Heterogeneous 1H and 13C Parahydrogen-Induced Polarization of Acetate and Pyruvate Esters

Article abstract of DOI:10.1002/cphc.202100156

Magnetic resonance imaging of [1-¹³C]hyperpolarized carboxylates (most notably, [1-¹³C]pyruvate) allows one to visualize abnormal metabolism in tumors and other pathologies. Herein, we investigate the efficiency of ¹H and ¹³C hyperpolarization of acetate and pyruvate esters with ethyl, propyl and allyl alcoholic moieties using heterogeneous hydrogenation of corresponding vinyl, allyl and propargyl precursors in isotopically unlabeled and 1-¹³C-enriched forms with parahydrogen over Rh/TiO₂ catalysts in methanol-d₄ and in D₂O. The maximum obtained ¹H polarization was 0.6±0.2 % (for propyl acetate in CD₃OD), while the highest ¹³C polarization was 0.10±0.03 % (for ethyl acetate in CD₃OD). Hyperpolarization of acetate esters surpassed that of pyruvates, while esters with a triple carbon-carbon bond in unsaturated alcoholic moiety were less efficient as parahydrogen-induced polarization precursors than esters with a double bond. Among the compounds studied, the maximum ¹H and ¹³C NMR signal intensities were observed for propyl acetate. Ethyl acetate yielded slightly less intense NMR signals which were dramatically greater than those of other esters under study.

Full text of DOI:10.1002/cphc.202100156

Accepted Article
Title: Heterogeneous 1H and 13C Parahydrogen-Induced Polarization
of Acetate and Pyruvate Esters
Authors: Oleg G. Salnikov, Nikita V. Chukanov, Larisa M. Kovtunova,
Valerii I. Bukhtiyarov, Kirill V. Kovtunov, Roman V. Shchepin,
Igor V. Koptyug, and Eduard Y. Chekmenev
This manuscript has been accepted after peer review and appears as an
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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.202100156
Link to VoR: https://doi.org/10.1002/cphc.202100156
01/2020

10.1002/cphc.202100156
ChemPhysChem
ARTICLE
Heterogeneous 1H and 13C Parahydrogen-Induced Polarization of
Acetate and Pyruvate Esters
Oleg G. Salnikov,*[a,b,c] Nikita V. Chukanov,[a,c] Larisa M. Kovtunova,[a,b,c] Valerii I. Bukhtiyarov,[b,c] Kirill V.
Kovtunov,†[a,c] Roman V. Shchepin,[d] Igor V. Koptyug,[a] and Eduard Y. Chekmenev*[e,f]
Dedicated to the memory of Dr. Kirill V. Kovtunov (1983–2020), friend, colleague, and mentor.
[a]
Dr. O. G. Salnikov, Dr. N. V. Chukanov, Dr. L. M. Kovtunova, Dr. K. V. Kovtunov, Prof. I. V. Koptyug
International Tomography Center SB RAS
3A Institutskaya St., 630090 Novosibirsk, Russia
E-mail: salnikov@tomo.nsc.ru
[b]
[c]
Dr. O. G. Salnikov, Dr. L. M. Kovtunova, Prof. V. I. Bukhtiyarov
Boreskov Institute of Catalysis SB RAS
5 Acad. Lavrentiev Pr., 630090 Novosibirsk, Russia
Dr. O. G. Salnikov, Dr. N. V. Chukanov, Dr. L. M. Kovtunova, Prof. V. I. Bukhtiyarov, Dr. K. V. Kovtunov
Department of Natural Sciences
Novosibirsk State University
2 Pirogova St., 630090 Novosibirsk, Russia
Prof. R. V. Shchepin
Department of Chemistry, Biology, and Health Sciences
South Dakota School of Mines & Technology
Rapid City, South Dakota 57701, United States
Prof. E. Y. Chekmenev
[d]
[e]
Department of Chemistry, Integrative Biosciences (Ibio), Karmanos Cancer Institute (KCI)
Wayne State University
Detroit, Michigan 48202, United States
E-mail: chekmenevlab@gmail.com
[f]
Prof. E. Y. Chekmenev
Russian Academy of Sciences
14 Leninskiy Prospekt, 119991 Moscow, Russia
Deceased
†
Supporting information for this article is given via a link at the end of the document.
