Heterogeneous Parahydrogen Pairwise Addition to Cyclopropane

Article abstract of DOI:10.1002/cphc.201800690

Hyperpolarized gases revolutionize functional pulmonary imaging. Hyperpolarized propane is a promising emerging contrast agent for pulmonary MRI. Unlike hyperpolarized noble gases, proton-hyperpolarized propane gas can be imaged using conventional MRI scanners with proton imaging capability. Moreover, it is non-toxic odorless anesthetic. Furthermore, propane hyperpolarization can be accomplished by pairwise addition of parahydrogen to propylene. Here, we demonstrate the feasibility of propane hyperpolarization via hydrogenation of cyclopropane with parahydrogen. ¹H propane polarization up to 2.4 % is demonstrated here using 82 % parahydrogen enrichment and heterogeneous Rh/TiO₂ hydrogenation catalyst. This level of polarization is several times greater than that obtained with propylene as a precursor under the same conditions despite the fact that direct pairwise addition of parahydrogen to cyclopropane may also lead to formation of propane with NMR-invisible hyperpolarization due to magnetic equivalence of nascent parahydrogen protons in two CH₃ groups. NMR-visible hyperpolarized propane demonstrated here can be formed only via a reaction pathway involving cleavage of at least one C–H bond in the reactant molecule. The resulting NMR signal enhancement of hyperpolarized propane was sufficient for 2D gradient echo MRI of ～5.5 mL phantom with 1×1 mm² spatial resolution and 64×64 imaging matrix despite relatively low chemical conversion of cyclopropane substrate.

Full text of DOI:10.1002/cphc.201800690

Accepted Article
Title: Heterogeneous Parahydrogen Pairwise Addition to Cyclopropane
Authors: Oleg Salnikov, Kirill Kovtunov, Panayiotis Nikolaou, Larisa
Kovtunova, Valerii I Bukhtiyarov, Igor V Koptyug, and Eduard
Y. Chekmenev
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemPhysChem 10.1002/cphc.201800690
Link to VoR: http://dx.doi.org/10.1002/cphc.201800690
A Journal of
www.chemphyschem.org

ChemPhysChem
10.1002/cphc.201800690
COMMUNICATION
Heterogeneous Parahydrogen Pairwise Addition to Cyclopropane
Oleg G. Salnikov*,[a,b] Kirill V. Kovtunov,[a,b] Panayiotis Nikolaou, Larisa M. Kovtunova,
[c]
[d,b]
Valerii I.
Bukhtiyarov,[d,b] Igor V. Koptyug,[a,b] and Eduard Y. Chekmenev*[c,e,f]
Abstract: Hyperpolarized gases revolutionize functional pulmonary
imaging. Hyperpolarized propane is a promising emerging contrast
agent for pulmonary MRI. Unlike hyperpolarized noble gases,
proton-hyperpolarized propane gas can be imaged using
used for clinical pulmonary imaging of chronic obstructive
pulmonary disease (COPD).[1, 2] However, these techniques
have drawbacks of (i) a patient exposure to ionizing radiation,
and (ii) lacking functional information to report on gas ventilation,
conventional MRI scanners with proton imaging capability. Moreover, diffusion and perfusion. Hyperpolarization of nuclear spins is a
it is non-toxic odorless anesthetic. Furthermore, propane
hyperpolarization can be accomplished by pairwise addition of
parahydrogen to propylene. Here, we demonstrate the feasibility of
propane hyperpolarization via hydrogenation of cyclopropane with
highly efficient way to boost the sensitivity of NMR and MRI
through the increase of P by several orders of magnitude.[
Hyperpolarization techniques such as dynamic nuclear
polarization (DNP),[4-7] spin-exchange optical pumping (SEOP) of
noble gases,[1, 2, 8-10] and parahydrogen-induced polarization
(PHIP)[11-15] can produce hyperpolarized (HP) gases, which can
be potentially inhaled. The inhaled HP gas can be imaged on a
single breath hold resulting in 2D and 3D functional MRI images
of gas ventilation, diffusion and perfusion.[2, 16, 17] Currently, the
1-3]
1
parahydrogen. H propane polarization up to 2.4% is demonstrated
here using 82% parahydrogen enrichment and heterogeneous
2
Rh/TiO hydrogenation catalyst. This level of polarization is several
times greater than that of propylene precursor under the same
conditions despite the fact that direct pairwise addition of
parahydrogen to cyclopropane may also lead to formation of
propane with NMR-invisible hyperpolarization due to magnetic
most widely used HP gases are 129Xe and 3He, produced by
SEOP[
1, 2, 18]
and successfully utilized for preclinical and clinical
equivalence of nascent parahydrogen protons in two CH
3
groups.
imaging of COPD.[2, 19-23] However, SEOP requires sophisticated
hyperpolarization hardware (including high-power lasers), and
NMR-visible hyperpolarized propane demonstrated here can be
formed only via a reaction pathway involving cleavage of at least one
C–H bond in the reactant molecule. The resulting NMR signal
enhancement of hyperpolarized propane was sufficient for 2D
[
24-
has a throughput limitation of a few liters of HP gas per hour.
