Catalytic Hydrogenation of Trivinyl Orthoacetate: Mechanisms Elucidated by Parahydrogen Induced Polarization

Article abstract of DOI:10.1002/cphc.202000957

Parahydrogen (pH₂) induced polarization (PHIP) is a unique method that is used in analytical chemistry to elucidate catalytic hydrogenation pathways and to increase the signal of small metabolites in MRI and NMR. PHIP is based on adding or exchanging at least one pH₂ molecule with a target molecule. Thus, the spin order available for hyperpolarization is often limited to that of one pH₂ molecule. To break this limit, we investigated the addition of multiple pH₂ molecules to one precursor. We studied the feasibility of the simultaneous hydrogenation of three arms of trivinyl orthoacetate (TVOA) intending to obtain hyperpolarized acetate. It was found that semihydrogenated TVOA underwent a fast decomposition accompanied by several minor reactions including an exchange of geminal methylene protons of a vinyl ester with pH₂. The study shows that multiple vinyl ester groups are not suitable for a fast and clean (without any side products) hydrogenation and hyperpolarization that is desired in biochemical applications.

Full text of DOI:10.1002/cphc.202000957

Accepted Article
Title: Catalytic hydrogenation of trivinyl orthoacetate: mechanisms
elucidated by parahydrogen induced polarization
Authors: Andrey Pravdivtsev, Arne Brahms, Stephan Kienitz, Frank D.
Sönnichsen, Jan-Bernd Hövener, and Rainer Herges
This manuscript has been accepted after peer review and appears as an
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To be cited as: ChemPhysChem 10.1002/cphc.202000957
Link to VoR: https://doi.org/10.1002/cphc.202000957
01/2020

10.1002/cphc.202000957
ChemPhysChem
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Catalytic hydrogenation of trivinyl orthoacetate: mechanisms
elucidated by parahydrogen induced polarization
Andrey N. Pravdivtsev[a]†*, Arne Brahms[b]†, Stephan Kienitz[b], Frank D. Sönnichsen[b], Jan-Bernd
Hövener[a]‡, Rainer Herges[b]‡*
[a]
Dr. A.N. Pravdivtsev*, Prof. Dr. J-B. Hövener
Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology
University Medical Center Kiel, Kiel University
Am Botanischen Garten 14, 24114, Kiel, Germany
* andrey.pravdivtsev@rad.uni-kiel.de
[b]
Ms. A. Brahms, Ms. S. Kienitz, Porf. Dr. F.D. Sönnichsen, Prof. Dr. R. Herges*
Otto Diels Institute for Organic Chemistry
Kiel University
Otto Hahn Platz 5, 24098, Kiel, Germany
* rherges@oc.uni-kiel.de
†,‡ this authors contributed equally
Supporting information for this article is given via a link at the end of the document.
Abstract: Parahydrogen (pH2) induced polarization (PHIP) is a
unique method that is used in analytical chemistry to elucidate
catalytic hydrogenation pathways and to increase the signal of small
metabolites in MRI. PHIP is based on adding or exchanging at least
one pH2 molecule with a target molecule. And thus, the spin order
available for hyperpolarization is often limited to that of one pH2
molecule. To break this limit, we investigated the addition of multiple
pH2 molecules to one precursor. We studied the feasibility of the
simultaneous hydrogenation of three arms of trivinyl orthoacetate
(TVOA) intending to obtain hyperpolarized acetate. It was found that
molecules by a catalytic hydrogenation reaction (Figure 1),[20] or
exchanged.
Parahydrogen And Synthesis Allow Dramatically Enhanced
Nuclear Alignment (PASADENA) is an experiment that exploits
pH2 hydrogenation at high magnetic fields.[21] The unique property
of PASADENA is its anti-phase shape of spectral lines in the basic
excitation and acquisition NMR experiment, while normal or
thermal MR resonances are always in-phase. This feature is used
to study hydrogenation routes and also reveals a fraction of
pairwise hydrogenation.[22] The advantage of PHIP as
a
semihydrogenated TVOA underwent
a
fast decomposition
hyperpolarization method is its cost-efficiency: with only little
investment[23–25] highly polarized samples can be produced in a
accompanied by several minor reactions including an exchange of
geminal methylene protons of a vinyl ester with pH2. The study shows
that multiple vinyl ester groups are not suitable for a fast and clean
(without any side products) hydrogenation and hyperpolarization that
is desired in biochemical applications.
batch process[26,27] or continuously[28]
.