Abstract: Magnetic resonance imaging of [1-13C]hyperpolarized
carboxylates (most notably, [1-13C]pyruvate) allows one to visualize
abnormal metabolism in tumors and other pathologies. Here we
dissolution Dynamic Nuclear Polarization (d-DNP) technique[7–10]
provides nuclear spin polarization of tens % corresponding to
NMR signal enhancement by 4–5 orders of magnitude at
magnetic fields of several tesla. Compounds hyperpolarized by
d-DNP have been successfully employed as molecular contrast
agents for metabolic studies in vivo.[11–13] For example,
hyperpolarized (HP) [1-13C]pyruvate has demonstrated its utility
as a molecular contrast agent for tumor diagnosis[14,15] and
monitoring of response to tumor treatment[16,17] due to enhanced
pyruvate metabolism in tumor tissues compared to normal
tissues (Warburg effect[18]). Moreover, HP [1-13C]pyruvate has
been successfully employed in clinical trial MRI of prostate
cancer.[19,20] Other molecular contrast agents hyperpolarized by
d-DNP are being considered, including carboxylates such as [1-
13C]acetate[21,22] and [1,4-13C2]fumarate.[23] [1-13C]acetate has
attracted research interest as a potential contrast agent for
metabolic investigations in brain,[24,25] kidney,[21,22] liver[26] and
muscle.[27] HP [1,4-13C2]fumarate showed the prospects for its
application as a noninvasive marker of cellular necrosis in heart
disease.[23]
1
investigate the efficiency of H and 13C hyperpolarization of acetate
and pyruvate esters with ethyl, propyl and allyl alcoholic moieties
using heterogeneous hydrogenation of corresponding vinyl, allyl and
propargyl precursors in isotopically unlabeled and 1-13C-enriched
forms with parahydrogen over Rh/TiO2 catalysts in methanol-d4 and
1
in D2O. The maximum obtained H polarization was 0.6 ± 0.2% (for
propyl acetate in CD3OD), while the highest 13C polarization was
0.10 ± 0.03% (for ethyl acetate in CD3OD). Hyperpolarization of
acetate esters surpassed that of pyruvates, while esters with a triple
carbon-carbon bond in unsaturated alcoholic moiety were less
efficient as parahydrogen-induced polarization precursors than
esters with a double bond. Among the compounds studied, the
maximum 1H and 13C NMR signal intensities were observed for
propyl acetate. Ethyl acetate yielded slightly less intense NMR
signals which were dramatically greater than those of other esters
under study.
Despite the success of d-DNP, this technique has
a
significant drawback of highly expensive and complex
hyperpolarization equipment, making its widespread use in the
clinical setting challenging. Moreover, d-DNP technique requires
relatively long 13C hyperpolarization times of ~1 h. The more
affordable alternative is Parahydrogen-Induced Polarization
(PHIP) technique which employs nuclear spin order of
Introduction
Hyperpolarization techniques enable dramatic increase in
sensitivity of NMR spectroscopy and magnetic resonance
imaging (MRI) techniques through the increase of nuclear spin
polarization (P) by several orders of magnitude.[1–6] For example,
parahydrogen
(p-H2)
molecule
as
a
source
of
1
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10.1002/cphc.202100156
ChemPhysChem
ARTICLE
hyperpolarization.[1,28,29] In PHIP, p-H2 is added to an asymmetric
unsaturated substrate in a pairwise manner, which means that
two atoms from the same p-H2 molecule end up in the same
reaction product molecule. 1H hyperpolarization in solution
usually relaxes with spin-lattice relaxation time T1 of several
seconds. To prolong the hyperpolarization lifetime, polarization
can be transferred from 1H to heteronuclei such as 13C or 15N
with T1 values ranging from tens of seconds to tens of
minutes.[30–34] Transfer of hyperpolarization to heteronuclei can
be carried out at a high magnetic field of NMR spectrometer
using dedicated radiofrequency (RF) pulse sequences,[35–40] or
by magnetic field cycling (MFC) of the HP sample through
microtesla magnetic fields where protons and heteronuclei of the
hyperpolarized molecule come into level anti-crossing (LAC)
regime.[41–44]
Recently, we presented an efficient synthetic approach for
the preparation of 1-13C-labeled acetate and pyruvate esters
containing vinyl, allyl and propargyl alcoholic moieties (Scheme
1),[75] and investigated their use as unsaturated precursors for
homogeneous PHIP-SAH studies.[76] Here, we employed these
compounds for systematic HET-PHIP-SAH investigations using
Rh/TiO2 catalysts for pairwise p-H2 addition in methanol and in
water aiming to compare the efficiency of HET-PHIP
hyperpolarization of acetate and pyruvate esters with different
alcoholic moieties.
A number of biologically relevant compounds have been
directly hyperpolarized by PHIP technique so far, including
succinate,[45–48]
phospholactate,[48–51]
and
fumarate.[52–54]
Moreover, PHIP by means of side arm hydrogenation (PHIP-
SAH), the approach developed by Reineri and co-workers,[31]
enables 13C polarization of carboxylates which cannot be
hyperpolarized by PHIP directly due to the lack of corresponding
unsaturated precursors. In PHIP-SAH the starting material is a
13C-labeled ester containing unsaturated alcoholic moiety which
is hydrogenated with p-H2. Next, polarization is transferred from
1H to 13C nuclei of the reaction product either using RF pulse
sequences[40,55] or MFC.[31,56,57] Subsequent cleavage of the
formed ester via alkaline hydrolysis provides 13C HP carboxylate,
e.g., [1-13C]pyruvate or [1-13C]acetate.
Scheme 1. Structures of unsaturated esters employed in this study for HET-
PHIP-SAH experiments (shown here in isotopically unlabeled form).