3
1]
Moreover, HP noble gases ( He, 129Xe, etc.) cannot be
3
directly imaged on clinical MRI scanners, because they require
heteronuclear MRI hardware and software capabilities, which is
currently available only on highly-specialized research MRI
scanners. PHIP is a significantly less expensive and faster
alternative to SEOP. PHIP has been shown to produce proton-
HP gases, e.g. propane,[32-36] which can be detected on any
conventional MRI scanner. PHIP is based on a pairwise addition
2
gradient echo MRI of ~5.5 mL phantom with 1×1 mm spatial
resolution and 64×64 imaging matrix despite relatively low chemical
conversion of cyclopropane substrate.
Despite its high importance as a powerful tool for clinical
diagnostics of various diseases and pathologies, magnetic
resonance imaging (MRI) suffers from inherently low sensitivity
of two atoms from the same parahydrogen (p-H
2
) molecule to an
molecule[11,
12]
asymmetric unsaturated substrate
over
-6
-5
caused by low (10 -10 ) nuclear spin polarization P. The low
sensitivity issue additionally exacerbates the challenges for MRI
of lungs due to their inherently low spin density. As a result,
computed tomography (CT) and chest radiography are typically
homogeneous[ or heterogeneous[38] hydrogenation catalyst.
37]
Recent progress in heterogeneous catalytic systems[32, 38-40]
has achieved more than 10% contribution of pairwise p-H
exceeding 10%).[41, 42] Moreover,
2
addition (i.e. polarization P
H
heterogeneous catalysts are robust and well-suited for
production of pure from catalyst HP gases for potential in vivo
and clinical use for pulmonary and other bioimaging applications.
Currently, one of the most promising proton-HP candidates for in
vivo applications is propane gas.[1, 43-45] Propane has low toxicity
since it is not readily absorbed and is not biologically active, and
can be administered in vivo via inhalation as an anesthetic.[
[a]
[b]
[c]
O. G. Salnikov, Dr. K. V. Kovtunov, Prof. I. V. Koptyug
International Tomography Center, SB RAS
3A Institutskaya st., Novosibirsk 630090, Russia
E-mail: salnikov@tomo.nsc.ru
O. G. Salnikov, Dr. K. V. Kovtunov, Dr. L. M. Kovtunova,
Prof. V. I. Bukhtiyarov, Prof. I. V. Koptyug
Novosibirsk State University
46]
HP propane can be produced by pairwise addition of p-H
2
to
2
Pirogova st., Novosibirsk 630090, Russia
propylene over
a
number of heterogeneous catalysts.[32]
Dr. P. Nikolaou, Prof. E. Y. Chekmenev
However, the use of propylene is undesirable in case of its
incomplete conversion because of propylene unpleasant odor.
In this communication, we explore the feasibility of
production of HP propane gas via hydrogenation of
cyclopropane with p-H . The advantage of cyclopropane as an
2
unsaturated precursor for HP propane production is its well-
established prior use in anesthesia.[47] Since cyclopropane does
not contain C=C bonds, it is unlikely that it could be coordinated
to a transition metal complex and, hence, hydrogenated over
this type of catalyst. Indeed, no reaction was observed between
Vanderbilt University Institute of Imaging Science (VUIIS),
Department of Radiology, Department of Biomedical Engineering,
and Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University
Medical Center, Nashville, TN 37232-2310, United States
Dr. L. M. Kovtunova, Prof. V. I. Bukhtiyarov
[d]
[e]
[f]
Boreskov Institute of Catalysis, SB RAS
5
Acad. Lavrentiev pr., Novosibirsk 630090, Russia
Prof. E. Y. Chekmenev
Russian Academy of Sciences
14 Leninskiy prospect, Moscow 119991, Russia
Prof. E. Y. Chekmenev
Department of Chemistry, Integrative Biosciences (Ibio), Wayne
State University, Karmanos Cancer Institute (KCI)
Detroit, MI 48202, United States
cyclopropane and p-H
Rh(NBD)(dppb)]BF in CD
,4-bis(diphenylphosphino)butane), i.e. under conditions when
2
in the presence of homogeneous catalyst
[
4
3
OD (NBD = norbornadiene, dppb =
E-mail: chekmenev@wayne.edu
1
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

ChemPhysChem
10.1002/cphc.201800690
COMMUNICATION
highly polarized propane is formed from propylene and p-H
mixture.[48]
2
show considerable activity in flow conditions though slow
formation of propane was observed after interruption of gas flow
In principle, considering the broad range of processes which
may occur on the surface of supported metal nanoparticles
during hydrogenation,[49-52] the reaction of cyclopropane with p-
(Figure 1c). Pt/TiO
propane was formed even at flow conditions but PHIP effects
were not detected (Figure 1b). In contrast, utilization of Rh/TiO
2
catalyst was the most active; indeed,
2
H
2
over supported metal catalysts may lead to three types of HP
propane molecules with p-H -derived protons in CH group and
CH group via route #1, in two different CH groups via route #2
or in the same CH group via route #3 (Scheme 1a). The routes
2 and #3 are of particular interest, because pH -derived
catalyst allowed to observe pronounced PASADENA signals of
HP propane in flow conditions (Figure 1a) similar to those
