Low-Flammable Parahydrogen-Polarized MRI Contrast Agents

Article abstract of DOI:10.1002/chem.202004168

Many MRI contrast agents formed with the parahydrogen-induced polarization (PHIP) technique exhibit biocompatible profiles. In the context of respiratory imaging with inhalable molecular contrast agents, the development of nonflammable contrast agents would nonetheless be highly beneficial for the biomedical translation of this sensitive, high-throughput and affordable hyperpolarization technique. To this end, we assess the hydrogenation kinetics, the polarization levels and the lifetimes of PHIP hyperpolarized products (acids, ethers and esters) at various degrees of fluorine substitution. The results highlight important trends as a function of molecular structure that are instrumental for the design of new, safe contrast agents for in vivo imaging applications of the PHIP technique, with an emphasis on the highly volatile group of ethers used as inhalable anesthetics.

Full text of DOI:10.1002/chem.202004168

Accepted Article
Accepted Article
Title: Low-Flammable Parahydrogen-Polarized MRI Contrast Agents
Authors: Baptiste Joalland, Nuwandi M. Ariyasingha, Hassan R.
Younes, Shiraz Nantogma, Oleg G. Salnikov, Nikita V.
Chukanov, Kirill V. Kovtunov, Igor V. Koptyug, Juri G.
Gelovani, 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
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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: Chem. Eur. J. 10.1002/chem.202004168
Link to VoR: https://doi.org/10.1002/chem.202004168
0
1/2020

Chemistry - A European Journal
10.1002/chem.202004168
RESEARCH ARTICLE
Low-Flammable Parahydrogen-Polarized MRI Contrast Agents
[
a]
[a]
[a]
[a]
Baptiste Joalland, Nuwandi M. Ariyasingha, Hassan R. Younes, Shiraz Nantogma, Oleg G.
[
b,c,d]
[b,c]
[b,c]
[b,c]
[a,e]
Salnikov,
Nikita V. Chukanov,
Kirill V. Kovtunov,
Igor V. Koptyug,
Juri G. Gelovani,
and
[
a,f]
Eduard Y. Chekmenev*
[
a]
Dr. B. Joalland, N. M. Ariyasingha, H. R. Younes, S. Nantogma, Prof. J. G. Gelovani, Prof. E. Y. Chekmenev
Department of Chemistry,
Integrative Biosciences (Ibio),
Karmanos Cancer Institute (KCI),
Wayne State University,
Detroit, Michigan 48202, United States
E-mail: chekmenev@wayne.edu
[
[
b]
c]
Dr. O. G. Salnikov, Dr. N. V. Chukanov, Dr. K. V. Kovtunov. Prof. I. V. Koptyug
International Tomography Center SB RAS,
Institutskaya St. 3A, 630090 Novosibirsk, Russia
Dr. O. G. Salnikov, Dr. N. V. Chukanov, Dr. K. V. Kovtunov. Prof. I. V. Koptyug
Department of Natural Sciences,
Novosibirsk State University,
Pirogova St. 2, 630090 Novosibirsk, Russia
Dr. O. G. Salnikov
Boreskov Institute of Catalysis SB RAS,
Acad. Lavrentiev Prospekt 5, 630090 Novosibirsk, Russia
Prof. J. G. Gelovani,
[
[
[
d]
e]
f]
United Arab Emirates University,
Al Ain, United Arab Emirates
Prof. E. Y. Chekmenev,
Russian Academy of Sciences,
Leninskiy Prospekt 14, Moscow, 119991, Russia
Abstract: Many MRI contrast agents formed with the parahydrogen-
induced polarization (PHIP) technique exhibit biocompatible profiles.
In the context of respiratory imaging with inhalable molecular
contrast agents, the development of nonflammable contrast agents
would nonetheless be highly beneficial for the biomedical translation
of this sensitive, high-throughput and affordable hyperpolarization
technique. Pointing the way in this direction, we assess the
hydrogenation kinetics, the polarization levels and the lifetimes of
PHIP hyperpolarized products (acids, ethers and esters) at various
degrees of fluorine substitution. The results highlight important
trends as a function of molecular structure that are instrumental to
design new, safe contrast agents for in vivo imaging applications of
the PHIP technique, with an emphasis on the highly volatile group of
ethers used as inhalable anesthetics.
by the proton nuclear spin evolution. Proton RASER allows for
determining J-coupling constants and chemical shift differences
while surpassing the nominal spectroscopic resolution and
uncovering nonlinear effects in coupled spin oscillators, e.g.,
[
9-12]
frequency combs, line collapse, chaos, etc.