Results and Discussion
General remarks. HET-PHIP-SAH experiments were performed
using Rh/TiO2 catalysts (0.97 wt.% or 20 wt.% of Rh metal) in
liquid phase with methanol-d4 or D2O as solvents. Rh/TiO2
catalysts were chosen because they previously demonstrated
the highest polarization levels among various monometallic
supported metal catalysts.[65,77,78] The following PHIP
experiments were carried out: PASADENA[29] (hydrogenation
with p-H2 at high magnetic field), ALTADENA[79] (hydrogenation
with p-H2 at Earth’s magnetic field with subsequent transfer of
the sample to the high field), and MFC[41] (hydrogenation with p-
H2 at Earth’s magnetic field with subsequent transfer of the
sample to magnetic shield and then to the high field) for
polarization transfer to 13C nuclei. Since PHIP experiments were
performed with a broadly varied p-H2 fraction (from 58 to 89%),
the observed polarizations were recalculated to the highest
utilized p-H2 fraction of 89% (see SI). Unless otherwise specified,
all reported polarization values correspond to 89% p-H2 fraction.
Hyperpolarization of ethyl acetate by HET-PHIP-SAH.
Heterogeneous liquid-phase hydrogenation of vinyl [1-
13C]acetate with p-H2 over Rh/TiO2 catalysts to form HP ethyl [1-
13C]acetate was previously investigated by some of us.[61,72] Here
we revisited this reaction to compare the obtained polarization
levels of ethyl [1-13C]acetate with those of other esters under
study at the same experimental conditions. To this end, 0.97
wt.% Rh/TiO2 catalyst was tested in ALTADENA polarization of
ethyl [1-13C]acetate in methanol-d4 (Figure 1b,c) and in D2O
Most PHIP studies employ transition metal complexes as
homogeneous hydrogenation catalysts to implement pairwise p-
H2 addition.[58,59] These catalysts yield P of up to ~60% for the
resultant HP reaction product.[55] However, metal-based
catalysts are toxic and thus should be separated from the HP
compound before its administration to a subject. Reineri et al.
demonstrated that the use of an immiscible with water organic
solvent (e.g., chloroform) in PHIP-SAH experiments enables
separation of a 13C HP carboxylate (which resides in aqueous
phase after ester hydrolysis) and catalyst.[31] An alternative
approach is the use of heterogeneous (HET) hydrogenation
catalysts which can be easily filtered out of the solution[60,61] or
can be used in a continuous vapor phase hydrogenation of an
unsaturated ester with subsequent hydrolysis downstream.[62]
Moreover, HET-PHIP catalysts can be potentially recycled.[63]
Heterogeneous catalysts provide somewhat lower polarization
levels compared to homogeneous catalysts due to lower
contribution of pairwise hydrogen addition route to the overall
hydrogenation mechanism.[64–66] Nevertheless, the HET-PHIP
catalyst development remains a hot area of research with the
key goals to expand the scope of amenable substrates[67–69] and
improve polarization yields.[66,70,71] In PHIP-SAH studies,
heterogeneous Rh/TiO2 catalyst allowed obtaining 13C
polarization (P13C) of 0.035% for ethyl [1-13C]acetate in organic
solvents[72] and P13C = 0.011% in aqueous media.[61] Ligand-
capped Pd and Rh nanoparticles provided higher 13C
polarization levels of up to 1.3% for ethyl [1-13C]acetate, but at
the expense of lower chemical conversion of the reactant vinyl
[1-13C]acetate to reaction product.[33,73] Also heterogeneous
PHIP-SAH approach was utilized to produce 13C HP amino acids
with P13C = 0.29% after side arm cleavage.[74]
1
(Figure 1d,e), yielding H polarizations (P1H) of 0.5 ± 0.2% and
0.12 ± 0.04%, respectively. The obtained P1H in methanol-d4 was
greater than that in the previous study by a factor of 17.[72] The
2.5-fold increase of polarization levels should be expected
based on the higher p-H2 fraction employed here (89% vs. 50%).
The additional ~7-fold increase is probably due to the fact that in
2
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10.1002/cphc.202100156
ChemPhysChem
ARTICLE
this study we employed 0.97 wt.% Rh/TiO2 catalyst instead of
23.2 wt.% Rh/TiO2. Catalysts with higher metal loading provide
greater chemical conversion of the reactant; however, the
resultant polarization levels tend to be lower.[72,80] Here, we
obtained ~40% total conversion of the reactant, although ~16–
30% of the reacted vinyl acetate formed ethylene, ethane and
acetic acid due to C–O bond hydrogenolysis process (Table S1).
Next, MFC experiments were performed for the transfer of
polarization to 13C nuclei of ethyl [1-13C]acetate. The obtained
P13C were 0.10 ± 0.03% in methanol-d4 (Figure 1g,h) and 0.07 ±
0.02% in D2O (Figure 1i,j)—also several times greater than in
the previous studies.[61,72]
Hyperpolarization of propyl acetate by HET-PHIP-SAH.