observed in PASADENA hydrogenation of propylene.[ This
result is consistent with several previous studies on
2
3
38]
2
3
3
#
2
hydrogenation of alkenes with p-H
RhTiO catalyst provides higher PHIP signals intensities than
Pt/TiO or Pd/TiO , indicating that contribution of route of
pairwise H addition to C=C bonds is greater in the case of
2
, where it was shown that
protons are located in magnetically equivalent positions in
reaction product molecules. Due to magnetic equivalence,
hyperpolarization of these molecules cannot be revealed by
direct NMR spectroscopy, similarly to singlet state of p-H
molecule or nuclear spin isomers of ethylene produced by
2
2
2
2
Rh/TiO
produced from hydrogenation of cyclopropane on Rh/TiO
were %P ~0.34–0.84% at 82% p-H enrichment depending on
2
.[32,
52]
The estimated polarizations of HP propane
2
2
to acetylene.[
53]
NMR spectra
pairwise addition of p-H
2
H
2
simulations of such spin states of HP propane performed using
standard density matrix formalism indeed show that no NMR
reactants’ gas flow rates. These values are the lower estimates
of propane polarizations, because spectra acquired after
interruption of gas flow and complete relaxation of HP state were
used as thermal references. Therefore, some additional amount
of reaction product may be formed during this delay leading to
signal should occur from p-H
hand, these symmetric states of HP propane could be very long
lived similar to p-H
and nuclear spin isomers of ethylene,[53]
2
derived protons. On the other
2
making them potentially possible to use as a reservoir for
storage of hyperpolarization.
H
overestimation of the denominator of P calculation. At the same
time, overall hydrogenation activity of Rh catalyst in PASADENA
The performance of three supported metal catalysts (Pt/TiO
Pd/TiO and Rh/TiO in cyclopropane hydrogenation was
studied in PASADENA
with p-H was carried out in high magnetic field of NMR
spectrometer inside a 5 mm NMR tube. Pd/TiO catalyst did not
2
,
conditions was very low (≤1% conversion of cyclopropane).
2
2
)
[
Rh/TiO
of cyclopropane with p-H
PASADENA signals of HP propane (Figure S1).
2
catalyst was also tested in liquid phase hydrogenation
12]
conditions, i.e. when hydrogenation
2
in CD OD and yielded some weak
3
2
2
Scheme 1. (a) Reaction scheme of cyclopropane hydrogenation with p-H
2
over heterogeneous catalyst. (b) Possible mechanisms of HP propane formation via
-H and H -H
reaction of cyclopropane with p-H over Rh/TiO catalyst. p-H molecules are denoted as H
2
2
2
A
B
C
D
.
This article is protected by copyright. All rights reserved.

ChemPhysChem
10.1002/cphc.201800690
COMMUNICATION
acquired with 1×1 mm2 spatial resolution and 64×64 imaging
matrix (Figure 3). Importantly, these images are the first
demonstration of high field MRI of HP propane in a stopped flow
mode, contrary to previously shown high field MRI of
continuously flowing HP propane gas.[32] The feasibility of
stopped flow MRI is important, because this regime will be
implemented in case of HP propane inhalation by a patient.
Considering relatively fast T
possibility to obtain its MR image
1
relaxation of HP propane, the
few seconds after
a
interruption of gas flow demonstrates the promising prospects
for application of HP propane as a contrast agent for lung MRI.
Figure 1. (a) Reaction scheme of cyclopropane hydrogenation with p-H
2
. (b–d)
1
H NMR spectra acquired in PASADENA hydrogenation of cyclopropane with
0% enriched p-H at 90 °C over 10 mg of (b) 1 wt.% Rh/TiO catalyst, (c) 2
wt.% Pt/TiO catalyst, (d) 2 wt.% Pd/TiO catalyst in flowing gas conditions (30
sccm of cyclopropane and 100 sccm of H at 90 psig total pressure).
5
2
2
2
2
2
Due to relatively low efficiency of PASADENA hydrogenation of
cyclopropane, we explored the possibility of performing
hydrogenation reaction outside the NMR spectrometer in the
Earth’s magnetic field (ALTADENA[54] conditions) using a high-
pressure setup with temperature control. In our case, the
maximum signals were observed at 720 standard cubic
centimetres per minute (sccm) total gas flow rate (Figure S2).
Conversion values at these conditions did not exceed 0.3%,
despite the use of higher catalyst loads (Table S1). Temperature
dependence indicates that moderate temperature (~110–135 °C)
is needed in order to obtain the most intensive ALTADENA
signals (Figure S3). Despite the low reaction yield, the use of
cyclopropane as a precursor of HP propane is promising due to
remarkably high levels of polarization. The highest obtained
Figure 2. (a) Reaction scheme of cyclopropane hydrogenation with p-H
2
over
1
Rh/TiO
2
catalyst. (b–c)
H
NMR spectra acquired in ALTADENA
at 130 °C and 90 psig
catalyst (b) while the gas was
flowing and (c) after interruption of gas flow. The gas flow rates of
cyclopropane and H were 240 and 480 sccm, respectively. The spectra are
hydrogenation of cyclopropane with 84% enriched p-H
total pressure over 280 mg of 1 wt.% Rh/TiO
2
2
2
presented on the same vertical scale.
