Parahydrogen-Induced Radio Amplification by Stimulated Emission of Radiation

Article abstract of DOI:10.1002/anie.201916597

Radio amplification by stimulated emission of radiation (RASER) was recently discovered in a low-field NMR spectrometer incorporating a highly specialized radio-frequency resonator, where a high degree of proton-spin polarization was achieved by reversible parahydrogen exchange. RASER activity, which results from the coherent coupling between the nuclear spins and the inductive detector, can overcome the limits of frequency resolution in NMR. Here we show that this phenomenon is not limited to low magnetic fields or the use of resonators with high-quality factors. We use a commercial bench-top 1.4 T NMR spectrometer in conjunction with pairwise parahydrogen addition producing proton-hyperpolarized molecules in the Earth's magnetic field (ALTADENA condition) or in a high magnetic field (PASADENA condition) to induce RASER without any radio-frequency excitation pulses. The results demonstrate that RASER activity can be observed on virtually any NMR spectrometer and measures most of the important NMR parameters with high precision.

Full text of DOI:10.1002/anie.201916597

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International Edition: DOI: 10.1002/anie.201916597
German Edition: DOI: 10.1002/ange.201916597
Hyperpolarization
Parahydrogen-Induced Radio Amplification by Stimulated Emission of
Radiation
Baptiste Joalland, Nuwandi M. Ariyasingha, Sçren Lehmkuhl, Thomas Theis, Stephan Appelt,
and Eduard Y. Chekmenev*
Abstract: Radio amplification by stimulated emission of
radiation (RASER) was recently discovered in a low-field
NMR spectrometer incorporating a highly specialized radio-
frequency resonator, where a high degree of proton-spin
polarization was achieved by reversible parahydrogen ex-
change. RASER activity, which results from the coherent
coupling between the nuclear spins and the inductive detector,
can overcome the limits of frequency resolution in NMR. Here
we show that this phenomenon is not limited to low magnetic
fields or the use of resonators with high-quality factors. We use
a commercial bench-top 1.4 T NMR spectrometer in conjunc-
tion with pairwise parahydrogen addition producing proton-
hyperpolarized molecules in the Earthꢀs magnetic field (AL-
TADENA condition) or in a high magnetic field (PASADE-
NA condition) to induce RASER without any radio-frequency
excitation pulses. The results demonstrate that RASER activity
can be observed on virtually any NMR spectrometer and
measures most of the important NMR parameters with high
precision.
RASER is induced by continuous coherent oscillation of
radio waves at much lower frequencies through the coupling
between nuclear-spin magnetization and an LC resonance
[1]
circuit. Because the required magnetization, that is, the
product of the concentration of nuclear spins and their
nuclear-spin polarization (P) or the degree of the spin
alignment with the static magnetic field of the NMR magnet,
is very high, RASER-based NMR spectroscopy is difficult to
achieve using thermal nuclear-spin polarization. Hyperpola-
rization techniques allow for enhancing the nuclear-spin
[3–7]
[8,9]
polarization by several orders of magnitude
up to unity.
Suefke and co-workers thus employed the technique of signal
amplification by reversible exchange (SABRE) to provide
a highly magnetized sample in their pioneering RASER
[
10]
demonstration.
change between parahydrogen (p-H , the source of hyper-
SABRE relies on the simultaneous ex-
2
[
11]
polarization) and a substrate on a metal complex. With
SABRE, the spontaneous polarization of proton spins is
efficient in the magnetic-field range of 1 to 10 mT. There-
fore, Suefke and co-workers employed NMR detection at
magnetic fields of several mT with corresponding resonance
[
12]
Introduction
[
1,2]
frequencies in the range of 41–512 kHz. These authors also
employed SABRE because it allows for continuously regen-
Suefke and co-workers reported recently (in 2017) on the
first experimental observation of radio amplification by
erating the proton polarization via the sustained delivery of p-
[
1,2]
[1]
stimulated emission of radiation (RASER) of protons.