Next, allyl acetate was employed as a PHIP precursor to HP
propyl acetate. In PASADENA experiments with 0.97 wt.%
Rh/TiO2 catalyst in methanol-d4 P1H = 0.3 ± 0.1% was obtained
(Figure S1b,c), while ALTADENA experiments under the same
conditions yielded P1H = 0.6 ± 0.2% (Figure 2b,c). In D2O, 0.97
wt.% Rh/TiO2 catalyst provided lower 1H polarization levels of
0.25 ± 0.08% and 0.28 ± 0.08% in PASADENA and ALTADENA
experiments, respectively (Figure S1d,e and Figure 2d,e). 9.79
wt.% Rh/TiO2 catalyst in D2O provided PASADENA P1H = 0.09%
at slightly lower conversion level than in the case of 0.97 wt.%
catalyst (Table S2 and Figure S2b,c). Next, we tested 20 wt.%
Rh/TiO2 catalyst for allyl acetate hydrogenation with p-H2 in D2O
which allowed to increase conversion to 65%, although at the
expense of significantly diminished polarization levels (P1H
=
0.02 0.01% in PASADENA experiment, Figure S2d,e).
±
Therefore, the use of the catalyst with higher Rh loading for
hyperpolarization of propyl acetate seems impractical for future
applications of HP compound. Hydrogenation of allyl acetate
with p-H2 over 0.97 wt.% Rh/TiO2 catalyst in methanol-d4 with
subsequent MFC allowed detecting 13C HP propyl acetate even
at natural abundance of 13C nuclei (Figure 2g). Corresponding
P13C was estimated as 0.09 ± 0.03% using 0.74 M solution of
vinyl [1-13C]acetate in methanol-d4 as an external reference.
Hydrogenation of allyl [1-13C]acetate over 0.97 wt.% Rh/TiO2 in
D2O with MFC yielded P13C = 0.03 ± 0.01% (Figure 2i,j). It should
be noted that only ~60% of the reacted allyl acetate formed
propyl acetate upon hydrogenation in both solvents, while the
rest ~40% formed propylene, propane and CH3COOH as a
result of C–O bond hydrogenolysis (Table S2).
Hyperpolarization of allyl acetate by HET-PHIP-SAH.
When propargyl acetate was hydrogenated with p-H2 over 0.97
wt.% Rh/TiO2 catalyst in methanol-d4, formation of both allyl and
propyl acetates was observed (Table S3). Also, C–O bond
hydrogenolysis took place leading to formation of propylene,
propane and acetic acid. As a result of lower conversion of the
reactant (~17%) and selectivity of its hydrogenation to allyl
acetate (~40%), only ~7% of the propargyl acetate was
converted to allyl acetate after 10–20 s of H2 bubbling through
the solution (Table 1). PASADENA and ALTADENA P1H were
0.16 ± 0.05% and 0.22 ± 0.07%, respectively (Figure S3b,c and
Figure S4b,c). When propargyl [1-13C]acetate was hydrogenated
with p-H2 over 0.97 wt.% Rh/TiO2 in methanol-d4 with
subsequent magnetic field cycling, P13C of ca. 0.01% was
observed for resulting allyl [1-13C]acetate (Figure S5). Taken
together, HET-PHIP-SAH of allyl acetate in methanol-d4 was
significantly less efficient than that of ethyl and propyl acetates
in terms of both polarization and conversion levels. In aqueous
Figure 1. (a) Reaction scheme of hydrogenation of vinyl [1-13C]acetate with p-
H2 over 0.97 wt.% Rh/TiO2 catalyst. (b) ALTADENA 1H NMR spectrum of HP
ethyl [1-13C]acetate in CD3OD and (c) corresponding thermal 1H NMR
spectrum (multiplied by a factor of 8). ε1H = 168, P1H = 0.49% (0.51% at 89%
p-H2 fraction). (d) ALTADENA 1H NMR spectrum of HP ethyl [1-13C]acetate in
D2O and (e) corresponding thermal 1H NMR spectrum. ε1H = 35, P1H = 0.10%
(0.12% at 89% p-H2 fraction). (f) Scheme of polarization transfer from 1H to 13
C
nuclei in ethyl [1-13C]acetate. (g) 13C NMR spectrum of HP ethyl [1-13C]acetate
in CD3OD and (h) corresponding thermal 13C NMR spectrum (multiplied by a
factor of 16). ε13C = 124, P13C = 0.09% (0.10% at 89% p-H2 fraction). (i) 13C
NMR spectrum of HP ethyl [1-13C]acetate in D2O and (j) corresponding thermal
13C NMR spectrum (multiplied by
a
factor of 2, acquired with
4 signal
accumulations). ε13C = 86, P13C = 0.06% (0.07% at 89% p-H2 fraction).