The observation of such high levels of propane polarization in
cyclopropane hydrogenation is unexpected, because only route
signal enhancement was 460–480, corresponding to 1.5–1.6%
1H polarization (Table S1). The polarization levels obtained
using propylene as a precursor were ~4 times lower under
conditions of optimized temperature and otherwise similar
experimental parameters at nearly 100% conversion.
#1 (see Scheme 1a) contributes to the observable PHIP signal,
while all propane molecules prepared via routes #1–3 as well as
via non-pairwise hydrogen addition contribute to the signal of
thermally polarized propane used as
and %P estimation. Moreover, intuitively route #2 should be
preferred over route #1 for ring opening, since the former is most
likely just pairwise addition of p-H to adsorbed cyclopropane
a reference for SE
To explore the possibility of the use of HP propane
(
produced from cyclopropane) for MRI, the reactor containing >2
H
times Rh/TiO catalyst load (280 mg vs. 118 mg) was prepared.
2
First, the resultant setup was tested in ALTADENA conditions.
The increased catalyst loading allowed to reach 2.8%
cyclopropane conversion with SE = 600–620, corresponding to
2
while the latter should involve cleavage of at least one C–H
bond present in the reactant molecule (see Scheme 1b for
possible mechanisms). Therefore, the actual propane
polarization and hence the contribution of pairwise addition
routes #1–3 to the overall hydrogenation reaction may be
significantly underestimated. The relative contribution of each
route was not investigated in this initial report, and future
mechanistic studies are certainly warranted. Moreover, future
1.9–2.0% propane polarization (Figure 2). Notably, both
chemical conversion and P were enhanced with this catalyst
H
load compared to the previous load under otherwise similar
conditions. Higher propane polarization was observed (SE =
740–750, 2.4% propane polarization) at doubled gas flow rates
(
likely due to reduced %P relaxation), though at the expense of
H
studies should certainly attempt to determine the lifetime of 1
H
cyclopropane conversion (0.7%). The polarization levels of
obtained HP propane were indeed sufficient for MRI (despite
very low conversion levels), as was demonstrated on the
example of 2D gradient echo (GRE) MRI of a ~5.5 mL phantom,
HP states produced via routes #2 and #3. These future studies
would benefit immensely from significantly higher conversion
rate (which would require massively larger catalyst quantities not
This article is protected by copyright. All rights reserved.

ChemPhysChem
10.1002/cphc.201800690
COMMUNICATION
available to us at the time of these experiments) and
excess of alkali to RhCl
3
2
and H [PtCl
6
], respectively. The resulting
precipitates were washed with excess of cold water until the negative
reaction to the chloride ions, and dissolved in nitric acid. The resulting
rhodium(III) and platinum(IV) nitrate solutions as well as commercial
palladium(II) nitrate solutions were used for the preparation of supported
2
combination of PHIP with D tracer studies.
Rh, Pt and Pd catalysts, respectively. The TiO
2
powder was calcinated at
5
00 °C for 2 h prior to use. Then TiO was impregnated with the mixture
2
of required amount of corresponding nitrate solution and water for 1 h at
room temperature. The solvent excess was evaporated, and the samples
were dried in air at 120 °C for 4 h and calcinated in air at 400 °C for 3 h,
followed by reduction in 25/75 vol% H /N flow at 300 °C for 3 h.
2 2
NMR and MRI Experiments. Cyclopropane (ChemSampCo, Dallas, TX,
USA, 97–99%), propene (Sigma-Aldrich, ≥99 %) and hydrogen (ultra-
pure) were used as received. Hydrogen was enriched with p-H
to 50% by passing it through a copper spiral tubing with a layer of
FeO(OH) powder (Sigma-Aldrich) immersed in liquid N or up to 82–84%
using home-built cryocooling parahydrogen generator. 50% enriched p-
was used for homogeneous hydrogenation, heterogeneous liquid
2
either up
2
H
2
phase hydrogenation and some of gas phase PASADENA hydrogenation
experiments (see corresponding figure captions). All other experiments
were performed with 82–84% enriched p-H . Gas flow rates of
2
cyclopropane and hydrogen were regulated in standard cubic
centimeters per minute (sccm) using mass flow controllers (Sierra
Instruments, Monterey, CA, model # C50LAL-DD-2-PV2-V0).
