Structural exploration of rhodium catalysts and their kinetic studies for efficient parahydrogen-induced polarization by side arm hydrogenation

Article abstract of DOI:10.1039/c9ra02580d

Parahydrogen-induced polarization (PHIP) is a rapid and cost-effective hyperpolarization technique using transition metal-catalysed hydrogenation with parahydrogen. We examined rhodium catalysts and their kinetic studies, rarely considered in the research

Full text of DOI:10.1039/c9ra02580d

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Structural exploration of rhodium catalysts and
their kinetic studies for efficient parahydrogen-
induced polarization by side arm hydrogenation†
Cite this: RSC Adv., 2019, 9, 18183
ab
a
Marino Itoda,a Yuki Naganawa,
Makoto Ito,a Hiroshi Nonaka
*
ac
*
and Shinsuke Sando
Parahydrogen-induced polarization (PHIP) is a rapid and cost-effective hyperpolarization technique using
transition metal-catalysed hydrogenation with parahydrogen. We examined rhodium catalysts and their
kinetic studies, rarely considered in the research of current PHIP. It emerged that rhodium complexes
with electron-donating bisphosphine ligands, with a dicyclohexylphosphino group, appear to be more
effective than conventional rhodium catalysts.
Received 6th April 2019
Accepted 3rd June 2019
DOI: 10.1039/c9ra02580d
rsc.li/rsc-advances
relaxation, and thus it is preferable that the polarization is
Introduction
transferred from 1H to other heteronuclei such as 13C and 15
N
with larger T1, by eld cycling or using radio frequency pulse,
where the hyperpolarized spin state can be retained for
longer periods of time.5 Therefore, the rst hydrogenation
with parahydrogen is regarded as the dominant step of PHIP
to realize sufficient polarization levels. Hyperpolarization
levels are positively correlated with the reaction rate of the
hydrogenation reaction; therefore, this key step should be
completed as soon as possible with highly active transition
metal catalysts.
Regarding the choice of metal catalysts, homogeneous
rhodium complexes have been applied to hydrogenation in
PHIP because the pairwise addition to unsaturated bonds
must take place to retain the initial spin character of para-
hydrogen.6,7 Commercially available [Rh(nbd)(dppb)]BF4 (1)
(nbd ¼ 2,5-norbornadiene, dppb ¼ 1,4-bis(diphenylphos-
phino)butane) has been employed in typical PHIP experi-
ments, although the catalytic activity of this conventional
cationic rhodium complex 1 (see Fig. 1a) is sometimes inad-
equate. For example, Chekmenev and co-workers8 reported
PHIP experiments of [1-13C]vinyl acetate (VA) with 1, wherein
high hydrogen pressure was required to complete the hydro-
genation within a few seconds. In this case, hydrogenation of
80 mM VA solution in methanol-d4 at 40 ꢀC under standard
pressure (1 bar) was not completed aer 100 s.8a
Nuclear magnetic resonance (NMR) spectroscopy is one of the
attractive techniques for non-invasive biological analysis.
However, in vivo analysis at a molecular level by NMR spec-
troscopy is oen problematic because of the intrinsic low
sensitivity. Hyperpolarization techniques have been developed
to enhance the intensity of NMR signals of target nuclei
dramatically. Theoretically in the case of 13C nuclei, hyperpo-
larization should enhance intensities of NMR signals up to 105
times more than in the thermal equilibrium.1 Among various
protocols, the dissolution dynamic nuclear polarization (d-
DNP) method has become a mainstream technique to achieve
high polarization levels, although several unsolved issues do
remain, such as the requirement for expensive equipment and
prolonged operating times of several hours.2
Meanwhile, parahydrogen-induced polarization (PHIP),3
in addition to signal amplication by reversible exchange
(SABRE),4 has drawn increasing attention as an easy and cost-
effective hyperpolarization technique. PHIP utilizes transi-
tion metal-catalysed hydrogenation of carbon–carbon
unsaturated bonds in precursor molecules with para-
hydrogen, the spin isomer of molecular hydrogen with anti-
parallel nuclear spins (Scheme 1). The rapid decay of
hyperpolarization generally proceeds through spin–lattice
aDepartment of Chemistry and Biotechnology, Graduate School of Engineering, The
University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan. E-mail:
ssando@chembio.t.u-tokyo.ac.jp
bInterdisciplinary Research Center for Catalytic Chemistry, National Institute of
Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba,
Ibaraki, 305-8565, Japan. E-mail: yuki.naganawa@aist.go.jp
cDepartment of Bioengineering, Graduate School of Engineering, The University of
Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra02580d
Scheme 1 Experimental concept of PHIP.