PHIP and other hyperpolarization techniques such as
[
13]
dissolution Dynamic Nuclear Polarization (d-DNP)
and Spin-
[
14]
Exchange Optical Pumping (SEOP)
attention for their potential for in vivo applications.
Hyperpolarized (HP) compounds can indeed be employed as
have attracted much
[
15-23]
[
24, 25]
injectable or inhalable contrast agents.
applications of hyperpolarization methods use C and
nuclei because of the greater lifetimes of their HP states
Currently, in vivo
1
3
129
Xe
1
3
129
compared to those of protons (>10 s for C and Xe vs. ~1-2 s
1
[17, 26-28]
13
for H).
However, despite major successes of HP C and
Xe contrast agents in a number of biomedical studies and
1
29
1
3
129
clinical trials, C and Xe detection is not available on clinical
MRI scanners. As a result, a costly (~$0.5M) and clunky
hardware upgrades and custom MRI sequences must be
Introduction
NMR and MRI represent a set of powerful techniques to provide
diagnostic information through molecular characterization, yet
their signal intensity is directly proportional to the nuclear spin
implemented on
a clinical MRI scanner to enable these
129
13
functionalities. All-in-all, even though the
Xe and C-based
contrast agents are ready for prime time biomedical applications,
the MRI scanner availability is clearly a substantial translational
barrier.
-
5
polarization (P) that is only about 10
physiologically and clinically relevant
for protons in
[
1]
conditions.
Hyperpolarization techniques aim at increasing P through the
manipulation of the population difference between nuclear spin
levels, resulting in several orders of magnitude gains in
The unveiling of long-lived singlet states (LLS) by M. H.
Levitt and colleagues, with TLLS values significantly greater than
corresponding spin-lattice relaxation time constant
1
T , has
[
2-5]
sensitivity.
PHIP) converts the singlet spin-order of parahydrogen (p-H
into a large P via the pairwise addition of p-H to an unsaturated
One of them, Parahydrogen-Induced Polarization
revived the interest in imaging of proton-hyperpolarized contrast
(
2
)
[29-32]
agents.
Interestingly, we have recently demonstrated the
2
existence of LLS in HP propane and HP diethyl ether in the gas
[
6-8]
substrate.
pool of p-H
The high magnetization of the hyperpolarized (HP)
-derived protons induces the occurrence of RASER
[33-
phase using homogeneous and heterogeneous (HET) PHIP
37]
2
—
HET-PHIP is particularly promising since it allows
(
Radiofrequency Amplification by Stimulated Emission
production of pure catalyst-free HP hydrocarbon gas. Both
compounds (propane and diethyl ether) with anaesthetic
features showed promising enough polarization levels and
Radiation), a quantum effect in which the radiofrequency modes
of the inductive detector of an NMR spectrometer are enslaved
1
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Chemistry - A European Journal
10.1002/chem.202004168
RESEARCH ARTICLE
lifetimes (TLLS of 3-4 s at physiologically relevant conditions) to
envision testing them as inhalable contrast agents in our up-and-
coming preclinical laboratory. It should be stressed that this gain
in the HP state lifetime is substantial – for example, HP propane
would retain less than 15% of its potency during 2-s long
the PHIP technique have been reported previously, showing
1
19
possibility for inducing polarization transfer from H to F via
[
43-45]
magnetic field cycling
or for taking advantage of the
[
46]
lipophilic propensity of fluorocarbons in in vivo imaging, both
examples illustrating valuable advantages in using HP
fluorinated compounds other than non-flammability. However,
the previous works have been focused on materials intended for
the use in the liquid state. As the medical field of
anaesthesiology employs nowadays a group of highly volatile,
halogenated, and non-flammable ethers as inhalable
inhalation if stored using T
1
versus retaining over 50% of its
under
The key benefits of
potency during 2-s long inhalation if stored in accord to T
1
[
33-37]
physiologically relevant conditions.
proton-hyperpolarized inhalable contrast agents is their low cost
of precursors, low cost of hyperpolarization process and high
1
29
production throughput. Moreover, unlike HP
Xe, proton-
anaesthetics, such as isoflurane CF
3
CHClOCHF
2
, sevoflurane
, this work
hyperpolarized contrast agents can be readily detected on
already installed clinical MRI scanners thereby making this new
technology readily available to the doctors and patients.
(CF CHOCH CH F, and desflurane CF
3
)
2
2
2
3
CHFOCHF
2
examines alternative scenarios for PHIP, which could eventually
provide novel in vivo molecular contrast agents combining
inhalable, anaesthetic and non-flammable properties with the
high detection sensitivity and simplicity of the PHIP
hyperpolarization technique.