Although PHIP has many powerful features, its scope was
restricted until recently to a few organic molecules with few
biochemical applications.[29] The utilization of functionalized vinyl
or propargyl groups, so-called PHIP side arm hydrogenation
(PHIP-SAH) opened new applications. Here a side arm is
hydrogenated and then polarization is transferred to the target site
of the polarized molecule, which often is the 13C nucleus of a
carboxyl group. PHIP-SAH enabled hyperpolarization of a larger
number of endogenous molecules including acetate (Figure 1a),
pyruvate,[30] amino acids[31] and peptides.[32]
Recently, metabolites hyperpolarized with PHIP-SAH were tested
in cell-cultures[33] and in vivo.[34] PHIP-SAH at high magnetic fields
demonstrated more than 50% 13C polarization of ethyl acetate-d6
and 19% of acetate-d3 within seconds.[35]
Still, there is much room to improve the polarization level of PHIP.
While exchange based methods[36,37] allow continuous re-
hyperpolarization of the target molecule,[38] the spin order
available to hydrogenation-based methods to polarize the target
is limited to that of a single pH2 molecule.
Introduction
Magnetic resonance (MR) is a versatile physical effect that is
widely used in science and clinical medicine. Its applications span
from analysis of protein structure with a sub-angstrom precision
and microseconds times scale[1,2] to anatomical and physiological
imaging.[3–6] Some applications, like measuring metabolites,[7] are
severely hampered by the low sensitivity of the technique or a low
signal-to-noise ratio (SNR). To address these shortcomings, the
sensitivity of MR was increased steadily by hardware
developments. About one order of magnitude of the signal gain
can be reached using cryoprobes[8,9] or cryomagnets with higher
magnetic fields.[10,11]
Nuclear spin hyperpolarization is a family of methods that brings
a 10 to 105 fold signal gain using physical or chemical effects.[12–
15] Instead of improving the detection electronics[16,17] or increasing
the magnetic field, these methods use special techniques to
increase the polarization of the spins directly.[18–20]
Parahydrogen based methods employ the highly ordered spin
state of parahydrogen (pH2) to achieve net polarization of a target
molecule. To do so, a pH2 molecule is either added to a target
Thus, we investigated the question, if multiple pH2 molecules can
be added to a target molecule and used for hyperpolarization of
the target site of the molecule. We pursued the hypothesis that
multiple hydrogenations of the same molecule with pH2 will lead
to a higher level of polarization of the target fragment.
Towards this goal, we introduce a new experiment: PHIP by
hydrogenation of three sidearms (PHIP-HOT, Figure 1b). Here,
1
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the target fragment (acetate) is functionalized with three
equivalent vinyl groups, resulting in trivinyl orthoacetate (TVOA).
Employing a reaction similar to PHIP-SAH, we aimed at
hyperpolarizing the same molecule, acetate. Contrary to our
expectations, however, an entirely different reaction took place.
These findings are reported in this paper.
Figure 1. Reaction schemes of hydrogenation and side-arm cleavages confirmed for PHIP-SAH (a) and expected (marked with "?") for PHIP-HOT (b). (a)
Hydrogenation of vinyl acetate (VA) results in the production of ethyl acetate (EA). The cleavage of the ester in the presence of a base and water leads to acetate
(Ac) and ethanol. (b) Hydrogenation of trivinyl orthoacetate (TVOA) with three pH2 molecules is expected to lead to triethyl orthoacetate (TEOA). The cleavage of
ethyl groups in the presence of NaOH and water was expected to result in acetate (Ac) and three molecules of ethanol. In both cases, only acetate and ethanol
would be the products. Note that full hydrogenation of TVOA was assumed. Red arrows indicate expected hyperpolarized spins: ethanol is polarized because of
the chemical reaction of the vinyl group with pH2. Optionally, polarization may be transferred from ethyl to 13C after hydrogenation that is indicated by the arrow next
to C of acetate.[34,35] It has been shown experimentally that rapid TEOA dissociation occurs during stage 1, i.e. without adding NaOH. TVOA hydrogenation with
[Rh(dppb)(COD)]BF4 catalyst was studied here in details.
orthoacetate or any semihydrogenated TVOA, i.e. divinyl ethyl
orthoacetate, were not found.
Results
The experiment was repeated in chloroform-d. EA was found to
be polarized to a much higher level, while ethanol was polarized
to a lesser extend. The concentration ratio of the products of the
TVOA hydrogenation and decomposition was determined by
PASADENA experiments (Figure 1b, stage 1) were conducted
with TVOA and catalyst [Rh(dppb)(COD)]BF4 = [1] (CAS: 79255-
71-3) at 25 oC and ambient pressure with 0.2 bar pH2
overpressure in acetone-d6. Enhanced, PASADENA-type anti-
phase signals were observed for the following molecules
(Figures 2,3): ethyl acetate (EA), ethanol, acetaldehyde, vinyl
acetate, H2 and other unassigned products. After 5 minutes of
constant H2 bubbling, high-resolution NMR spectra were acquired.