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hexane and dried in vacuo. The product was recrystallized from
ethanol to give red crystal (252 mg, 41%).
1H NMR (CDCl3, 400 Hz) d ¼ 5.54 (s, 4H), 4.23 (s, 2H), 2.03–
1.70 (m, 20H), 1.39–1.02 (m, 30H); 13C NMR (CDCl3, 125 MHz)
d ¼ 85.4, 71.7, 55.7, 35.4–35.7 (m), 29.5, 29.0, 27.1 (t, J ¼ 4.7 Hz),
26.7 (t, J ¼ 4.0 Hz), 26.4, 25.9, 21.1 (t, J ¼ 16 Hz); 31P NMR
(CDCl3, 162 Hz) d ¼ 70.2 (d, J ¼ 153 Hz); HRMS(ESI): m/z calc.
for C33H56P2Rh+ [M–BF4ꢁ]+ ¼ 617.2907, found ¼ 617.2900.
Synthesis of [Rh(nbd)(dcpp)]BF4 (3). [Rh(nbd)2]BF4 (63.4 mg,
0.170 mmol) and 1,3-bis(cyclohexylphosphino)propane bis(te-
trauoroborate) (104 mg, 0.170 mmol) were dissolved in
dichloromethane (3.5 mL). N,N-diisopropylethylamine (29.5 mL,
0.339 mmol) was added and the mixture was stirred for 5 h at
room temperature. Then, n-hexane was poured into the solution
to afford an orange precipitate. The precipitate was ltered and
washed with n-hexane and dried in vacuo. The product was
recrystallized from methanol to give red crystal (89.4 mg, 73%).
1H NMR (CDCl3, 400 Hz) d ¼ 5.18 (s, 4H), 4.14 (s, 2H), 2.20–
1.14 (m, 52H); 13C NMR (CDCl3, 100 MHz) d ¼ 80.2, 70.7, 54.4,
36.9 (t, J ¼ 11 Hz), 30.4, 28.7, 27.5 (t, J ¼ 5.7 Hz), 26.8 (t, J ¼ 4.8
Hz), 26.0, 22.5, 17.8 (t, J ¼ 13.8 Hz); 31P NMR (CDCl3, 162 Hz) d ¼
16.3 (d, J ¼ 148 Hz); HRMS(ESI): m/z calc. for C34H58P2Rh+ [M–
BF4ꢁ]+ 631.3063, found 631.3050.
Fig. 1 (a) Structural exploration of conventional rhodium complex 1.
(b) Rhodium complexes 2–5 selected based on the screening of
ligands.
Synthesis of [Rh(nbd)(dcpb)]BF4 (4). [Rh(nbd)2]BF4 (374 mg,
1.00 mmol) and 1,4-bis(cyclohexylphosphino)butane (451 mg,
1.00 mmol) were dissolved in dichloromethane (20 mL). The
mixture was stirred for 6 h at room temperature and then n-
hexane was poured into the solution to afford an orange
precipitate. The precipitate was ltered and washed with n-
hexane and dried in vacuo. The product was recrystallized twice
from methanol to give red crystal (589 mg, 80%).
In the eld of organometallic chemistry, the development of
various rhodium catalysts for hydrogenation has thus far been
devoted to the achievement of high reactivity and efficiency. In
contrast, such careful investigations on rhodium catalysts have
rarely been considered for PHIP experiments,9 especially for
PHIP by side arm hydrogenation (PHIP-SAH).10 PHIP-SAH is
a promising method which can hyperpolarize carboxylic acid
such as pyruvic acid, an attractive substrate for hyperpolarized
magnetic resonance imaging (MRI).11 We therefore focused our
attention and efforts on the structural exploration of
[Rh(nbd)(PP)]BF4 (PP ¼ bisphosphine ligand) and kinetic
studies to improve the efficiency of PHIP experiments (see
Fig. 1a).