Pulmonary functional imaging is a substantial unmet medical
need: there is currently no widespread clinical imaging modality
to perform high-resolution functional lung imaging: Computed
Tomography (CT), conventional MRI, and X-ray can only provide
structural images of dense tissues—informing about pathologies
like tumors and pneumonia—but yielding little or no information
about lung ventilation, perfusion, alveoli size, gas-exchange
efficiency, etc. Deadly diseases such as chronic obstructive
pulmonary disease (COPD), Asthma, Constrictive Bronchiolitis,
Lung Injury, and Pulmonary Fibrosis affect >300 million people
worldwide and cause ~3 million annual deaths (5% of all deaths
Scheme 1. PHIP reactions reported in the present study. Pairwise addition of
parahydrogen in CD
3
OD is found efficient for all unsaturated substrates, at the
exception of 17FPDe, which dissolves poorly in methanol, and 10FPVE, for
2
which the reaction with H leads to the formation of hydrofluoric acid (HF).
O
H
H
O
VA
EA
O
O
[
38]
Vinyl Acetate
Ethyl Acetate
worldwide). These diseases do not have any clinical imaging
marker, especially in the early disease stages when intervention
can be potentially curative. This state of affairs is in contrast with
that of cancer imaging, which includes a wide range of imaging
modalities with their own merits, such as MRI, CT, ultrasound,
mammography, Positron Emission Tomography (PET), and
others—collectively enabling early diagnosis via population
screening and monitoring response to treatment. Furthermore,
CT scans (2D and 3D X-ray) expose the body to ionizing
radiation, and thus cannot be performed frequently due to
increased risk associated with cancer-inducing radiation. On the
other hand, MRI involves no ionizing radiation, and is effectively
non-invasive. Inhalable HP contrast agents can provide 3D
Rh cat.
O
O
3
FVA
3FEA
CF3
O
CF3
O
Vinyl Trifluoroacetate
Ethyl Trifluoroacetate
O
O
OH
OH
HEA
O
O
HEP
2
-Hydroxyethyl Acrylate
2-Hydroxyethyl Propionate
O
CF3
O
CF3
3FEAcr
3FEP
O
O
2,2,2-Trifluoroethyl Acrylate
2,2,2-Trifluoroethyl Propionate
O
CF3
O
CF3
6FPA
6FPP
O
CF3
O
CF3
[
17, 21]
functional lung imaging information on single breath hold
—
1,1,1,3,3,3-Hexafluoroisopropyl
Acrylate
1,1,1,3,3,3-Hexafluoroisopropyl
Propionate
[
23]
thus, the use of proton-hyperpolarized contrast agents has a
potential to revolutionize pulmonary health care.
12FHAO
CF2
CF2
CF2
O
CF2
CF2
CF2
CF2
CF2
CF2H
CF2
CF2
CF2H
O
O
12FHP
In our recent work, we have demonstrated the feasibility of
clinical-scale production of HP propane gas and its high-
2
,2,3,3,4,4,5,5,6,6,7,7-Dodecafluoroheptyl 2,2,3,3,4,4,5,5,6,6,7,7-Dodecafluoroheptyl
Acrylate
Propionate
2
[39]
resolution (0.3´0.3 mm pixel size).
The feasibility of
EVE
O
O
DE
pulmonary imaging even when using non-hyperpolarized
propane has been demonstrated by Hane and co-workers in
Ethyl Vinyl Ether
Diethyl Ether
[
40]
rats.
Feasibility of HP diethyl ether MRI has also been
3FEVE
[
41]
demonstrated.
O
CF3
O
CF3 3FDE
Although diethyl ether is approved for medical use in some
countries including Russia, the development of a new, gas-
phase, inhalable proton-hyperpolarized contrast agent demands
to address flammability concerns specifically. For example, the
use of the first commercially developed anesthetic (diethyl ether)
has been phased out in many developed countries and WHO
2
,2,2-Trifluoroethyl Vinyl Ether
2,2,2-Trifluoroethyl Ethyl Ether
OH
OH
MAA
MPA
O
O
Methacrylic Acid
2-Methylpropanoic Acid
CF3
CF3
OH
OH
[
42]
3FMAA
3FMPA
removed it from the list of essential medications after 2003. In
this realm, we report here on the chemical conversion and
proton polarization build-up, maxima and lifetimes of PHIP
products fluorinated to various extents, revealing trends as a
function of structure and bonding patterns that are essential to
tackle with the development of efficient and low-flammable PHIP
contrast agents. Fluorinated hydrocarbons hyperpolarized via
O
O
2
,2,2-Trifluoromethylacrylic Acid
2-Trifluoromethylpropanoic Acid
CF2
CF2
CF2
CF2
CF2
CF2
CF2
CF2
CF2
CF2
CF2
CF3
CF2
CF2
CF2
CF3
17FPDe
17FPDa
1H,1H,2H-Perfluoro-1-Decene
1H,1H,1H,2H,2H-Perfluoro-1-Decane
1
0FPVE CF
CF2
CF3
O
CF2
!