H gas to the sample placed inside the NMR detector.
2
Unlike lasers and masers, which employ self-organizing
systems emitting coherent optical light and microwaves,
RASER activity is initiated when the radiation damping rate
1/tRD satisfies the following condition:
1=tRD > 1=T2*
ð1Þ
[
*] Dr. B. Joalland, N. M. Ariyasingha, Prof. E. Y. Chekmenev
Department of Chemistry, Integrative Biosciences (Ibio)
Karmanos Cancer Institute (KCI), Wayne State University
Detroit, MI 48202 (USA)
where 1/T * defines the modified spin–spin relaxation rate
2
and 1/tRD the radiation-damping rate, which is given by
E-mail: Chekmenev@wayne.edu
Dr. S. Lehmkuhl, Prof. T. Theis
Department of Chemistry, North Carolina State University
Raleigh, NC 27695-8204 (USA)
2
1
=tRD ¼ ꢀðm =2Þh Q g M ¼ ꢀðm =4Þh Q g ꢀh n P
ð2Þ
0
0
0
S
where m , h, Q, g, ꢀh , and n are defined as the vacuum
0
S
Prof. S. Appelt
permeability, the filling factor of the resonator, the quality
factor of the resonator, the gyromagnetic ratio, Planckꢀs
constant, and the spin-number density, respectively. The
initial magnetization is given as M = (1/2) ꢀh gn P, where P
Institut fꢀr Technische und Makromolekulare Chemie (ITMC)
RWTH Aachen University
52056 Aachen (Germany),
and
0
S
Central Institute for Engineering, Electronics and Analytics—
Electronic Systems (ZEA 2), Forschungszentrum Jꢀlich GmbH
[1]
is the degree of spin polarization. Note that if P > 0, the rate
/tRD is negative and the associated line is additionally
1
52425 Jꢀlich (Germany)
broadened by radiation damping with a total damping rate
Prof. E. Y. Chekmenev
Russian Academy of Sciences
Leninskiy Prospekt 14, Moscow, 119991 (Russia)
ktot = (1/T *ꢀ1/t ) > 1/T *. If P < 0, which corresponds to
2
RD
2
a population inversion, 1/t
is positive and the line is
RD
narrowed due to the decreased total damping rate ktot < 1/T *.
RASER activity starts if ktot < 0, as described by Equation (1).
To fulfill this condition for proton spins at low frequencies,
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201916597.
2
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Suefke and co-workers employed high-quality (Q ꢁ 300)
resonators, which reduce the RASER-threshold require-
[
13]
[1]
ments for polarization and concentration significantly.
Hence, the experimental conditions used for this first
demonstration RASER, that is, low magnetic field, high-Q
resonator, and continuous regeneration of hyperpolarization,
seem very peculiar. As a matter of fact, RASER activity is
a much more common phenomenon than one could expect, as
we will show below.
Results and Discussion
We provide evidence that a commercial high-field NMR
system with standard inductive detection (that is, without
specialized high-Q resonators) can readily detect RASER
when combined with the parahydrogen-induced polarization
[
14]
(
PHIP) technique.
Specifically, we employ a 1.4 T
(
61.7 MHz) bench-top NMR spectrometer (SpinSolve Car-
bon 60, Magritek, New Zealand) with Q = 68 to induce
RASER of protons in hyperpolarized (HP) ethyl acetate
(
EA) and 2-hydroxyethyl propionate (HEP). These HP
compounds are formed through the pairwise addition of p-
H to the unsaturated C=C bonds of the substrates vinyl
2
acetate (VA) and 2-hydroxyethyl acrylate (HEA), respec-
tively (Figure 1a,b). The symmetry breaking of the nascent p-
H -derived protons allows for the hyperpolarization to
2
[
7,15]
become observable.