1H NMR (CDCl3, 400 Hz) d ¼ 4.93 (s, 4H), 4.09 (s, 2H), 2.15
(m, 4H), 2.03–1.60 (m, 30H), 1.46–1.18 (m, 20H); 13C NMR
(CDCl3, 100 MHz) d ¼ 76.7–77.3 (m), 69.8, 53.7, 36.7 (t, J ¼ 11
Hz), 31.0, 28.7, 27.6 (t, J ¼ 5.7 Hz), 26.9 (t, J ¼ 4.3 Hz), 26.1, 24.2,
17.1 (t, J ¼ 11 Hz); 31P NMR (CDCl3, 162 Hz) d ¼ 27.7 (d, J ¼ 153
ꢁ +
Hz); HRMS(ESI): m/z calc. for C35H60P2Rh+ [M–BF4
645.3220, found 645.3208.
]
¼
Synthesis of [Rh(nbd)(dcpf)]BF4 (5). [Rh(nbd)2]BF4 (66.7 mg,
0.178 mmol) and 1,10-bis(cyclohexylphosphino)ferrocene (105 mg,
0.181 mmol) were dissolved in dichloromethane (3.5 mL). The
Experimental
1
Synthesis
General information. Reagents and solvents were purchased mixture was stirred for 6.5 h at room temperature and then n-
from standard suppliers and used without further purication. hexane was poured into the solution to afford an orange precipi-
NMR spectra were measured using JEOL ECS400 spectrometer tate. The precipitate was ltered and washed with n-hexane and
and Bruker Ascend 500 NMR spectrometer. Chloroform-d1 (7.26 dried in vacuo. The product was recrystallized twice from methanol
ppm) and methanol-d4 (3.31 ppm) were used as the internal to give red crystal (92.4 mg, 60%).
standards for 1H NMR. Chloroform-d1 (77.2 ppm) and meth-
1H NMR (CDCl3, 400 Hz) d ¼ 5.06 (s, 4H), 4.47 (s, 4H), 4.29 (s,
anol-d4 (49.0 ppm) were used as the internal standards for 13C 4H), 4.15 (s, 2H), 2.33 (m, 4H), 2.18–1.06 (m, 42H); 13C NMR
NMR. Phosphoric acid (0.0 ppm) was used as the external (CDCl3, 100 MHz) d ¼ 75.4, 73.5, 72.0, 69.6, 53.7, 37.1 (t, J ¼ 10
standard for 31P NMR. ESI mass spectra (MS) were measured Hz), 30.0, 30.0, 27.6 (t, J ¼ 6.2 Hz), 26.7 (t, J ¼ 4.8 Hz), 26.0; 31
P
using Bruker micrOTOF II.
NMR (CDCl3, 162 Hz) d ¼ 29.8 (d, J ¼ 162 Hz); HRMS(ESI): m/z
Synthesis of [Rh(nbd)(dcpe)]BF4 (2). [Rh(nbd)2]BF4 (329 mg, calc. for C41H60FeP2Rh [M–BF4ꢁ]+ 773.2575, found 773.2551.
0.881 mmol) and 1,2-bis(cyclohexylphosphino)ethane (372 mg,
0.881 mmol) were dissolved in dichloromethane (17 mL). The
2
Ligand screening
General information. Reagents and solvents were purchased
mixture was stirred for 7 h at room temperature, and then n-
hexane was poured into the solution to afford an orange
precipitate. The precipitate was ltered and washed with n- from standard suppliers and used without further purication. 1H
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Table 1 Result of ligand screening in hydrogenation of VAa
mL minꢁ1) was bubbled into the mixture at 50 ꢀC for 30 s under
ordinary pressure. Conversion of vinyl acetate was determined by
1H NMR.
Entry
Ligand
Conversion of VAb [%]
1
2
Trace
16
3
Hydrogenation kinetics
General information. Reagents and solvents were purchased
3
4
24
33
from standard suppliers and used without further purication.