HF
CF2
2
Perfluoro Propyl Vinyl Ether
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Chemistry - A European Journal
10.1002/chem.202004168
RESEARCH ARTICLE
Results and Discussion
and polarization levels were calibrated against reference spectra
1
3
of neat C-labeled ethyl acetate (Figure 1a,b). RASER activity,
which prevents from measuring polarization levels just as the
reaction is completed, is only briefly observed with 40 mM
solutions after full polarization build-up for the most strongly
hyperpolarized molecules, i.e. ethyl acetate and propionates.
Therefore, a delay of only 5 seconds in the Earth’s magnetic
field before inserting the samples in the bore of the spectrometer
was necessary to avoid RASER. The polarization levels were
back calculated to account for the corresponding relaxation.
Significant RASER activity can however be easily observed at
higher concentrations, that is even for HP molecules with
relatively modest polarization levels of a few %, such as shown
in Figure 1c,d for 3FDE where a two-mode RASER is induced
without any radiofrequency excitation pulse.
The hydrogenation reactions studied here are shown in Scheme
1
. The fluorinated molecules include:
-
Vinyl trifluoroacetate (3FVA) leading to ethyl trifluoroacetate
(
3FEA);
Trifluoroethyl acrylate (3FEAcr), hexafluoroisopropyl acrylate
6FPA), and dodecafluoroheptyl acrylate (12FHA), leading to
trifluoroethyl propionate (3FEP), hexafluoroisopropyl
propionate (6FPP), and dodecafluoroheptyl propionate
12FHP), respectively;
-
(
(
-
-
Trifluoroethyl vinyl ether (3FEVE), the first halogenated
hydrocarbon anesthetic to be produced (a.k.a. fluroxene),
leading to trifluoroethyl ethyl ether (3FDE);
Trifluoromethyl acrylic acid (3FMAA) leading to 2-
trifluoromethyl propanoic acid (3FMPA).
The results are compared to those obtained with corresponding
non-fluorinated molecules: vinyl acetate (VA) leading to ethyl
acetate (EA), hydroxyethyl acrylate (HEA) to hydroxyethyl
propionate (HEP), ethyl vinyl ether (EVE) to diethyl ether (DE),
and methacrylic acid (MAA) to 2-methyl propanoic acid (MPA).
Note that two other fluorinated precursors were tentatively
hydrogenated: 1H,1H,2H-Perfluoro-1-decene (17FPDe) and
perfluoro propyl vinyl ether (10FPVE). For alkene 17FPDe, the
chemical conversion toward alkane 17FPDa (~15-20% after 30 s
1
reaction) and the H polarization of 17FPDa (~0.1% at 10 s
reaction) were low and 17FPDe was poorly dissolved in solvent
methanol-d4, aborting further experiments with this molecule.
For ether 10FPVE, the hydrogenation reaction was found
hazardous due to the formation of hydrofluoric acid (HF) seen as
glass NMR tube melting.
All measurements were performed with standard high-
throughput 5 mm NMR tubes filled under argon atmosphere.
The solutions contained ~ 40 mM of substrates and ~4 mM of
rhodium catalyst dissolved in CD
EVE + p-H ® DE reaction for which 186 mM of EVE were used
in a recent study. The samples were pressurized at 8 bar with
p-H (>99%) and heated at 80 °C for 30 s. Note that all studied
3
OD, at the exception of the
2
[
37]
2
compounds are volatile liquids under normal pressure—as a
result, if the depressurization of the HP liquid would render the
expansion of HP proton-hyperpolarized gas. However, this
depressurization would lead to unwanted polarization losses and
make the comparison and quantitative studies of reaction
kinetics rather challenging. As a result, the NMR detection of
proton-hyperpolarized compounds was performed in the liquid
state in 5 mm NMR tubes.
1
Figure 1. a) H NMR spectrum of HP 3FDE in CD
3
OD solution acquired using
8° flip angle. Polarization of 3.2% was measured after correction for
evaporation and the Earth’s field relaxation. b) Corresponding NMR spectrum
of neat thermally polarized ethyl-acetate-1- C. c) ALTADENA RASER signal
of HP 3FDE recorded without excitation pulse. d) Fourier transform (FT)
spectra of the RASER signal for the regions outlined by purple and orange
boxes in panel c (HA / HB two-mode RASER).