0.4m of substrates and 4 mm of catalyst (bicyclo-
2.2.1]hepta-2,5-diene)[1,4-bis(diphenylphosphino)butane]-
rhodium(I) tetrafluoroborate] (Sigma–Aldrich, P/N 341126-
00MG) in CD OD. Nearly 100% p-H was employed using
The solutions were prepared with
ꢁ
[
1
3
2
[
16]
a home-built cryogenic generator. At 758C and 100 psi, the
substrates were fully converted into their respective HP
products via bubbling p-H for 15 s with a 150 sccm flow rate
2
Figure 1. a),b) Reaction schemes for the pairwise p-H addition to
vinyl acetate (VA) yielding ethyl acetate (EA) and to 2-hydroxyethyl
acrylate (HEA) yielding 2-hydroxyethyl propionate (HEP). c) Experimen-
tal setup. d),e) ALTADENA and PASADENA protocols used to evidence
parahydrogen-induced RASER activity.
controlled by a mass-flow controller, as described previously
2
[
17]
(
Figure 1c).
The chemical conversion was monitored by
1
comparing the H NMR spectra of thermally polarized
samples taken before and after the PHIP reactions (Figur-
es S1 and S2 in the Supporting Information). The polarization
of HA and H was estimated to be between 10% and 20%
B
[18]
based on a previous study, and their T relaxation times
tioned 4–5 cm above the RF coil so the catheter could be
removed without interfering with the signal detection, which
was initiated before the hydrogenation reaction was com-
pleted. Once the reaction was completed and the catheter
removed, the sample was pushed inside the RF coil (Fig-
ure 1e).
1
were measured to be ꢁ 16–25 s (Figure S3).
Two main experimental protocols were followed. The first
[
19]
protocol corresponds to the ALTADENA condition. In this
case, the samples were hydrogenated in the Earthꢀs magnetic
field ( ꢁ 50 mT). The p-H2 flow was then interrupted, the
sample depressurized, the catheter removed, the pulse-and-
acquire sequence initiated, and the sample inserted into the
NMR spectrometer (Figure 1d). To make sure that the
sample does not experience any radiofrequency (RF) excita-
tion, the sample was inserted several seconds after a RF pulse
with a flip angle lower than 0.018 (for inconvenient technical
reasons, we were not able to open the detection channel
without executing a pulse). The detector channel was opened
for up to 32 s. The second protocol corresponds to the
The main results obtained for EA and HEP are illustrated
in Figures 2 and 3, respectively. For both ALTADENA and
PASADENA experiments, the NMR signal exhibits the
characteristic features of RASER activity: Signal persistence
[
1,13]
for significantly longer periods of time than T * of ꢁ 0.6 s.
2
The Fourier-transformed spectra of selected regions with
a defined duration of the RASER-active signals, for example,
Figure 2b,c for ALTADENA and Figure 2i–l for PASADE-
NA, clearly show evidence for the enhanced spectral reso-
lution due to RASER activity with sharp peaks with
FWHM < 0.2 Hz, whereas the resolution of the spectrometer
is ꢁ 0.5 Hz after full shimming and ꢁ 2 Hz in case of
[
20]
PASADENA condition in which the hydrogenation reac-
tion was performed at 1.4 T, that is, inside the spectrometer.
During the hydrogenation reaction, the sample was posi-
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1
Figure 2. H NMR spectroscopy of solution-phase PHIP of 0.4m HP ethyl acetate (EA) probed at 1.4 T. a) ALTADENA RASER signal recorded
without a RF pulse after hydrogenation in the Earth’s magnetic field. b),c) Fourier spectra of the regions outlined by red and purple boxes,
respectively, in panel (a). d),e) Partial ALTADENA RASER signal and Fourier spectrum obtained with a ꢁ38 RF pulse. f),g) Canonical ALTADENA
(
non-RASER) FID and Fourier spectrum recorded after further polarization decay. h) PASADENA RASER signal recorded without a RF pulse after
hydrogenation at 1.4 T. i)–l) Fourier spectra of the regions outlined by red, purple, green, and orange boxes, respectively, in panel (h).