UV-vis spectra were measured using JASCO V-630 UV-VIS spec-
trophotometer. NMR spectra were measured using JEOL
ECS400 spectrometer. Hydrogen owing was controlled using
EYELA MFC-1000-H2.
5
6
39
23
Molar extinction coefficient before hydrogenation. 5 mM
stock solutions of catalysts were prepared with HPLC-grade
methanol. The stock solution was diluted to 0.5, 0.4, 0.3, 0.2
and 0.1 mM, respectively. Molar extinction coefficient at
absorption maximum around 470–480 nm (ref. 12) was deter-
mined from an inclination of an approximate line in
concentration-UV absorbance plot.
7
71
8
9
69
73
Molar extinction coefficient aer hydrogenation. 5 mM of
catalyst solutions were set into a disposable UV cell with a cap.
Hydrogen was bubbled at room temperature under ordinary
pressure until activation was completed. (Bubbling duration
was roughly estimated using 5 mM catalyst in methanol-d4.)
Aer the activation of 5.0, 4.0, 3.0, 2.0 and 1.0 mM (cat 1, 2 and
4), 2.5, 2.0, 1.5, 1.0 and 0.5 mM (cat 3), 1.25, 1.0, 0.75, 0.5 and
0.25 mM (cat 5) of each catalyst solution, UV-vis spectra of these
activated solutions were measured. Apparent molar extinction
coefficient was determined from an inclination of an approxi-
mate line in concentration–absorbance plot.
Determination of activation rates. 5 mM stock solutions of
catalysts were prepared with HPLC-grade methanol. The stock
solution was diluted to 0.5 mM in a UV quartz cell with septum
screw cap. The cell was degassed and lled with 1 atm of
hydrogen. Immediately aer replacement with hydrogen, UV-vis
absorbance measurement was started. Linear approximation
was applied during 30–90 s, because the absorbance wasn't
stable during 0–30 s.
10
11
12
25
81
29
13
14
45
5
15
n.d.
Determination of TOF for vinyl acetate. 5 mM of catalyst
solution in methanol-d4 containing 1 M of vinyl acetate was set
into an NMR tube with a cap. 20 mL minꢁ1 of normal hydrogen
was bubbled for 30 s at 30 ꢀC and 1H NMR spectrum was
measured. A series of hydrogen bubbling and 1H NMR
measurement was repeated at least 5 times. Catalysts contain-
ing Cy ligands were completely activated within 30 s, but it took
30–60 s for [Rh(nbd)(dppb)]BF4 (cat 1) to be completely acti-
vated. Therefore, D mM (product concentration) from 60 s (cat
1) and D mM from 30 s (cat 2–5) were plotted.
16
17
PPh3 (2 eq.)
PCy3 (2 eq.)
19
5
a
Hydrogen (20 mL minꢁ1, 1 atm) was bubbled into a solution of VA in
methanol-d4 (150 mM) with 5 mM of rhodium catalyst in an NMR tube
for 30 s at 50 ꢀC. The conversion rate was determined by 1H NMR
b
analysis. n.d. ¼ not detected.
NMR spectra were measured using JEOL ECS400 spectrometer.
Hydrogen owing was controlled using EYELA MFC-1000-H2.
Ligand screening for vinyl acetate. Ligand (3.5 mmol or 7.0
mmol for PPh3 and PCy3) and [Rh(nbd)2]BF4 (3.5 mmol) were dis-
solved in dichloromethane (200 mL) and the mixture was vortexed
for 90 min. The solvent was removed under reduced pressure. The
residue was re-dissolved in methanol-d4 (690 mL). Vinyl acetate (9.7
mL) was added to the mixture (nal concentration 150 mM), which
was then transferred into an NMR tube. The mixture in an NMR
tube was warmed in a water bath at 50 ꢀC for 10 s and hydrogen (20
4
Hyperpolarization experiments
General information. Methanol-d4 was degassed by N2
bubbling just before experiments. NMR spectra were measured
using JEOL ECS400 spectrometer. 92% para-enriched
a
hydrogen was produced using Bruker ParaHydrogen Generator.