In PASADENA[12] experiments, hydrogenation reactions were carried out
at 90 psig total pressure in medium-wall 5 mm NMR tubes (Wilmad glass
P/N 503-PS-9) tightly connected with ¼ inch outer diameter (OD) PTFE
tubes. For homogeneous hydrogenation experiments, the NMR tube was
Figure 3. 2D MRI of HP propane gas in ~5.5 mL spherical phantom. HP
propane was produced by hydrogenation of cyclopropane with 82% enriched
p-H
2
over 280 mg of 1 wt.% Rh/TiO
2
catalyst at 140 °C and 240/480 sccm
cyclopropane/H
2
gas flow rate. Images (a-d) were acquired on a 4.7 T Varian
filled with 0.5 mL of 5 mM solution of [Rh(NBD)(dppb)]BF
norbornadiene, dppb = 1,4-bis(diphenylphosphino)butane) in CD
4
(NBD =
OD
MRI scanner after interruption of gas flow every ~0.35 sec with the following
imaging parameters: 2D GRE pulse sequence, 64×64 matrix with TR ~4.5 ms,
3
2
2
no slice selection, field of view 64×64 mm , pixel size 1×1 mm . The imaging
artifacts in the areas of reduced intensities are due to tubing and glue inside
the phantom. The HP gas flow was stopped immediately before image
under Argon atmosphere and heated inside the NMR spectrometer to
40 °C. Cyclopropane and p-H2 were bubbled through the solution either
simultaneously (10 sccm cyclopropane and 30 sccm p-H
first, the solution was saturated with cyclopropane, and then p-H
bubbled through at 30 sccm). For heterogeneous hydrogenation of
cyclopropane in liquid phase, 10 mg of 1 wt.% Rh/TiO catalyst was
placed in the bottom of NMR tube and 0.5 mL of CD OD was added. The
tube was heated inside the NMR spectrometer to 40 °C. Cyclopropane
and p-H were bubbled through the solution either simultaneously (15
sccm cyclopropane and 20 sccm p-H ) or sequentially (first, the solution
was saturated with cyclopropane, and then p-H was bubbled through at
0 sccm). For heterogeneous gas phase hydrogenation experiments in
2
) or sequentially
acquisition. The intensity reduction in images b), c), and d) is due to T
1
(
2
was
relaxation of HP state.
2
3
In conclusion, hydrogenation of cyclopropane with p-H
2
over
heterogeneous Rh/TiO catalyst was shown to be a promising
2
2
2
approach for production of HP propane with high level of proton
spin polarization for MRI applications. We note that both
substrate and the product of PHIP process are previously FDA-
approved anesthetics, which is very advantageous for future
rapid clinical translation. Relatively low chemical conversion of
cyclopropane demonstrated here may be further improved by
increasing the catalyst load or the use of more active catalysts. It
2
3
PASADENA conditions, the catalysts (10 or 15 mg) were placed in the
bottom of the NMR tube heated to 70 or 90 °C. General scheme of
PASADENA experimental setup was presented elsewhere.[48]
In ALTADENA[54] experiments, hydrogenation was carried out at 90 psig
total pressure in specially designed reactor positioned outside the NMR
spectrometer in Earth’s magnetic field. The reactor represented a copper
tubing (¼ inch OD, ~0.186-inch. inner diameter) comprised of three
sections (each 16-cm length). The 1st and the 3rd sections were filled with
H
should also be noted that significant %P fraction in our
experiments is lost due to relaxation effects. Optimization of
experimental setup may allow to reach significantly higher HP
propane polarization and improved chemical conversion.[55] The
formation of magnetically equivalent HP methyl protons in a
pseudo singlet state likely formed via routes #2–3 is intriguing,
because the produced HP states may have ultra-long life time –
subject of our ongoing studies.
~
13 g of 20–30 mesh copper granules, while the 2nd section was filled
with the mixture of copper granules (11.4 g) and 1 wt.% Rh/TiO catalyst
118 or 280 mg). Copper granules were employed to provide efficient
2
(
heat exchange inside the reactor. The masses were adjusted in order to
obtain ~12 cm length copper or copper+catalyst layers in all sections,
which were separated by ~4 cm layers of fiberglass wool (~2 cm ends of
the reactor were also filled with fiberglass). The first two sections were
heated with ovens while the third one was cooled with a fan. All sections
st
had an independent temperature control. Thus, in the 1 section gas
Experimental Section
mixture was heated to required temperature, in the 2nd one it reacted to
produce HP propane, while in the 3rd one it was cooled down. The
resultant gas mixture was headed to a medium-wall 5 mm NMR tube
Catalysts Preparation. Materials: TiO
m /g), 10% palladium(II) nitrate solution in 10% nitric acid (Aldrich
2
powder (Hombifine N, SBET = 107
2
(Wilmad glass P/N 503-PS-9) located inside the NMR spectrometer. The
3
80040), 8% chloroplatinic acid aqueous solution (Aldrich 262587),
RhCl hydrate (CAS 20765-98-4), NaOH (CAS 1310-73-2), HNO (CAS
697-37-2). First, Rh(OH) and H [Pt(OH) ] were formed by adding an
overall scheme of ALTADENA experimental setup is presented in Figure
3
3
4.
7
3
2
6
This article is protected by copyright. All rights reserved.

ChemPhysChem
10.1002/cphc.201800690
COMMUNICATION
Figure 4. Schematics of ALTADENA experimental setup.
[
3]
P. Nikolaou, B. M. Goodson, E. Y. Chekmenev, Chem. Eur. J. 2015, 21,
For MRI experiments, generally the same ALTADENA setup was utilized,
except that the resultant gas mixture was headed to a ~5.5 mL spherical
phantom located inside a MRI scanner instead of the NMR tube. The
phantom was connected with the setup using two PTFE tubing lines
3
[
156-3166.