m),n) Canonical PASADENA (non-RASER) FID and Fourier spectrum acquired with a ꢁ38 RF pulse after further polarization decay (ꢁ30 s).
conventional HP experiments. Immediately after these RAS-
ER-active signals were recorded, additional NMR spectra
were acquired using a ꢁ 3.38 excitation RF pulse. The first of
those spectra shows partially RASER-active NMR lines (see
Figure 2e for ALTADENA and Figure 3l for PASADENA),
while the subsequent acquisitions correspond to normal,
hyperpolarized ALTADENA (Figures 2g and 3g) and PA-
SADENA (Figures 2n and 3n) spectra.
With ALTADENA, the Fourier spectra of the time slices
of the RASER-active signals (displayed in Figures 2a and 3a)
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1
Figure 3. H NMR spectroscopy of solution-phase PHIP of 0.4m HP 2-hydroxyethyl propionate (HEP) probed at 1.4 T. a) ALTADENA RASER signal
recorded without a RF pulse after hydrogenation in the Earth’s magnetic field. b),c) Fourier spectra of the regions outlined by red and purple
lines, respectively, in panel (b). d),e) Partial ALTADENA RASER signal and Fourier spectrum acquired using a ꢁ38 RF pulse. f),g) Canonical
ALTADENA (non-RASER) FID and Fourier spectrum recorded after further polarization decay (ꢁ30 s). h) PASADENA RASER signal recorded
without a RF pulse after hydrogenation at 1.4 T. i),j) Fourier spectra of the regions outlined by red and purple lines, respectively, in panel (h).
k),l) Partial PASADENA RASER signal and Fourier spectrum acquired using a ꢁ38 RF pulse. m),n) Canonical PASADENA (non-RASER) FID and
Fourier spectrum acquired with a ꢁ38 RF pulse after further polarization decay (ꢁ30 s).
show a doublet (Figures 2b and 3b). These two RASER
resonances can be attributed to lines in the PHIP spectra
depicted in Figures 2g and 3g, respectively. In particular, each
of the three triplet lines corresponding to proton HB are
population-inverted (have negative sign) and its two most
intense lines are RASER-active. The doublet is separated by
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a splitting corresponding to the spin–spin coupling J
of
with more dilute samples, as illustrated by the NMR signal
shown in Figure S4 and obtained with a 40 mm VA solution.
This indicates that PHIP RASER occurs at relatively low
concentrations of the HP substrate; in particular, lower
concentrations than those reported previously for the sponta-
neous emission of NMR signals with the dissolution dynamic
HAꢀHB
7
.0 Hz between proton HA and H in EA and HEP
B
[21]
(
Figures 2b and 3b, respectively).
While the HP state
decays, the number of RASER-active lines changes, for
example from two RASER-active lines in Figures 2b and 3b
to one single line in Figures 2c and 3c. This can be explained
by different transverse relaxation rates and multiplicities of
each RASER line. For instance, at low polarization, only one
line with the highest amplitude in the NMR spectrum and
with the smallest linewidth overcomes the RASER threshold
and is RASER-active.
[23]
nuclear polarization (d-DNP) technique.
ALTADENA
RASER activity was also observed while leaving the catheter
(1/16’’ outer diameter, 1/32’’ inner diameter) inside the NMR
tube, thus creating more stringent conditions for its occur-
rence because the presence of the catheter leads to a signifi-
All ALTADENA-hyperpolarized RASER spectra in
Figures 2 and 3 differ significantly from the corresponding
PHIP spectra in Figures 2g and 3g. The latter feature the HP
resonances of H and H with the quartet and triplet lines of
cant susceptibility-induced B gradient and effectively shorter
0
T * (see Figures S5,S6). Note that in additional PASADENA
2
experiments, the hydrogenation reactions were performed
within the RF coil, and RASER was detected immediately
A
B
opposite signs. These are separated by ꢁ 2.8 ppm ( ꢁ 174 Hz)
for EA and ꢁ 1.2 ppm ( ꢁ 74 Hz) for HEP. Specifically, the
linewidth of the quartet FWHM of ꢁ 4 Hz in Figure 2g is
significantly broader compared to the linewidth of each of the
triplet lines with a FWHM of ꢁ 2 Hz. This is more pro-
nounced in Figure 2e, where the difference in linewidth is
more than one order of magnitude. The same trend is
observed in Figure 3e,g. The reason for this is the sign and the
magnitude of the HP state, which introduce a broadening with
ktot > 1/T * of the quartet lines and a narrowing with k < 1/
after the cessation of p-H bubbling because the bubbles
2
induce a significant degradation of T * (likely below 1 ms)
2
that prevents RASER activity at this magnetic field.