Magnetic eld cycling (MFC) systems were prepared according
to a previous report.8 Polarization level was determined
according to the procedure reported previously.8a
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apparatus and slowly pulled up out from the apparatus in about
4 s) under 0.2 mT was conducted to transfer hyperpolarization
from 1H to 13C. The data represent mean values ꢂ s.d. for 3
samples.
PHIP experiment of propargyl acetate. 2.5 mM of catalysts 1–
5 and 50 mM of propargyl acetate (35 mmol, natural abundant)
in 700 mL of methanol-d4 was set in an NMR tube. Immediately
aer parahydrogen bubbling at 50 ꢀC under 1 atm for 10 s, eld
cycling procedure under 0.2 mT was conducted to transfer
hyperpolarization from 1H to 13C. The data represent mean
values ꢂ s.d. for 3 samples.
5
Hyperpolarization using ow system
General information. Methanol was degassed by N2
bubbling just before experiments. EYELA SynpleFlow MCR-1000
was used as a ow reactor. NMR spectra were measured using
a JEOL ECS400 spectrometer. 92% para-enriched hydrogen was
produced using Bruker ParaHydrogen Generator. Magnetic eld
cycling (MFC) systems were prepared according to a previous
report.8
Hyperpolarization using ow system. Catalyst 1 or 4 (5.0
mmol, nal concentration 5.0 mM) and vinyl acetate (1.0 mmol,
nal concentration 1.0 M) were dissolved in 1 mL of degassed
methanol. A column of the reactor was lled with sea sand and
ꢀ
heated to 50 C. Back pressure was set to 0.39 MPa. Aer 3.0
mL minꢁ1 of mobile phase (methanol) owing and 100
mL minꢁ1 of 92% para-enriched hydrogen owing became
stable, the mixture of catalyst and substrate was injected to the
ow reactor. The effluent was collected in an NMR tube and
Fig. 2 (a) Conditions of the PHIP experiment of VA. (b) Polarization
13
level % P C at carbonyl carbon of EA. (c) Conversion rate of VA to EA.
1
(d) 13C NMR spectrum of natural abundant EA (ca. 40 mM) in thermal
equilibrium state (30ꢀ pulse, 1 scan). (e) 13C NMR spectra (30ꢀ pulse, 1
scan) of EA produced upon PHIP (initial concentration of VA 50 mM)
with catalyst 1 or 4. S/N means signal to noise ratio with standard
deviation (n ¼ 3). (f) Stacked 13C NMR spectra of the hyperpolarized EA.
PHIP experiments were conducted under the following conditions: 20
mL minꢁ1 parahydrogen (1 atm) was bubbled for 10 s into 700 mL of
methanol-d4 containing 5 mM catalyst and 50 mM VA, followed by
polarization transfer.
MFC was conducted to transfer hyperpolarization from H to
13C. The data represent mean values ꢂ s.d. for 3 samples.
Results and discussion
Initial ligand screening based on catalytic activity
We commenced our evaluation of various rhodium catalysts in
the hydrogenation of VA, which is a minimal model molecule
usually applied to PHIP-SAH.10a All experiments were conducted
in methanol or methanol-d4 because most of the ligands were
insoluble in water. We examined the hydrogenation of VA in the
presence of rhodium complexes prepared in situ from
[Rh(nbd)]2BF4 with various phosphine ligands (Scheme S1†).
The reaction was carried out using a solution of VA in methanol-
d4 (150 mM) with 5 mM of rhodium catalyst, under constant
bubbling of hydrogen (1 atm, 20 mL minꢁ1) into an NMR tube
for 30 s at 50 ꢀC. The conversion rate was then determined by 1H
NMR analysis. Screening of various phosphine ligands revealed
that highly electron-donating bisphosphine ligands with
a dicyclohexylphosphino group (PCy2 group) were particularly
promising in terms of their catalytic activity (Table 1, entries 7–9
and 11).
Scheme 2 Two steps of rhodium-catalysed hydrogenation.