13
1
Figure 2 shows the H polarization levels P
H
measured as a
The hydrogenation reaction was achieved by bubbling p-H
2
function of reaction (bubbling) time t and fitted to:
though the solution at a flow rate of 150 standard cubic
centimeter per minute (sccm) in the Earth’s magnetic field (50
ꢄꢅꢆꢇ
ꢒꢍꢒꢓ
ꢒꢍꢒꢓ
ꢀꢁ
ꢂ = ꢃ
ꢏꢐꢑ − ꢈꢉꢆꢊ − ꢏꢐꢑ −
Eq. 1
[
47]
ꢈꢉꢆꢊ/ꢈꢋꢋꢌꢍꢎ
ꢈꢋꢋꢌ
μT), corresponding to ALTADENA conditions —the sample
transfer took less than 2 seconds from cessation of p-H flow
in order to derive Pmax, the theoretical maximum polarization
neglecting relaxation, and Tcat, the time constant for the catalytic
2
and spectrum acquisition unless noted otherwise. The chemical
conversion was evaluated for each sample from the thermal
spectra acquired before and after the reaction, as well as the
reaction (or polarization build-up), while leaving t
and LLS fixed to the -H averaged values measured
independently in the Earth’s magnetic field (~50 μT, see Figure
S2). Figure 3 compiles Pmax, Tcat, TLLS, and T (measured at 1.4
T, see Figure S2) values for all compounds shown in Figure 2, at
the exception of 3FEA for which the measured P were too low.
For 3FVA / 3FEA, it is clear that the presence of the CF
0
fixed to 1 s
T
H
A
B
3
residual concentration of the products in CD OD (liquid fraction)
1
in the case of highly volatile ethers. H polarization levels were
corrected accordingly (see Supporting Information for details).
1
We note that no HP resonances was observed before p-H
bubbling. Moreover, once p-H bubbling stopes, the chemical
reaction is effectively ceased under our conditions.
2
H
3
2
1
[
48]
group on the carboxylic side induces deleterious effects: the H
polarization reaches maximum of about 0.1% and the
chemical conversion is less than 40% after 10 s of reaction,
1
a
H NMR spectra were measured with a benchtop NMR
spectrometer (Spinsolve Carbon 60, Magritek, 61 MHz / 1.4 T)
3
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Chemistry - A European Journal
10.1002/chem.202004168
RESEARCH ARTICLE
Figure 2. PHIP kinetics for hydrogenation reactions in CD
3
OD at 8 bar and
whereas in the non-fluorinated case (VA / EA) the chemical
conversion is complete after 10 s of reaction with Pmax = 25%
and Tcat ~ 1 s. These results are in sharp contrast with those
obtained for the series of acrylates / propionates. We find that
8
0 °C. All reactions were studied with ~ 40 mM solutions, at the exception of
the EVE + p-H
2
® DE reaction ([EVE] = 186 mM). Solid circles correspond to
protons (methine CH group of 2-methylpropanoic acid
(MPA) and 2-trifluoromethylpropanoic acid (3FMPA), methylene CH2 group in
all other cases) and empty squares correspond to polarization of H protons
methyl CH group). and H polarizations were averaged in the fit. (a)
polarization of H
A
2 3 2 5 2
the replacement of –CH OH by –CF or even –(CF ) CF H does
B
1
(
3
H
A
B
H
not affect much of the speed and specificity of the catalytic
pairwise addition reaction, with Pmax on the order of 20%, Tcat ~ 1
s and full chemical conversion after 10 s of reaction. In the case
of the branched 6FPP, Pmax and Tcat are equal to 14% and ~1 s,
respectively, and the chemical conversion is also completed
polarization of ethyl acetate and ethyl trifluoroacetate (EA and 3FEA) as a
1
function of reaction time. (b) H polarization of propionates (HEP, 3FEP, 6FPP
1
and 12FHEP) as a function of reaction time. (c) H polarization of diethyl ether
and 2,2,2-trifluoroethyl ethyl ether (DE and 3FDE) as a function of reaction
time. Insert represents the liquid fraction of EVE / DE and 3FEVE / 3FDE,
1
which decreases with reaction time due to evaporation (d) H polarization of 2-
2
after 10 s of p-H supply. The negative inductive effect of the
MPA and 3FMPA as a function of reaction time.