These findings are crucial in the context of PHIP studies
and biomedical applications. The HP substrates used here can
indeed be employed as in-vivo contrast agents. For example,
HP HEP has been extensively studied as a potential contrast
[
24–26]
agent in angiography studies.
techniques rely on the application of RF pulses, especially in
Because some of the PHIP
1
3
the case of polarization transfer from protons to
C
2
tot
[
27–35]
T * of the triplet lines. For the RASER lines in Figure 2b and
2
nuclei,
the RF coils may interact with the highly
3
b, ktot is negative and the linewidth, in principal, is only
proton-hyperpolarized compounds, resulting in complicated
non-linear effects and depletion of hyperpolarization via
RASER activity. Therefore, RASER effects may be consid-
ered as an obstacle in this context. The use of untuned RF
limited by the finite measurement time and ultimately by the
[
22]
Cramꢁr–Rao condition.
spectra of VA and HEP hyperpolarized by ALTADENA
allow the J-coupling constant J to be determined with
We conclude that the RASER
[
36,37]
coils
may help mitigate the occurrence of RASER, so
HAꢀHB
enhanced precision but the chemical-shift difference between
that the hyperpolarized proton pool is not depleted prior to its
utilization during contrast-agent preparation. Moreover, the
recent advent of PHIP via side-arm hydrogenation (SAH)
significantly expanded the range of biomolecules (including
H and H is not measurable in this RASER experiment.
A
B
The analysis of the RASER-active signals in the PASA-
DENA case (Figures 2h and 3h) renders other interesting
observations in addition to the anticipated line-narrowing. In
particular, the Fourier spectra of the RASER-active signals
[17,38]
ethyl acetate) that can be hyperpolarized via PHIP.
With
this technique, a wide range of carboxylic acids have been
hyperpolarized and employed in vivo for metabolism track-
(
Figures 2i and 3i) exhibit two large central RASER lines
[
21,27,38–42]
separated by the chemical-shift difference dHA ꢀd between
ing.
Amid the peer-review evaluation of the present work,
another interesting study regarding PHIP-RASER by Prav-
HB
the HA and HB protons, that is, dHA ꢀd = 2.8 ppm
HB
(
ꢁ 174 Hz) for EA and 1.2 ppm ( ꢁ 74 Hz) for HEP. The
[
43]
two central lines are accompanied by evenly spaced small
sidebands, and the distance between two consecutive lines is
divtsev and co-workers was reported. In contrast with the
common and somewhat ordinary conditions we have pre-
sented here, Pravdivtsev et al. designed a specific experiment
dedicated to observe parahydrogen-induced RASER activity
under PASADENA conditions at a magnetic field of 14 T
exactly dHA ꢀd . This can be explained by the non-linear
HB
interaction between different RASER-active modes (here:
[
2]
two) leading to a frequency-comb-like spectrum. We also
even found frequency-comb-like spectra in the case of the
ALTADENA-pumped RASER, where the two central modes
[
43]
(600 MHz) and with a cryogenically cooled coil (Q ꢁ 500).