PHIP experiment of vinyl acetate. 5 mM of catalysts 1–5 and
50 mM of vinyl acetate (35 mmol, natural abundant) in 700 mL of
methanol-d4 was equipped in an NMR tube. Immediately aer
parahydrogen bubbling at 50 ꢀC under 1 atm for 10 s, eld
cycling procedure (the NMR tube was quickly dropped into MFC
Hyperpolarization experiment of VA
Based on the screening of ligands, we next prepared rhodium
complexes [Rh(nbd)(dcpe)]BF4 (2), [Rh(nbd)(dcpp)]BF4 (3),
[Rh(nbd)(dcpb)]BF4 (4) and [Rh(nbd)(dcpf)]BF4 (5) (see Fig. 1b).
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ꢀ
tubes at 50 C under the Earth magnetic eld. Then, the sample
was quickly inserted in 0.2 mT eld and pulled out slowly (ca. 4 s) to
transfer the hyperpolarization from nascent protons to 13C with
longer T1 (ALTADENA conditions) (Fig. 2a and Scheme S2†). Our
PHIP-SAH experiments of VA using catalysts 1–5 resulted in the
successful observation of hyperpolarized 13C NMR signals of ethyl
13
acetate (EA). The polarization level % P C at the carbonyl carbon of
EA reached about 1.5%, which was comparable in the case of
conventional catalyst 1 and modied catalysts 2–5 (Fig. 2b). In
contrast, the conversion rate of the hydrogenation with catalysts 2–
5 was uniformly higher than that with 1 (Fig. 2c).14 As a result, the
signal-to-noise (S/N) ratios of the 13C NMR signals obtained when
using catalysts 2–5 were enhanced; they were three to four times
higher than when using conventional catalysis 1 (Fig. 2d–f).
Fig. 3 Measurement of activation rates. (a) UV-vis spectra of 0.5 mM
of Rh-dcpb complex with and without nbd. (b) Determination of
activation rates. Activation rates were determined by monitoring
absorption around 470–480 nm of 0.5 mM catalyst solution at 1 atm of
hydrogen.
Hydrogenation kinetics
To gain further insight into the origin of the better catalytic
activities of 2–5, we investigated the kinetics of the hydroge-
nation. In the initial stage of hydrogenation, the removal of the
coordinated nbd ligand of 1–5 must be carried out to generate
active species under reductive conditions (Step 1 in Scheme 2).
Thus, we rst determined the activation rate of 1–5 under
hydrogen (1 atm) by UV-Vis analysis of the coordinated nbd
ligands, with the maximum absorption wavelength at 470–
Fig. 4 TOF of Rh catalysts 1–5 in hydrogenation for vinyl acetate (VA). 480 nm (Fig. 3a). Subsequently, the removal rate of a nbd ligand
Determination of TOF for VA (cat 1–5). 5 mM of catalyst solution in
of modied catalysts 2–5 was determined to be 4.0–5.7 ꢃ
methanol-d4 containing 1 M of VA was set into an NMR tube, and
10ꢁ3 mM sꢁ1
(Fig. 3b).
,
whereas that of 1 was 1.2 ꢃ 10ꢁ3 mM sꢁ1
14
bubbled with normal hydrogen (20 mL min–1).
Next, we checked the turnover frequency (TOF) of the
completely activated rhodium catalysts in the hydrogenation of
VA with bubbling of hydrogen (1 atm) (Step 2 in Scheme 2). The
TOF of catalysts 2–5 was determined to be 1.8–2.0 times higher
than that of 1 (Fig. 4).14 Overall, these two kinetic studies
revealed that both catalyst activation (Step 1) and hydrogena-
tion (Step 2) proceeded rapidly in the case of catalysts 2–5,
resulting in higher performance in the PHIP experiments.
Possible reaction mechanism
To further consider the reasons for the high catalytic activity
of 2–5, details of differences in each of the possible reaction
mechanism are illustrated in Fig. 5. In the general pathway,
with cationic rhodium catalysts such as 1, it is well known
that hydrogenation takes place via the initial coordination of
substrates before the oxidative addition of hydrogen, which
is irreversible15 (‘Unsaturated route’, le in Fig. 5).16 In
contrast, Imamoto and co-workers propose that cationic
rhodium complexes [RhS2(PP)]BF4 with an electron-donating
bisphosphine ligand bearing alkyl groups are rst converted
to the corresponding dihydride complexes [RhH2S2(PP)]BF4,
rather than the coordination of substrates, due to the stabi-
lizing effect on the high oxidation state of a rhodium centre
(‘Hydride route’, right in Fig. 5).17 It has been also examined
that the reversible addition of hydrogen and ortho–para
interconversion occur in the hydrogenation with catalyst 1
and the formation of rhodium hydride species is more fav-
oured with the more basic phosphine ligands.18 In addition,
Fig. 5 Two different catalytic cycles of hydrogenation. nbd ¼ 2,5-
norbornadiene, S ¼ solvent, VA ¼ vinyl acetate, EA ¼ ethyl acetate, PP
¼ bisphosphine ligand.