electron-accepting fluorinated group, which affects the electron
density at the CC double bond through the conjugated π-system
involving the CO carbonyl group, is thus only deleterious at short
distance; in 3FEP, 6FPP and 12FHP the fluorinated groups and
the conjugated systems are separated by an aliphatic carbon so
that little effects on the hydrogenation reaction outcomes are
observed. On the other hand, expectedly, the larger the carbon
framework is the shorter is the relaxation constant (both TLLS in
In the case of highly volatile ethers EVE / DE, substituting
3
the methyl group with –CF induces a decrease of polarization
by a factor of ~2.5. However, the hydrogenation reaction
remains fast with 100% conversion reached after 10 s of
reaction, and neither the relaxation nor the buildup time are
affected by the presence of F atoms. Non-specific interactions in
the catalytic hydrogenation reaction are therefore more
pronounced for HP ethers than HP propionates, but remain far
from deleterious.
1
the strong coupling regime and T in the weak coupling regime),
with a clear 3FEP > 6FPP > 12FHP trend.
a25
ethyl acetate
2
1
1
0
5
0
5
0
O
EA
H A
a30
25
b14
12 Tcat
average of H
A
and H over
O
B
Pmax
5
measurements
H B
3FEA
50
10
20
15
10
8
6
0
10
10
10
10
20
30
40
60
60
60
60
4
reaction time / s
5
0
b20
2
propionate
0
1
5
HEP
3
FEP
FPP
c16
d40
35
30
25
20
15
10
5
1
0
6
14
@ 1.4 T
T
T1
LLS
5
0
12FHP
12
@
HA
HB
10
50 μT
8
6
4
2
0
0
20
30
40
50
reaction time / s
c
8
7
6
5
4
3
2
1
0
diethyl ether
DE
1
0.8
0.6
0.4
0
3
FDE
EVE+DE
FEVE+3FDE
0.2
3
0
0
20
40
60
reaction time / s
Figure 3. (a) Maximum polarization without relaxation Pmax. (b) Build-up time
cat. (c) Earth’s field relaxation time constant TLLS. (d) High field (1.4 T)
relaxation time constant T . H and H polarizations are averaged to derive
max (a), Tcat (b) and TLLS (c). H notation corresponds to HP protons of CH
group (in case of MPA and 3FMPA) or CH group (in all other cases) and H
notation correspond to HP protons of CH group.
T
0
20
30
40
50
1
A
B
reaction time / s
P
A
d 6
2
B
2
-methyl
propanoic acid
3
5
4
3
2
1
0
MPA
3FMPA
0
20
30
40
50
reaction time / s
4
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Chemistry - A European Journal
10.1002/chem.202004168
RESEARCH ARTICLE
Methacrylic acid represents a test case for F substitution on
a methyl group that forms a branch adjacent to the double bond
The boiling point of 3FDE is estimated to be 15 °C lower than
the one of DE (35 °C), bringing it to room temperature.
Consequently, this partially fluorinated ether exhibits rather ideal
2
hosting the pairwise addition of p-H . For both MPA and 3FMPA
hydrogenated products, the chemical conversion is found similar, properties for engineering
a
simple vaporizer with no
i.e., 79% and 75% after 10 s of reaction, respectively, and the
condensation issues. The moderate fluorinated content of 3FDE
buildup time constants are significantly longer (7 to 9 s) than for
(F = 0.3) does not however imply non-flammability.
the other compounds studied here. Interestingly, the effective P
H
F rate
L (vol%)
U (vol%)
0
0.4
0.8
0
4
8
0
20
40
of 3FMPA is found about 3 times higher than the one of MPA,
even though HP MPA and 3FMPA show similar relaxation
constants at both Earth’s field and high field. Note that, methine
CH CH(CF )OCH CF CF
3
2
3
2
3
2
3
2
2
3
CH
CH
CH
CH
CH
C(CF
3
)OCH
2
CF
CF
2 3
2
CF
3
CH(CF
C(CF )OCH
CH OCF CF
CHOCF CF
COOCH (CF
CHCOOCH (CF
COOCH(CF
CHCOOCH(CF
CH COOCH CF
CHCOOCH CF
CH OCH CF (3FDE)
CHOCH CF (3FEVE)
3
)OCH
3
2
CF
3
2
2
3
(
H
A
) and methyl (H
B
) groups exhibit a pronounced difference in
2
3
T
1
at high field, with values > 30 s for methine and < 10 s for
CH
3
CH
2
2
2
)
5
CF H(12FEP)
2
CH
CH
CH
CH
CH
CH
CH
2
2
2
)
5
CF
2
H (12FEA)
methyl. This is also manifested in the strong coupling regime (at
Earth’s magnetic field), with methyl group polarization values
inferior by about 20% when compared to methine group values.