3
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10.1002/cphc.202100156
ChemPhysChem
ARTICLE
phase hydrogenation of propargyl acetate with p-H2 over 0.97
wt.% Rh/TiO2, only ~1% conversion of the reactant was obtained
(Table S3). Nevertheless, it was possible to detect 1H
PASADENA and ALTADENA polarization of allyl acetate with
P1H of ca. 0.6% and ca. 0.3%, respectively (Figure S3d,e and
Figure S4d,e). Because the corresponding thermal 1H NMR
signals were almost at the noise level, these estimates are not
particularly accurate. While 9.79 and 20 wt.% Rh/TiO2 catalysts
provided a higher conversion of ~5% in D2O, the resultant 1H
PASADENA signals were lower in intensity due to lower P1H
=
0.14
±
0.05% (Figure S6). All attempts to observe 13C
polarization of allyl acetate in D2O using 0.97 wt.% Rh/TiO2 and
MFC were unsuccessful despite the use of the 13C-enriched
precursor.
Hyperpolarization of ethyl pyruvate by HET-PHIP-SAH.
Next, heterogeneous PHIP-SAH of ethyl pyruvate was
investigated. Hydrogenation of vinyl pyruvate with p-H2 over 0.97
wt.% Rh/TiO2 catalyst in methanol-d4 provided HP ethyl pyruvate
with P1H = 0.11 ± 0.03% in both PASADENA and ALTADENA
experiments (Figure S7 and Figure S8). Note that in methanol
the pyruvate esters are present in two forms (ketone and
1
hemiketal) with the prevalence of the latter. H chemical shifts of
alcoholic moieties of vinyl and ethyl pyruvates are similar for
both forms. Therefore, the estimated P1H corresponds to the sum
of both ketone and hemiketal forms. Conversion of vinyl
pyruvate to ethyl pyruvate was ~15% (Table S4). Because of the
lower conversion and polarization levels for ethyl pyruvate
compared to those for allyl acetate, it was not possible to detect
13C hyperpolarization of ethyl pyruvate at natural abundance of
13C nuclei in MFC experiments (13C-enriched precursor was not
available to us due to inefficient vinyl pyruvate synthesis[75]).
Aqueous phase hydrogenation of vinyl pyruvate was also
unsuccessful—no reaction product was detected when either
0.97 or 20 wt.% Rh/TiO2 was utilized.
Hyperpolarization of propyl pyruvate by HET-PHIP-SAH.
Hydrogenation of allyl pyruvate with p-H2 over 0.97 wt.%
Rh/TiO2 catalyst in methanol-d4 under PASADENA conditions
yielded HP propyl pyruvate with P1H = 0.25 ± 0.08% (Figure S9).
In ALTADENA experiment in methanol-d4, P1H = 0.3 ± 0.1% was
observed (Figure 3b,c). However, the selectivity of allyl pyruvate
hydrogenation to propyl pyruvate was only ~22%—the rest of
reacted precursor molecules converted to propylene, propanol,
propane and pyruvic acid as
a
result of C–O bond
hydrogenolysis (Table S5). Hydrogenation of allyl pyruvate over
1
0.97 wt.% Rh/TiO2 catalyst in D2O gave similar H polarization
levels of 0.21 ± 0.07% and 0.3 ± 0.1% in PASADENA and
ALTADENA experiments, respectively (Figure S10 and Figure
3e,f). However, total conversion of the reactant was only 8–
10%—taking into account the similarly low selectivity to
formation of propyl pyruvate, conversion of allyl pyruvate to the
hydrogenated ester was only ~2%. In spite of a low amount of
propyl pyruvate formed upon hydrogenation and modest P1H, it
was possible to detect 13C HP propyl pyruvate in MFC
experiments in methanol-d4 with P13C = 0.01% (Figure S11).
Note that propyl and allyl pyruvates were present in two forms in
both methanol-d4 and D2O solvents, similar to ethyl and vinyl
pyruvates. P1H values were estimated for combination of both
forms of propyl pyruvate which had similar chemical shifts, while
P13C was calculated using signal of hemiketal form only because
it was not possible to detect thermal 13C NMR signal of ketone
form of propyl pyruvate.
Figure 2. (a) Reaction scheme of hydrogenation of allyl acetate with p-H2 over
0.97 wt.% Rh/TiO2 catalyst. (b) ALTADENA 1H NMR spectrum of unlabeled
HP propyl acetate in CD3OD and (c) corresponding thermal 1H NMR spectrum
(multiplied by a factor of 16). ε1H = 167, P1H = 0.49% (0.64% at 89% p-H2
fraction). (d) ALTADENA 1H NMR spectrum of HP propyl [1-13C]acetate in D2O
and (e) corresponding thermal 1H NMR spectrum. ε1H = 94, P1H = 0.28%
(0.28% at 89% p-H2 fraction). (f) Scheme of polarization transfer from 1H to 13
C
nuclei in propyl [1-13C]acetate. (g) 13C NMR spectrum of HP propyl acetate
with natural abundance of 13C nuclei in CD3OD (multiplied by a factor of 8). (h)
Thermal 13C NMR spectrum of 0.74 M solution of vinyl [1-13C]acetate in
CD3OD used as a reference. ε13C = 72, P13C = 0.05% (0.09% at 89% p-H2
fraction). (i) 13C NMR spectrum of HP propyl [1-13C]acetate in D2O and (j)
corresponding thermal 13C NMR spectrum (multiplied by a factor of 4). ε13C
44, P13C = 0.03% (0.03% at 89% p-H2 fraction).