4] N. N. Kuzma, P. Hakansson, M. Pourfathi, R. K. Ghosh, H. Kara, S. J.
Kadlecek, G. Pileio, M. H. Levitt, R. R. Rizi, J. Magn. Reson. 2013, 234, 90-94.
[5] M. Pourfathi, N. N. Kuzma, H. Kara, R. K. Ghosh, H. Shaghaghi, S. J.
Kadlecek, R. R. Rizi, J. Magn. Reson. 2013, 235, 71-76.
6] B. Vuichoud, E. Canet, J. Milani, A. Bornet, D. Baudouin, L. Veyre, D.
(
mostly 1/16 inch OD, but with 1/8 inch OD connection to the phantom).
Production of HP propane for MRI experiments was carried out over 280
mg of 1 wt.% Rh/TiO catalyst at 140 °C, 90 psig total gas pressure and
40/480 sccm cyclopropane/H gas flow rate (p-H enrichment was
82%). All NMR spectra were acquired on 9.4 Bruker NMR
[
Gajan, L. Emsley, A. Lesage, C. Copéret, C. Thieuleux, G. Bodenhausen, I.
Koptyug, S. Jannin, J. Phys. Chem. Lett. 2016, 3235-3239.
[7]
Kurzbach, B. Vuichoud, S. Jannin, E. Y. Chekmenev, B. M. Goodson, D. A.
Barskiy, I. V. Koptyug, Chem. Asian J. 2018, doi:10.1002/asia.201800551.
[
[
2
2
~
2
2
K. V. Kovtunov, E. Pokochueva, O. G. Salnikov, S. Cousin, D.
T
spectrometer using π/4 radiofrequency (rf) pulse in PASADENA
experiments and π/2 rf pulse in ALTADENA experiments. The 2D MR
images were acquired on a 4.7 T Varian MRI scanner with the following
imaging parameters: 2D GRE pulse sequence, 64×64 matrix with TR
8]
9]
B. M. Goodson, J. Magn. Reson. 2002, 155, 157-216.
M. S. Rosen, T. E. Chupp, K. P. Coulter, R. C. Welsh, S. D. Swanson,
Rev. Sci. Instrum. 1999, 70, 1546-1552.
[10] B. M. Goodson, N. Whiting, A. M. Coffey, P. Nikolaou, F. Shi, B. M.
Gust, M. E. Gemeinhardt, R. V. Shchepin, J. G. Skinner, J. R. Birchall, M. J.
Barlow, E. Y. Chekmenev, Emagres 2015, 4, 797-810.
2
2
~
4.5 ms, no slice selection, field of view 64×64 mm , pixel size 1×1 mm .
[
[
11] C. R. Bowers, D. P. Weitekamp, Phys. Rev. Lett. 1986, 57, 2645-2648.
12] C. R. Bowers, D. P. Weitekamp, J. Am. Chem. Soc. 1987, 109, 5541-
5542.
Acknowledgements
[13] J.-B. Hövener, A. N. Pravdivtsev, B. Kidd, C. R. Bowers, S. Glöggler, K.
V. Kovtunov, M. Plaumann, R. Katz-Brull, K. Buckenmaier, A. Jerschow, F.
Reineri, T. Theis, R. V. Shchepin, S. Wagner, P. Bhattacharya, N. M.
Zacharias, E. Y. Chekmenev, Angew. Chem. Int. Ed. 2018, DOI
10.1002/anie.201711842.
OGS and KVK thank the grant from the Russian Science
Foundation (17-73-20030) for the support of heterogeneous
production of HP propane. IVK thanks SB RAS integrated
research program (# 0333-2018-0006 / II.1.13) and Federal
Agency for Scientific Organizations #0333-2017-0002 for
support of parahydrogen activation studies. EYC thanks NSF
CHE-1416268 and CHE-1416432, NIH 1R21EB020323 and
R21CA220137, and DOD CDMRP W81XWH-15-1-0271, and
W81XWH-15-1-0272, and RFBR (17-54-33037-OHKO_a) for
funding support of MRI studies. VIB and LMK thank BIC project
No. 0303-2016-0004 for the support of catalysts preparation.
[
14] T. C. Eisenschmid, R. U. Kirss, P. P. Deutsch, S. I. Hommeltoft, R.
Eisenberg, J. Bargon, R. G. Lawler, A. L. Balch, J. Am. Chem. Soc. 1987, 109,
8089-8091.
[
15] R. A. Green, R. W. Adams, S. B. Duckett, R. E. Mewis, D. C.
Williamson, G. G. R. Green, Prog. Nucl. Mag. Res. Spectrosc. 2012, 67, 1-48.
[16] L. L. Walkup, J. C. Woods, NMR Biomed. 2014, 27, 1429-1438.
[
17] I. Muradyan, J. P. Butler, M. Dabaghyan, M. Hrovat, I. Dregely, I. Ruset,
G. P. Topulos, E. Frederick, H. Hatabu, W. F. Hersman, S. Patz, J. Magn.
Reson. Imaging 2013, 37, 457-470.
[18] D. M. L. Lilburn, G. E. Pavlovskaya, T. Meersmann, J. Magn. Reson.
2
[
013, 229, 173–186.