Rhodium complexes of bisphosphine ligands with a dicyclo-
hexylphosphino group have been reported as catalysts for
hydrogenation; however, to our knowledge, they have not been
widely employed for PHIP experiments.13
With these promising rhodium catalysts in hand, we conducted
the PHIP-SAH experiment of VA according to procedure described
by Chekmenev and co-workers.8a We performed our hyperpolar-
ization experiment by bubbling parahydrogen (1 atm, 20
mL minꢁ1) for 10 s into a methanol-d4 solution of 13C natural
abundance VA (50 mM) and rhodium catalysts 1–5 (5 mM) in NMR
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to conclude which pathway would be more plausible for
hydrogenation with catalysts 2–5.
Hyperpolarization experiment of PA
With high-performance catalysts in hand, we then moved to
examine the hydrogenation of propargyl esters, which have also
been employed for PHIP-SAH experiments (Fig. 6).9,20 Fig. 6b
shows the conversion rate of the hydrogenation of a model
compound, propargyl acetate (PA), to allyl acetate (AA). As in the
case of VA, the yields of AA with 2–5 were uniformly higher than
that with 1. In reactions with 2–5, double hydrogenation
occurred to afford n-propyl acetate (n-PA), suggesting the
stronger reductive ability of these rhodium catalysts. Thus, we
demonstrated PHIP experiments of PA and observed the same
or slightly higher level of hyperpolarization at the carbonyl
carbon (Fig. 6c). Consequently, PHIP with catalyst 4 resulted in
13C NMR signals that were about four times higher than with
catalyst 1 (Fig. 6d and e).
Hyperpolarization using ow system
Finally, we tried to apply these rhodium catalysts to ow
hydrogenation systems23 to achieve continuous acquisition of
hyperpolarized samples in high concentration. We conducted
PHIP-SAH of 1 M VA in methanol using a ow reactor in
a combined phase of 100 mL minꢁ1 parahydrogen and 3
mL minꢁ1 substrate in methanol, as illustrated in Fig. 7. When
using one of the modied catalysts 4, the PHIP experiment
yielded a high concentration of EA (ca. 300 mM) with a polari-
zation level of ꢄ0.7%. Because of the slightly longer operation
time, in comparison with the batch reaction system, the
Fig. 6 (a) Conditions of PHIP experiment of PA. (b) Conversion rate of
13
PA to AA and n-PA. (c) Polarization level % P C at carbonyl carbon of AA
and n-PA. (d) 13C NMR spectrum of natural abundant AA (ca. 35 mM) in
thermal equilibrium state (30ꢀ pulse, 1 scan). (e) 13C NMR spectra (30ꢀ
pulse, 1 scan) of AA and n-PA produced upon PHIP (initial concen-
tration of PA 50 mM) with catalyst 1 or 4. S/N means signal to noise
ratio with standard deviation (n ¼ 3). PHIP experiments were con-
ducted under the following conditions: 20 mL minꢁ1 parahydrogen (1
atm) was bubbled for 10 s into 700 mL of methanol-d4 containing
2.5 mM catalyst and 50 mM PA, followed by polarization transfer.