=
4
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10.1002/cphc.202100156
ChemPhysChem
ARTICLE
and pyruvic acid due to C–O bond hydrogenolysis (Table S6).
The total conversion of propargyl pyruvate was lower than in the
case of allyl pyruvate hydrogenation (~15%). Considering low
activity of the Rh/TiO2 catalyst in production of allyl pyruvate
from propargyl pyruvate and low 1H polarization, it is not
unexpected that 13C NMR signals of HP allyl pyruvate were not
detected in MFC experiments even when 13C-enriched precursor
was utilized. The 0.97 wt.% Rh/TiO2 catalyst showed no activity
in aqueous phase hydrogenation of propargyl pyruvate—even
the NMR signal enhancement provided by the use of p-H2 did
not allow to detect allyl pyruvate. However, when 20 wt.%
Rh/TiO2 was employed, PASADENA and ALTADENA signals of
HP allyl pyruvate were detected with P1H of ca. 0.1% and ca.
0.08%, respectively (Figure S14 and Figure S15). Nevertheless,
conversion of propargyl pyruvate was only ~1% (Table S6).
Efficiency of HET-PHIP-SAH of acetates and pyruvates.
The obtained 1H and 13C polarization levels and NMR signal
intensities of HP acetate and pyruvate esters are summarized in
Table 1, along with conversions of the unsaturated precursors to
the desired esters. The difference in PASADENA and
ALTADENA polarizations is not unexpected due to different
protocols of corresponding experiments. While in ALTADENA
experiments significant part of polarization is lost because of
relaxation during transfer of the sample from the Earth’s
magnetic field to the NMR spectrometer, in PASADENA
experiments the observed NMR signal is diminished due to anti-
phase multiplet structure of PASADENA line.[81] Three important
trends can be deduced from the analysis of the data presented
in Table 1. First of all, the efficiency of HET-PHIP-SAH approach
for hyperpolarization of acetates significantly surpassed that of
pyruvates as a result of the fact that in the former cases the
polarization
levels,
conversions
and
selectivities
to
hydrogenated ester tend to be greater than those in the latter
cases. The reasons behind these observations are not clear.
One can speculate that the carbonyl group in pyruvate moiety
may coordinate to the metal surface, thus facilitating
hydrogenolysis of C–O bond which leads to lower selectivity
towards hydrogenated esters. The bulkiness of pyruvate moiety
may be a reason of lower catalytic activity in case of pyruvates.
The ability of pyruvates to form hemiacetals and heminal diols
can also have an important effect on the catalysts’ performance
in hydrogenation of these substrates with p-H2. Nevertheless, to
the best of our knowledge this is the first demonstration of HET-
PHIP hyperpolarization of pyruvate esters, and further catalyst
optimization can make this approach more efficient. Second, the
performance of Rh/TiO2 catalysts in hydrogenation of propargyl
esters with p-H2 was inferior to that in case of hydrogenation of
esters with a C=C bond. This is in agreement with results of gas-
phase hydrogenation of propyne and propylene with p-H2 over
Rh/TiO2 catalyst.[82] In that study the intensities of 1H NMR
signals of HP propane were higher than those of HP propylene
under otherwise similar reaction conditions. Therefore, Rh/TiO2
catalyst is apparently more efficient in hydrogenation of double
bonds with p-H2 than in hydrogenated of triple bonds. Third,
HET-PHIP-SAH in methanol-d4 was significantly more efficient
than in D2O. This is not unexpected because hydrogen solubility
in methanol is greater than in water, leading to higher
conversion of the reactant. As a result of the aforementioned
trends, the most intense 1H and 13C NMR signals among HP
esters under study were obtained for propyl acetate and ethyl
Figure 3. (a) Reaction scheme of hydrogenation of allyl pyruvate with p-H2
over 0.97 wt.% Rh/TiO2 catalyst in CD3OD. (b) ALTADENA 1H NMR spectrum
of HP propyl pyruvate in CD3OD and (c) corresponding thermal 1H NMR
spectrum. ε1H = 52, P1H = 0.15% (0.30% at 89% p-H2 fraction). (d) Reaction
scheme of hydrogenation of allyl pyruvate with p-H2 over 0.97 wt.% Rh/TiO2
catalyst in D2O. (e) ALTADENA 1H NMR spectrum of HP propyl pyruvate in
D2O and (f) corresponding thermal 1H NMR spectrum. ε1H = 57, P1H = 0.17%
(0.31% at 89% p-H2 fraction).
Hyperpolarization of allyl pyruvate by HET-PHIP-SAH.