19] A. Ouriadov, A. Farag, M. Kirby, D. G. McCormack, G. Parraga, G. E.
Santyr, Magn. Reson. Med. 2013, 70, 1699-1706.
20] B. Driehuys, S. Martinez-Jimenez, Z. I. Cleveland, G. M. Metz, D. M.
[
Beaver, J. C. Nouls, S. S. Kaushik, R. Firszt, C. Willis, K. T. Kelly, J. Wolber,
Keywords: hyperpolarization • parahydrogen-induced
M. Kraft, H. P. McAdams, Radiology 2012, 262, 279-289.
[
21] S. Patz, F. W. Hersman, I. Muradian, M. I. Hrovat, I. C. Ruset, S. Ketel,
F. Jacobson, G. P. Topulos, H. Hatabu, J. P. Butler, Eur. J. Radiol. 2007, 64,
35-344.
polarization • cyclopropane • contrast agent • hydrogenation
3
[
1]
D. A. Barskiy, A. M. Coffey, P. Nikolaou, D. M. Mikhaylov, B. M.
[22] J. P. Butler , S. H. Loring , S. Patz , A. Tsuda , D. A. Yablonskiy , S. J.
Mentzer N. Engl. J. Med. 2012, 367, 244-247.
[23] M. S. Albert, G. D. Cates, B. Driehuys, W. Happer, B. Saam, C. S.
Springer, A. Wishnia, Nature 1994, 370, 199-201.
[24] P. Nikolaou, A. M. Coffey, L. L. Walkup, B. M. Gust, N. R. Whiting, H.
Newton, I. Muradyan, M. Dabaghyan, K. Ranta, G. Moroz, S. Patz, M. S.
Rosen, M. J. Barlow, E. Y. Chekmenev, B. M. Goodson, Magn. Reson.
Imaging 2014, 32, 541-550.
Goodson, R. T. Branca, G. J. Lu, M. G. Shapiro, V.-V. Telkki, V. V. Zhivonitko,
I. V. Koptyug, O. G. Salnikov, K. V. Kovtunov, V. I. Bukhtiyarov, M. S. Rosen,
M. J. Barlow, S. Safavi, I. P. Hall, L. Schröder, E. Y. Chekmenev, Chem. Eur.
J. 2017, 23, 725–751.
[
2]
J. P. Mugler, T. A. Altes, J. Magn. Reson. Imaging 2013, 37, 313-331.
This article is protected by copyright. All rights reserved.

ChemPhysChem
10.1002/cphc.201800690
COMMUNICATION
[
[
25] I. C. Ruset, S. Ketel, F. W. Hersman, Phys. Rev. Lett. 2006, 96, 053002.
26] A. L. Zook, B. B. Adhyaru, C. R. Bowers, J. Magn. Reson. 2002, 159,
[41] A. Corma, O. G. Salnikov, D. A. Barskiy, K. V. Kovtunov, I. V. Koptyug,
Chem. Eur. J. 2015, 21, 7012-7015.
1
[
75-182.
27] B. Driehuys, G. D. Cates, E. Miron, K. Sauer, D. K. Walter, W. Happer,
Appl. Phys. Lett. 1996, 69, 1668-1670.
[42] E. W. Zhao, R. Maligal-Ganesh, C. Xiao, T.-W. Goh, Z. Qi, Y. Pei, H. E.
Hagelin-Weaver, W. Huang, C. R. Bowers, Angew. Chem. Int. Ed. 2017, 56,
3925-3929.
[
[
28] M. S. Freeman, K. Emami, B. Driehuys, Phys. Rev. A 2014, 90, 023406.
29] P. Nikolaou, A. M. Coffey, L. L. Walkup, B. M. Gust, N. Whiting, H.
[43] K. V. Kovtunov, A. S. Romanov, O. G. Salnikov, D. A. Barskiy, E. Y.
Chekmenev, I. V. Koptyug, Tomography 2016, 2, 49-55.
Newton, S. Barcus, I. Muradyan, M. Dabaghyan, G. D. Moroz, M. Rosen, S.
Patz, M. J. Barlow, E. Y. Chekmenev, B. M. Goodson, Proc. Natl. Acad. Sci. U.
S. A. 2013, 110, 14150-14155.
[44] D. A. Barskiy, O. G. Salnikov, A. S. Romanov, M. A. Feldman, A. M.
Coffey, K. V. Kovtunov, I. V. Koptyug, E. Y. Chekmenev, J. Magn. Reson.
2017, 276, 78-85.
[
30] P. Nikolaou, A. M. Coffey, K. Ranta, L. L. Walkup, B. Gust, M. J. Barlow,
M. S. Rosen, B. M. Goodson, E. Y. Chekmenev, J. Phys. Chem. B 2014, 118,
809–4816.
31] P. Nikolaou, A. M. Coffey, L. L. Walkup, B. Gust, C. LaPierre, E.
[45] D. B. Burueva, A. S. Romanov, O. G. Salnikov, V. V. Zhivonitko, Y.-W.
Chen, D. A. Barskiy, E. Y. Chekmenev, D. W.-H. Hwang, K. V. Kovtunov, I. V.