13C
polarization level % P
at the carbonyl carbon of EA was
slightly lower. Further improvements of a ow reactor, speci-
cally in terms of a shorter reaction pathway, would be helpful in
producing large amounts of product with higher polarization
efficiency.
an isolation of the related stable cationic rhodium hydride
complex of a bisphosphine ligand with a diisopropylphos-
phino group was reported.19 Thus, it may be possible to
reason that hydrogenation with our modied catalysts 2–5
might proceed mainly via the Hydride route.6,20,21 It should be
also noted that the Hydride route has been thought to be less
preferable for PHIP.6,22 In our attempt to determine the
plausible mechanism, the generation of the corresponding
dihydride species aer H2 bubbling with both catalysts 1 and
4 was observed (Fig. S1†). Therefore, further investigations,
e.g., identication of the rate-determining step, are required
Conclusions
In conclusion, we investigated structural modication of the
conventional rhodium catalyst 1 for PHIP experiments based on
a screening approach of organometallic chemistry. We found
that the modied catalyst candidates 2–5 with electron-
donating bisphosphine ligands, with a dicyclohexylphosphino
group, resulted in faster hydrogenation, with the same polari-
zation level, under our experimental conditions (50 ꢀC, para-
hydrogen 1 atm, continuous parahydrogen bubbling), thus
leading to higher 13C NMR signals. To further demonstrate the
utility of these catalysts, we used them in PHIP-SAH experi-
ments of VA in liquid–gas two-phase ow systems. Here, we
recorded the production of hyperpolarized EA in signicantly
high concentration (ca. 300 mM). It should be noted that in this
study we evaluated and optimized ligands based on the catalytic
hydrogenation activity. Further screening study focusing on
hyperpolarization efficiency, especially retention of para spin
during the catalytic reaction, would allow nding better cata-
lysts for PHIP.
Fig. 7 (a) Illustration of flow hydrogenation system used in this study.
(b) Reaction conditions for PHIP of VA in (a).
18188 | RSC Adv., 2019, 9, 18183–18190
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H. E. Hagelin-Weaver and C. R. Bowers, Angew. Chem., Int.
Ed., 2015, 54, 14270.
Conflicts of interest
8 (a) R. V. Shchepin, D. A. Barskiy, A. M. Coffey,
I. V. Manzanera Esteve and E. Y. Chekmenev, Angew.
Chem., Int. Ed., 2016, 55, 6071; (b) K. V. Kovtunov,
D. A. Barsliy, R. V. Shchepin, A. M. Coffey, K. W. Waddell,
I. V. Koptyug and E. Y. Chekmenev, Anal. Chem., 2014, 86,
6192.
There are no conicts to declare.
Acknowledgements
This work was supported by CREST (JPMJCR13L4), Japan
Science and Technology Agency. We thank Dr F. Reineri of the
University of Torino for experimental support and helpful
discussions. We also thank Prof. Dr K. Nozaki and Dr S. Kusu-
moto of the University of Tokyo for their kind donation of
phosphine ligands and carrying out NMR measurement.
9 (a) M. Roth, Sensitivity enhancement in NMR by using
parahydrogen induced polarization, PhD thesis, Johannes
¨
Gutenberg-Universitat Mainz, 2010; (b) R. V. Shchepin,
A. M. Coffey, K. W. Waddell and E. Y. Chekmenev, J. Phys.
Chem. Lett., 2012, 3, 3281.
10 (a) F. Reineri, T. Boi and S. Aime, Nat. Commun., 2015, 6,
5858; (b) N. V. Chukanov, O. G. Salnikov, R. V. Shchepin,
K. V. Kovtunov, I. V. Koptyug and E. Y. Chekmenev, ACS
Omega, 2018, 3, 6673; (c) O. G. Salnikov, R. V. Shchepin,
N. V. Chukanov, L. Jaigirdar, W. Pham, K. V. Kovtunov,
I. V. Koptyug and E. Y. Chekmenev, J. Phys. Chem. C, 2018,
122, 24740.
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22 Under high pressure PHIP in a batch system, relatively lower
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13
% P C values were observed for cat 4 (data not shown) than
for cat 1. This may be attributed to ortho–para conversion in
the ‘Hydride route’.
23 Examples of PHIP experiments using ow systems, see: (a)
L.-S. Bouchard, S. R. Burt, M. S. Anwar, K. V. Kovtunov,
I. V. Koptyug and A. Pines, Science, 2008, 319, 442; (b)
V.-V. Telkki, V. V. Zhivonitko, S. Ahola, K. V. Kovtunov,
18190 | RSC Adv., 2019, 9, 18183–18190
This journal is © The Royal Society of Chemistry 2019