A ratio of [ethyl acetate] : [acetaldehyde] : [ethanol] = 1 : 1.95 : 0.2
was found. Also of 2-chloroethanol and cyclooctene were found.
2-Chloroethanol was used in the synthesis of TVOA (see
Experimental Section) and traces thereof were found in the pre-
hydrogenation sample. Cyclooctene is the side product of the
catalyst [1] activation. It is formed by hydrogenation of the 1,5-
cyclooctadiene ligand of the Rh-catalyst. Note that triethyl
NMR after 20 minutes of H2 bubbling [ethyl acetate]
:
[acetaldehyde] : [vinyl acetate] : [ethanol]= 1 : 2.15 : 0.42 : 0.04.
Strongly polarized resonances of VA appeared; all these
resonances exhibited the PASADENA-type appearance in phase.
Rapid decomposition of the substrate after hydrogenation may
occur due to residual water and acids; possible decomposition
paths are discussed later (Figure 4). To reduce this effect, we
additionally purified the solvents by pouring acetone-d6 through a
dry magnesium sulfate powder and chloroform-d through a dry
basic aluminium oxide powder column, directly before sample
preparation. This filtration did not change our observations.
2
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Figure 2. 1H NMR spectrum of TVOA hydrogenated with pH2 and [1] in acetone-d6 at 14.1 T. The main polarized product identified was ethyl acetate (EA).
Ethanol and acetaldehyde showed much less polarization. Other side products were 2-chloroethanol, cyclooctene and various unassigned alkanes. Note that
cyclooctene is the side product of the catalyst activation and subsequent hydrogenation of 1,5-cyclooctadiene. Relevant sections of the spectrum with hyperpolarized
signals are magnified.
Figure 3. 1H NMR spectrum of TVOA hydrogenated with pH2 and [1] in chloroform-d at 14.1 T. Relevant sections of the spectrum with hyperpolarized signals
are magnified. The main polarized product identified was ethyl acetate (EA). Ethanol, acetaldehyde, vinyl acetate (VA) and H2 showed much less polarization than
EA. Note the partially negative line of H2 and polarized antiphase lines of CH2 protons of VA. Other side products were 2-chloroethanol, cyclooctene and various
unassigned alkanes. Note that cyclooctene is the side product of the catalyst activation and subsequent hydrogenation of 1,5-cyclooctadiene.
NMR showed multiple PASADENA signals but no signals from
semi- or fully hydrogenated TVOA (Figure 1-3). Because no
Discussion
hyperpolarized orthoacetate signals were observed, we assume
that after the first hydrogenation the product immediately
dissociates.
I.
A molecule with three unsaturated side arms TVOA was
successfully synthesized and subjected to PASADENA
Polarization of ethyl acetate and ethanol
a
Divinyl ethyl orthoacetate (DVEOA) should be the first product of
TVOA hydrogenation and we suggest three main pathways how
it can dissociate in the presence of water (Figure 4). First, a
experiment. Experimentally, TVOA was found to be stable in the
presence of [1] and dissociation started only after the addition of
H2.
3
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proton will activate one of the three ether side arms of DVEOA. If
the hydrogenated sidearm (ethyl) is activated the dissociation will
lead to hyperpolarized ethanol (Figure 4(1a)).
II.
Polarization of vinyl acetate
The PASADENA type polarization of CH2-protons of vinyl acetate
(VA, Figure 3) is a rather uncommon effect. It can be explained
by the pairwise exchange of CH2-protons with pH2 on the transient
complex, which consists of [1], TVOA and pH2 (Figure 5). The
result of this hydrogen exchange is a TVOA with a terminal
hyperpolarized sidearm. If this TVOA undergoes normal
hydrogenation and dissociation reaction on the pathways 1a or 1b
(Figure 4), a terminal hyperpolarized VA is obtained. The minor
level of polarization (Figure 3) indicates that it is not the major
polarization mechanism.
The other possibility is that one of the unsaturated sidearms
(vinyl) of DVEOA is activated (Figure 4(1b,1c)). In this case, the
dissociation could lead to hyperpolarized ethanol (1b) or
hyperpolarized ethyl acetate (EA, 1c). Note that emerging vinyl
acetate (VA) in 1a and 1b cases could also be hydrogenated and
hence EA will be polarized. All products of TVOA hydrogenation
and consequent dissociation pathways are summarized in the
table (Figure 4).