Koptyug, J. Phys. Chem. C 2017, 121, 4481–4487.
[46] R. H. McKee, D. Herron, M. Saperstein, P. Podhasky, G. M. Hoffman, L.
Roberts, Int. J. Toxicol. 2014, 33, 28S-51S.
4
[
Koehnemann, M. J. Barlow, M. S. Rosen, B. M. Goodson, E. Y. Chekmenev, J.
Am. Chem. Soc. 2014, 136 1636–1642.
[47] J. Boyd, Ulster Med. J. 1946, 15, 58–77.
[
32] K. V. Kovtunov, D. A. Barskiy, A. M. Coffey, M. L. Truong, O. G.
[48] O. G. Salnikov, D. A. Barskiy, A. M. Coffey, K. V. Kovtunov, I. V.
Koptyug, E. Y. Chekmenev, ChemPhysChem 2016, 17, 3395–3398.
[49] Y. Dong, M. Ebrahimi, A. Tillekaratne, J. P. Simonovis, F. Zaera, Phys.
Chem. Chem. Phys. 2016, 18, 19248-19258.
[50] P. S. Cremer, X. Su, Y. R. Shen, G. A. Somorjai, J. Phys. Chem. 1996,
100, 16302-16309.
Salnikov, A. K. Khudorozhkov, E. A. Inozemtseva, I. P. Prosvirin, V. I.
Bukhtiyarov, K. W. Waddell, E. Y. Chekmenev, I. V. Koptyug, Chem. Eur. J.
2
[
014, 20, 11636 – 11639.
33] L. S. Bouchard, K. V. Kovtunov, S. R. Burt, M. S. Anwar, I. V. Koptyug,
R. Z. Sagdeev, A. Pines, Angew. Chem. Int. Ed. 2007, 46, 4064-4068.
34] I. V. Koptyug, K. V. Kovtunov, S. R. Burt, M. S. Anwar, C. Hilty, S. I.
Han, A. Pines, R. Z. Sagdeev, J. Am. Chem. Soc. 2007, 129, 5580-5586.
35] L. S. Bouchard, S. R. Burt, M. S. Anwar, K. V. Kovtunov, I. V. Koptyug,
A. Pines, Science 2008, 319, 442-445.
36] A. Kopanski, F. Hane, T. Li, M. Albert, in 25th ISMRM Conference, April
2-27, Honolulu, Hawaii, 2017, p. 2162.
[
[51] F. Zaera, ACS Catalysis 2017, 7, 4947-4967.
[52] D. B. Burueva, O. G. Salnikov, K. V. Kovtunov, A. S. Romanov, L. M.
Kovtunova, A. K. Khudorozhkov, A. V. Bukhtiyarov, I. P. Prosvirin, V. I.
Bukhtiyarov, I. V. Koptyug, J. Phys. Chem. C 2016, 120, 13541-13548.
[53] V. Zhivonitko, K. Kovtunov, P. Chapovsky, I. Koptyug, Angew. Chem.
Int. Ed. 2013, 52, 13251-13255.
[
[
2
[
[
37] S. B. Duckett, R. E. Mewis, Acc. Chem. Res. 2012, 45, 1247-1257.
38] K. V. Kovtunov, V. V. Zhivonitko, I. V. Skovpin, D. A. Barskiy, I. V.
[54] M. G. Pravica, D. P. Weitekamp, Chem. Phys. Lett. 1988, 145, 255-258.
[55] D. A. Barskiy, K. V. Kovtunov, E. Y. Gerasimov, M. A. Phipps, O. G.
Salnikov, A. M. Coffey, L. M. Kovtunova, I. P. Prosvirin, V. I. Bukhtiyarov, I. V.
Koptyug, E. Y. Chekmenev, J. Phys. Chem. C 2017, 121, 10038–10046.
Koptyug, Top. Curr. Chem. 2013, 338, 123-180.
39] K. V. Kovtunov, M. L. Truong, D. A. Barskiy, I. V. Koptyug, A. M. Coffey,
K. W. Waddell, E. Y. Chekmenev, Chem. Eur. J. 2014, 20, 14629–14632.
40] K. V. Kovtunov, M. L. Truong, D. A. Barskiy, O. G. Salnikov, V. I.
[
[
Bukhtiyarov, A. M. Coffey, K. W. Waddell, I. V. Koptyug, E. Y. Chekmenev, J.
Phys. Chem. C 2014, 118, 28234–28243.
This article is protected by copyright. All rights reserved.

ChemPhysChem
10.1002/cphc.201800690
COMMUNICATION
Entry for the Table of Contents
Layout 1:
COMMUNICATION
Heterogeneous hydrogenation of
O. G. Salnikov*, K. V. Kovtunov, P.
cyclopropane with parahydrogen over
Rh/TiO catalyst was shown to be a
2
promising approach for production of
propane gas with high level of proton
polarization suitable for magnetic
resonance imaging applications.
Nikolaou, L. M. Kovtunova, V. I.
Bukhtiyarov, I. V. Koptyug, and E. Y.
Chekmenev*
Page No. – Page No.
Heterogeneous Parahydrogen
Pairwise Addition to Cyclopropane
This article is protected by copyright. All rights reserved.