This effect is not due to the presence of F atoms in the vicinity of
the HP protons, as it is observed similarly for MPA and 3FMPA.
We now turn the discussion toward the designing of an
effective, non-flammable and inhalable PHIP contrast agent. As
the flammability limits for most of the molecules studied here
3
2
3
2
3
2
CH
2
)
3 2
(6FEP)
3
)
2
(6FEA)
2
2
3
(3FEP)
2
3
(3FEA)
2
2
3
2
3
CH CH COOCH CH OH (HEP)
3
2
3
2
2
2
2
CH
CH
CH
CHCOOCH
2
CH
2
OH (HEA)
2
CH OCOCH
3
(EA)
(VA)
*nf
.625
EXP
CHOCOCH
3
0
MODEL
CH3CH2OCH2CH3 (DE)
CH
2
CHOCH
CHOCHCH
CH
OCH CF
CF(CF )OCH
CF CF OCH
2
CH
3
(EVE)
(
PHIP substrates and products) are yet unknown, we invoke the
CH
2
2
CF
3
CHFCF
CF
2
2 2
OCHF
empirical model developed by Kondo et al. to predict the lower
CHF
2
2
2
3
CF
CF
3
3
3
(
L) and upper (U) flammability limits (in vol%) of partially
[
49, 50]
3
2
2
3
fluorinated and perfluorinated compounds.
This model is
CHF CH OCF
2
2
3
2
2
3 2
CF CH OCHF
based on experimental values measured for 74 alkanes, alkenes,
2 2
CHF CF OCH
CH
3
[
51]
ethers, and esters following the ASHRAE criteria.
The
CF
CF
CHF
3
CH
CF
CF
2
OCF
2
CH
3
3
2
2
CH OCH
3
experimental values of L and U can be predicted with an
average relative deviation of 10% and 36%, respectively, as
shown in Figure 4 for a selection of 42 benchmark molecules
along with the PHIP substrates and hydrogenated products.
Although the predicted upper flammability limit of non-fluorinated
ethers such as EVE and DE are underestimated, this model
reproduces fairly well the subtle differences in partially
fluorinated ethers and esters that are closely related to the
molecules studied here.
2
2 2 2
CH OCHF
CF
3
CF
3
CH(CF
CHFCF
3
)OCH
OCH
3
2
3
CH
CF
CHF
3
CH
2
OCF
OCH
3
3
CH
2
3
2 2 3
CF OCH
CF
3
CF
3
CF
3
CHFOCH
CF OCH
OCH
3
2
3
3
CH CHCOOCH CH
2
3
2
3
3
2
3
CH
CH
CH
CH
CH
CHCOOCH
OCOCH
OCH
2 3
OCH
3
3
3
By comparing the chemical structures,
F rates, and
CF
CHFCFCF
CF CHCF
CH CFCF
CHFCHCF
CH CHCF
CH CFCH3
2
CFCF
3
experimental and predicted flammability limits within this
ensemble of molecules, one can derive the following general
trends in terms of flammability:
3
2
3
2
3
3
2
3
-
The larger the F substitution rate is, the less flammable the
compound is. Compounds with F > 0.625 are mostly non-
flammable.
2
CH
CH
2
CF
CHF
CH
CHCH
CH CH
CHCH
CH CH
CHCH
2
2
CH
CF
3
2
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
2
CH
3
CH
4
2 2 3
CH CH
-
Flammability further decreases when F atoms are attached to
2
2
CH
2
CH
3
C atoms adjacent to double bonds, whereas –C–CF
3
group
CH
2 3
2
2
CH
3
has no diminishing effect in flammability other than increasing
3
CH
2
CH
2
CH
3
CH
3
the F rate.
-
In ethers, –O–CF
while –O–CF= and –O–CF
Another important dimension that must be accounted for the
3
group significantly decreases flammability
2
– groups have no particular effect.
Figure 4. Fluorine substitution rate F and predicted lower (L) / upper (U)
flammability limits in vol% of the PHIP substrates (regular font) and products
development of PHIP inhalable contrast agents concerns the
normal boiling points (b.p.) of the hydrogenation products.
Overall, perfluorination and partial fluorination tend at
decreasing the boiling point, which is desirable to ensure an
efficient vaporization at atmospheric pressure of the HP PHIP
products. To estimate these values, we refer to the modified
Joback group contribution method developed by Devotta and
(
bold font) compared to a representative set of experimental measurements
obtained with non-fluorinated and fluorinated alkanes, alkenes, ethers and
[
50]
esters used to model L / U. The orange line in the F rate column represents
the minimal F substitution degree to allow for non-flammability (F = 0.625).