These possible pathways allow only EA or ethanol to be polarized.
Experimentally, fractions of EA and ethanol were changing with
the duration of bubbling; therefore, we could not unequivocally
determine a major pathway. However, it appears that EA
experiences a stronger polarization than ethanol (i) and the
obtained concentration ratio [acetaldehyde] : [ethyl acetate] is
close to 2 : 1 (ii). Both facts indicate that the reaction path 1c is
preferred (Figure 2,3), despite the signal ratios being different in
two solvents. The consumption of the H2O residues is one
possible reason for the product distribution varying with time.
It should be noted that only the unique signal enhancement
caused by pH2 addition allowed us to find this exchange of H2 on
geminal protons of TVOA. It would have been impossible with
normal H2. A similar effect was observed also by Bargon et al.
[39,40] when using rhodium and palladium catalysts to hydrogenate
styrene. In both cases, the structure of the substrate results in the
formation of a relatively long-lived intermediate. This is due to the
coordination of the benzene ring of styrene[39,40] or due to the
coordination of a second vinyl group of TVOA to the metal ion,
which leads to hyperpolarization of geminal protons.
Figure 5. Trivinyl orthoacetate – H2 exchange with experimental and
simulated (sim.) PASADENA spectra. TVOA exchanges its methylene
protons with pH2 when both (hydrogen and TVOA) are coordinating to [1]. After
dissociation according to pathway 1a or 1b, vinyl acetate (VA) with polarized
CH2-protons is produced. The following NMR parameters were used for
푎
simulations of polarized VA (sim.): chemical shifts: 훿퐶퐻 = 7.267 ppm, 훿퐶퐻
=
2
3
푎
4.85 ppm, 훿퐶퐻 = 4.59 ppm and J-coupling constants: 퐽퐶퐻−퐶퐻 = 13.9 Hz,
2
2
푏
3퐽퐶퐻−퐶퐻 = 6.34 Hz, 2퐽퐶퐻 = -1.4 Hz. It was assumed that the CH2 protons are
푏
2
2
Figure 4. Potential reactions of TVOA disintegration in presence of water
after hydrogenation with pH2 and [1], and corresponding table of products.
We assume that hydrogenation of TVOA results in divinyl ethyl ortho acetate
(DVEOA) with a polarized ethyl group. Three cleavage pathways are considered
here. If the hyperpolarized ethyl ether sidearm is cleaved first, this will lead to
vinyl acetate, acetaldehyde and hyperpolarized ethanol (1a). If the vinyl ether is
cleaved first, then either the products will be the same (1b) or two molecules of
acetaldehyde and hyperpolarized ethyl acetate will be produced (1c). Red
arrows in the scheme and numbers in the table indicate hyperpolarized protons
and molecules by hydrogenation with pH2. This cleavage scheme explains only
polarization of ethyl acetate and ethanol.
produced by pH2 (PASADENA effect, sim.). In the experiment and simulations
nonselective 45o excitation RF-pulses were used.
III.
Polarization of acetaldehyde
The PASADENA type polarization of the CH-proton of
acetaldehyde (AD) is another unexpected hyperpolarized signal
(Figure 2). Although it is a saturated aldehyde, its origin is
unsaturated vinyl alcohol, which was not hydrogenated by pH2.
4
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The tentative pathway that leads to the polarization of AD is a
pairwise exchange of CH and one CH2 proton of the vinyl group
of TVOA with pH2 on [1] (Figure 6). This unconventionally
polarized TVOA would lead to the observed polarized
acetaldehyde after the dissociation pathways 1a, 1b or 1c (Figure
4). This vicinal pairwise hydrogen exchange is an H2 exchange
mechanism occurring in addition to the previously discussed
The attempt to hydrogenate all three double C=C bonds of TVOA
was not successful. Ethyl acetate was the main product of
hydrogenation and not the expected products divinyl ethyl
orthoacetate or other orthoacetate derivatives. TVOA was
cleaved immediately in the presence of H2 and [1]. Even the
removal of acid traces in the solvents by filtration over a basic
Al2O3 column did not stop the instant decomposition of DVEOA.
Decomposition of DVEOA leads to the production of polarized
ethyl acetate, vinyl acetate, acetaldehyde, ethanol and H2.