Hydrogenation of propargyl pyruvate with p-H2 over 0.97 wt.%
Rh/TiO2 catalyst in methanol-d4 produced HP allyl pyruvate with
PASADENA P1H = 0.06 ± 0.02% (Figure S12) and ALTADENA
P1H = 0.11 ± 0.03% (Figure S13). These polarization values
were estimated for combination of both ketone and hemiketal
forms of allyl pyruvate present in methanolic solution. Similar to
the case of allyl and vinyl pyruvates hydrogenation, significant
amount of the reacted precursor produced propylene, propane
5
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10.1002/cphc.202100156
ChemPhysChem
ARTICLE
Table 1. The results of HET-PHIP-SAH experiments: conversion to hydrogenated esters (calculated as the product of total conversion of the reactant and
selectivity to the hydrogenated ester), polarization levels (recalculated to 89% p-H2 fraction for the sake of comparison) and relative intensities of NMR signals.
Conversion to
ester, %
PASADENA
P1H, %
ALTADENA
P1H, %
PASADENA signal,
a.u.
ALTADENA signal,
a.u.
13C signal,
a.u.
HP ester
Solvent
CD3OD
D2O
P13C, %
0.10 ±
0.03
0.07 ±
0.02
0.09 ±
0.03
0.03 ±
0.01
[a]
[a]
27 ± 11
35 ± 14
34 ± 14
20 ± 6
–
0.5 ± 0.2
–
270
18
150
21
Ethyl acetate
[a]
[a]
–
0.12 ± 0.04
0.6 ± 0.2
–
CD3OD
D2O
0.3 ± 0.1
67
22
550
58
170
Propyl
acetate
0.25 ± 0.08
0.28 ± 0.08
25
CD3OD
D2O
CD3OD
D2O
CD3OD
D2O
CD3OD
D2O[d]
7 ± 3
1
0.16 ± 0.05
0.6[b]
0.11 ± 0.03
0.22 ± 0.07
0.3[b]
0.11 ± 0.03
0.01
5.2
3.6
4.8
11
3.1
22
5.6
Allyl acetate
[c]
[c]
–
–
–
–
[c]
[c]
Ethyl
15 ± 6
no reaction
7 ± 3
2 ± 1
8 ± 4
1
pyruvate
Propyl
pyruvate
Allyl
0.25 ± 0.08
0.21 ± 0.07
0.06 ± 0.02
0.1[b]
0.3 ± 0.1
0.3 ± 0.1
0.11 ± 0.03
0.08[b]
0.01
13
19
1.0
[c]
[c]
–
5.0
4.4
1.0
3.4
4.1
1.0
–
[c]
[c]
–
–
[c]
[c]
pyruvate
–
–
[a] Not studied. [b] These estimations are approximate because thermal NMR signals of the reaction product were too weak for reliable integration. [c] The 13C
NMR signal was not detected. [d] The data were obtained using 20 wt.% Rh/TiO2 catalyst (in contrast to 0.97 wt.% Rh/TiO2 employed in other experiments
reported in this table).
acetate. This observation is in contrast with results of PHIP-SAH
of
the
same six esters
using cationic complex
norbornadiene, dppb 1,4-
[Rh(NBD)(dppb)]BF4 (NBD
=
=
Experimental Section
bis(diphenylphosphino)butane) as homogeneous hydrogenation
catalyst, where the highest hyperpolarization efficiency was
demonstrated for allyl pyruvate produced by pairwise p-H2
addition to propargyl pyruvate.[76] In HET-PHIP with Rh/TiO2
catalysts this ester yielded the least intense NMR signals;
however, it is possible that other heterogeneous hydrogenation
catalysts can be more efficient for hyperpolarization of this
compound.
Materials. Commercially available methanol-d4, D2O (Sigma-Aldrich-
Isotec) and ultra-high pure (UHP) hydrogen (>99.999%) were used as
received. Unsaturated precursors (vinyl acetate, allyl acetate, propargyl
acetate, vinyl pyruvate, allyl pyruvate and propargyl pyruvate, see
Scheme 1) were synthesized according to previously reported
procedures.[75] These compounds were employed in both unlabeled and
1-13C-labeled (~98% 13C enrichment in the carboxyl group) forms, with
the exception of vinyl esters (13C-enriched vinyl acetate and unlabeled
vinyl pyruvate were used). The catalysts preparation procedure is
described in the Supporting Information (SI).
PHIP experiments. p-H2 enrichment was achieved using custom-built
ParaSun p-H2 generator based on cryocooler module (SunPower, P/N
100490, CryoTel GT; a detailed description of the generator was
published elsewhere[75,83]). The generator was operated at 40−68 K,
resulting in ca. 89−58% p-H2 enrichment. For sample preparation, 20 mg
of Rh/TiO2 catalyst was placed at the bottom of a medium-wall 5 mm
NMR tube (Wilmad glass P/N 503-PS-9) tightly connected with ¼ in.
outer diameter PTFE tube. Next, 0.5 mL of 80 mM substrate solution in
deuterated solvent was added.