[
52, 53]
Increasing F substitution rate while keeping intact the carbon
framework and the hydrogen atoms on the hydrogenated arm of
Pendyala.
In this empirical model originally developed for
the screening of alternatives to chlorofluorocarbons (CFCs),
halogens are treated differently from other functional groups—
because of halogen-halogen and halogen-hydrogen nonbonding
interactions—so that isomeric features are taken into account.
diethyl ether leads to CH
.0, U = 15.2, and a boiling point of 19 °C. This molecule
certainly lies near the non-flammability boundary, if not in the
3 2 2 3
CH OCF CF (5FDE), with F = 0.5, L =
4
5
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.202004168
RESEARCH ARTICLE
nonflammable group. We plan to test it with PHIP once its
the efficiency and specificity of the reaction when the α-carbon
is not bound to F atoms.
2 2 3
precursor CH CHOCF CF (5FEVE) is available. Alternatives
exist with larger systems to further reduce flammability while
allowing for an effective PHIP process, as our results with
propionates and acids suggest. For instance, we envision
studying the following two candidates:
- For highly volatile ether such as diethyl ether, which
represents a promising class of PHIP molecules to be used as
inhalable anesthetics, the polarization levels are lowered by a
factor of ~ 2.5 with the F substitution of the methyl group. The
results are still deemed suitable for biomedical applications
with highly desirable reduced flammability.
-
CH
and b.p. = 50.4 °C);
CH CH(CF )OCH CF
vol%, b.p. = 71 °C).
3
CH(CF
3
)OCH
2
CF
3
(F = 0.5, L = 3.5 vol%, U = 12.4 vol%,
-
3
3
2
2
CF (F = 0.57, L = 3.5 vol%, U = 12.4
3
3
- A branched CF group directly attached to the methine group
of the CC double bond hosting the addition of parahydrogen
seems promising for reaching high fluorine content, because
the measured polarization levels are found significantly higher
than in the non-fluorinated case. This effect could possibly
mitigate the polarization decrease observed with linear,
partially fluorinated ethers.
These compounds are of interest especially because of the
-fold increase in polarization measured in the case of 3FMPA,
3
3
i.e. where a branched CF group is attached to the methine
carbon. This effect could possibly compensate for the
polarization loss observed when partial fluorination is used on
the non-hydrogenated arm of an ether. The potential
flammability should be assessed experimentally, because the
fluorine content of these systems is close to the elusive F =
In fine, all the hydrogenation reactions studied here were
intentionally catalyzed with the same Rh complex for
comparison purposes; nevertheless each reaction could also
benefit from the more rational design of a targeted catalyst.
0
.625 non-flammability limit. Further increasing F substitution
rate with larger carbon backbones would certainly guarantee
non-flammability, yet at the expense of increasing the boiling
point.
Acknowledgements
The feasibility imaging studies in the gas-phase is the next
logical step of this work to demonstrate the feasibility of
functional MRI using proton-hyperpolarized fluorinated
hydrocarbons. It should be noted that future HP gas imaging
studies would greatly benefit from MRI detection of long-lived
spin states in the gas phase as they enable a much longer
readout time window. These LLS persist in low magnetic field in
the strongly coupled regime, i.e., when the spin-spin coupling is
greater than the chemical shift difference of the nascent
parahydrogen derived protons. In practice, such field is achieved
below 0.4 T for propane and below 0.1 T for other less
symmetric hydrocarbons. A number of suitable low-field MRI
scanning platforms is becoming increasingly available: for
example, Time Medical PICA and Hyperfine MRI scanner to
This work was supported by the National Science Foundation
CHE-1904780, NHLBI 1R21HL154032, and DOD CDMRP
W81XWH-15-1-0271 and W81XWH-20-1-0576. The Russian
team thanks the Russian Foundation for Basic Research (Grants
1
7-54-33037, 19-53-12013, 19-29-10003, 19-33-60045) and the
Russian Ministry of Science and Higher Education (Grant AAAA-
A16-116121510087-5).
Keywords: parahydrogen • hyperpolarization • flammability •
fluorine • inhalable anaesthetics
name a few. Our ongoing efforts are currently focused on References
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Chemistry - A European Journal
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RESEARCH ARTICLE
Entry for the Table of Contents
To
inhalable contrast agents with the
parahydrogen-induced polarization
design
low-flammable
NMR/MRI
technique, trends are derived from kinetic,
polarization, and relaxation measurements
for a number of functionalized hydrocarbons
with various degrees of fluorine substitution.
8
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