The catalyst activity was tuned for building up polarization
throughout an extended period of time (about 10 min) with
a continuous delivery of p-H . The pairwise p-H addition was
and all sidebands are spaced by J
. Moreover, the
HAꢀHB
resonance frequencies of the RASER-active protons (Figur-
es 2b,c and 3b,c) are sometimes shifted by about 1 ppm when
compared with the partial RASER and hyperpolarized ones.
We speculate that this is due to the magnetic-field fluctuations
induced by RASER. A detailed evaluation of these and other
non-linear phenomena will be published elsewhere.
A series of additional experiments were performed,
demonstrating further that the experimental conditions
necessary for observing RASER through PHIP reactions
are not stringent at all. RASER bursts can indeed be observed
2
2
performed with two substrates incorporating CꢂC triple
bonds. Without RF-pulse excitation, RASER activity was
detected only after bubbling p-H2 for about 90 s. Only
chemical shifts but no J-couplings could be determined in
these very-high-field experiments and the reported linewidths
(in the order of 1 Hz) of the RASER-active lines do not differ
significantly from the linewidth obtained by a corresponding
standard NMR spectrum (a few ppb at 600 MHz). The work
presented in this article differs in many regards. First and
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foremost, the equipment employed here is a commercially
R21EB025313. T.T. and S.L. acknowledge funding from the
available NMR spectrometer with an unaltered room-tem-
perature RF coil with Q ꢁ 68—such instrumentation is widely
available, making our observations possible and easy to
replicate by others interested in using the PHIP RASER
North Carolina Biotechnology Center as well as the Mal-
linckrodt Foundation.
effect. Second, we demonstrated PHIP RASER under both Conflict of interest
PASADENA and ALTADENA conditions and showed
intriguing J-coupling and chemical-shift-controlled dynamics
of RASER-signal evolution. No RF stimulation was required
to induce the RASER effect. Third, we employed two
The authors declare no conflict of interest.
Keywords: hyperpolarization · NMR spectroscopy ·
parahydrogen · PHIP · RASER
[
44,45]
[25]
molecular moieties (acetate
and propionate via pair-
wise p-H addition to the C=C double bond) that have been
2
previously employed in in-vivo bio-imaging studies of perfu-
sion and metabolism. Importantly, we employed the process
[
34,35]
of batch hyperpolarization,
when a bolus of material is
hyperpolarized over a short period of time (circa 10 s), and
such bolus could be employed for in-vivo imaging applica-
tions, paving the way to a potential future use of RASER in
bio-imaging applications, which have the potential to revolu-
tionize MRI and medical imaging.
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applications of RF-excitation pulses and under both ALTA-
DENA and PASADENA conditions. J-coupling constants as
well as chemical-shift differences could be measured with
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researchers using standard, commercial NMR spectrometers
are therefore expected to experience RASER activity and
radiation-damping or line-narrowing phenomena routinely.
Appropriate considerations must be made when performing
NMR experiments with such highly polarized compounds.
Our observations are especially important for PHIP studies
that aim at providing highly polarized contrast agents for
imaging of metabolism, that is, where high levels of polar-
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[
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Version of record online: && &&
,
&&&&
&
&&&
www.angewandte.org
ꢀ 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2020, 59, 2 – 9
These are not the final page numbers!

Angewandte
Research Articles
Chemie
Research Articles
Hyperpolarization
The RASER’s cutting edge: Radio am-
plification by stimulated emission of
radiation (RASER) is demonstrated using
a 61 MHz NMR spectrometer in con-
junction with the pairwise addition of
parahydrogen, producing proton-hyper-
polarized molecules with NMR-signal
induction without any radio-frequency-
excitation pulses. These findings are
important for future applications of
RASER in many different fields of science
and technology.
B. Joalland, N. M. Ariyasingha,
S. Lehmkuhl, T. Theis, S. Appelt,
E. Y. Chekmenev*
&&&& — &&&&
Parahydrogen-Induced Radio
Amplification by Stimulated Emission of
Radiation
Angew. Chem. Int. Ed. 2020, 59, 2 – 9
ꢀ 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
&&&&
These are not the final page numbers!