The scheme of experimental setup is presented in Figure S16. The
samples were pressurized up to 70 psig and preheated up to 55 °C (for
CD3OD samples) or to 65 °C (for D2O samples) using NMR spectrometer
temperature control unit. Hydrogen gas flow rate (140 standard cubic
centimeters per minute, sccm) was regulated with a mass flow controller
(SmartTrak 50, Sierra Instruments, Monterey, CA); duration of p-H2
bubbling can be found in SI, Tables S1–S6. In PASADENA[29]
experiments the samples were located inside the probe of the NMR
spectrometer. In ALTADENA[79] experiments the samples were located at
the Earth’s magnetic field during p-H2 bubbling (in some experiments
they were additionally heated to 80–85 °C in a beaker with hot water).
After termination of p-H2 flow, the samples were transferred to the NMR
spectrometer for detection. MFC procedure was similar to ALTADENA
but in this case the samples were placed inside the MuMETAL magnetic
shield after cessation of p-H2 flow, and then slowly (∼1 s) pulled out of
the shield and quickly placed inside the probe of the NMR spectrometer.
The total sample transfer time in this case was ~8 s after the termination
of H2 gas bubbling. The magnetic field inside the shield was adjusted
using additional solenoid placed inside the previously degaussed three-
layered MuMETAL shield (Magnetic Shield Corp., Bensenville, IL, P/N
Conclusion
To conclude, we systematically investigated hyperpolarization of
acetate and pyruvate esters with ethyl, propyl and allyl alcoholic
moieties produced by heterogeneous hydrogenation of the
corresponding unsaturated vinyl, allyl and propargyl precursors
with p-H2 over Rh/TiO2 catalysts in methanol-d4 and D2O
solvents. 1H polarization levels of up to 0.6 ± 0.2% were
demonstrated in ALTADENA experiments, while magnetic field
cycling allowed to hyperpolarize 13C nuclei with polarization of
up to 0.10 ± 0.03%. The hydrogenation of corresponding
unsaturated precursors was accompanied by hydrogenolysis of
the C–O bond leading to formation of alkene and alkane
hydrocarbons from side arm alcoholic moiety and carboxylic
acids from carboxylic moiety. As a result, the efficiency of
conversion of unsaturated precursors to the hydrogenated
esters was diminished. The most intense 1H and 13C NMR
signals in both methanol-d4 and D2O solvents were obtained for
HP propyl acetate. Hyperpolarization of acetate esters was
superior to that of pyruvates, while hydrogenation of the C=C
bonds in vinyl and allyl moieties with p-H2 was more efficient
than hydrogenation of the C≡C bond in propargyl moiety. Further
optimization of reaction conditions and catalyst nature may
increase the efficiency of heterogeneous PHIP-SAH approach
for the preparation of HP biocompatible compounds for possible
MRI applications.
6
This article is protected by copyright. All rights reserved.

10.1002/cphc.202100156
ChemPhysChem
ARTICLE
ZG-206). This previously calibrated solenoid was powered by a direct
current (DC) power supply (GW-Instek, GPR-30600), and the DC current
was attenuated by a resistor bank (Global Specialties, RDB-10) to
achieve the desired magnetic field inside the MuMETAL shield. The
MuMETAL shield provides an isolation of approximately 1200 according
to the manufacturer’s specification; therefore, the use of the shield in the
Earth’s magnetic field results in the maximum residual magnetic field of
ca. 40 nT. The magnetic fields employed for MFC are presented in Table
S7.
NMR spectra were acquired on a 9.4 T Bruker NMR spectrometer using
π/4 RF pulse for PASADENA experiments and π/2 RF pulse for
ALTADENA and MFC experiments. The 1H ALTADENA and 13C PHIP
spectra were recorded as pseudo-two-dimensional (2D) sets consisting
of 64 1D NMR spectra (acquisition time 1 s) to avoid delays between
placing the sample into the probe and starting the acquisition. The
acquisition of these pseudo 2D data sets was always initiated before the
sample was placed inside the NMR probe.
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for Basic Research (grants 19-29-10003, 19-43-540004, and 19-
33-60045). L.M.K. thanks the Ministry of Science and Higher
Education of the Russian Federation (project # AAAA-A21-
121011390011-4) for the support of catalysts’ preparation. E.Y.C.
thanks NSF CHE-1904780, NCI 1R21CA220137, NHLBI
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1R21HL154032,
0159/BC112431.
and
DOD
CDMRP
W81XWH-12-1-
Keywords: parahydrogen • hyperpolarization • PHIP • NMR
spectroscopy • imaging agents
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Entry for the Table of Contents
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Parahydrogen-induced polarization of acetate and pyruvate esters with ethyl, propyl and allyl alcoholic moieties was obtained using
heterogeneous Rh/TiO2 catalysts. 1H and 13C polarizations of up to 0.6% and 0.10%, respectively, were demonstrated.
Hyperpolarization of propyl and ethyl acetates was the most efficient among the esters under study.
Institute and/or researcher Twitter usernames: @OlegSalnikovNMR, @mmt_lab, @itc_sbras, @e_chekmenev, @waynestatechem
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