wherein turning on the first guiding field comprises turning on the first guiding field across the path.

16. The method as claimed in claim 14 wherein transporting the set of samples comprises transporting the set of samples using a shuttle.

17. The method as claimed in claim 14, wherein transporting the set of samples comprises transporting the samples within a liquid flowing in a pipe.

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