Hence, the studies show that TVOA is not well suited for the
hydrogenation of “many side-arms”. We assume that a similar
approach will be also not successful for hyperpolarization of
pyruvate e.g. because three (or two) vinyl group will coordinate to
the metal complex (catalyst), which will slow down the
hydrogenation reaction; possibly side-reactions and products will
be observed similar to those that have been identified in this study.
PASADENA proved to be key to elucidate the underlying reaction
mechanism. Without the unique line shape, the pairwise H2
exchange of geminal protons of vinyl acetate and vicinal protons
of acetaldehyde would have remained unrecognized.
exchange of geminal protons with pH2 (Figure 5). Similar vicinal
[41]
pH2 exchange was observed by Skovpin et al.
in the
hydrogenation reaction of propylene with a silica-immobilized Rh
catalyst.
This is yet another proof that labelling with pH2 is a unique tool to
distinguish the pathways in hydrogenation reactions; - PHIP
provides a sophisticated analytical tool for the elucidation of
hydrogenation mechanisms, catalysis and other elementary
chemical reactions.
Experimental Section
I.
Sample preparation
Samples for PHIP-SAH and -HOT. 10 μl of TVOA (synthesized according
to a protocol described below) or vinyl acetate (CAS 108-05-4, Merck) was
dissolved in 600 μL of acetone-d6 or chloroform-d (Deutero GmbH)
yielding a 100 mmol/L concentration. For PHIP experiments the catalyst
[1,4-Bis(diphenylphosphino)butane(1,5-cyclooctadiene)rhodium(I)
tetrafluoroborate] [1] (CAS: 79255-71-3, Strem Chemicals) was added to
reach a concentration of 5 mmol/L. Chloroform-d and acetone-d6 were
dried by pouring it through a 3 cm column (ID = 5 mm) of basic aluminium
oxide powder and magnesium sulfate respectively directly before
preparation of the samples. Both powders were dried overnight at 120O.
Note, that even after drying, the residual HDO concentration was
determined to approx. 1 mM. These samples were flushed by pH2 to
produce hyperpolarization in the following stage.
Figure 6. Acetaldehyde exchange reaction pathway with experimental and
simulated (sim.) PASADENA spectra. TVOA exchanges one of its CH2-
protons and its CH-proton with pH2 when both (hydrogen and TVOA) are
coordinating to [1]. The hydrogenation and dissociation of this hyperpolarized
TVOA would lead to the observed polarized acetaldehyde. The following NMR
parameters were used for simulations of polarized acetaldehyde: chemical
3
shifts: 훿퐶퐻 = 9.7435 ppm, 훿퐶퐻 = 2.123 ppm and J-coupling constants: 퐽퐶퐻−퐶퐻
3
3
= 2.85 Hz. It was assumed that the CH and one of CH3 protons are resulting
from pH2 (PASADENA effect, sim.). In the experiment and simulations
nonselective 45o excitation RF-pulses were used.
Samples for reference NMR spectra. NMR spectra of the following
compounds dissolved in chloroform-d or acetone-d6 were measured at
concentrations of 10-100 mM: vinyl acetate (CAS: 108-05-4), ethyl-acetate
(CAS: 141-78-6), triethyl orthoacetate (CAS: 78-39-7), acetaldehyde
(CAS: 75-07-0), 2-chloroethanol (CAS: 107-07-3), ethyl alcohol (CAS: 64-
17-5). All compounds were purchased from Merck. These samples and the
corresponding spectra were used to assign the products of the TVOA
hydrogenation.
IV.
Polarization of H2
A partial negative line (PNL)[42,43] was observed on H2 in
chloroform after hydrogenation of TVOA with [1] (Figure 3). This
is a good indicator of a slow catalytic hydrogenation when pH2 is
not completely consumed by the catalyst but rather exchanges:
[
]
[
]
[ ]
M + H2 ↔ M − H2 . Here M stands for a metal complex or
[
]
catalyst. When para-hydrogen associates with M , its spin order
starts evolving in a so-called singlet-triplet conversion. If this
hydride dissociates instead of hydrogenating of a substrate, it
manifests itself as H2 with a PNL. One of the possible steps,
where this can happen, is the pH2↔H2 exchange, when vinyl
acetate or acetaldehyde are polarized (Figure 5, 6) where [M]
stands for [TVOA-[1]] complex.
II.
Synthesis
[44]
TVOA was synthesized according to the protocol in ref.
modifications. The implemented protocol consisted of 2 steps (Figure 7):
with some
Synthesis of tris(chloroethyl)orthoacetate. Trichloroacetic acid
(500 mg, 3.06 mmol, CAS: 76-03-9, Merck) was placed in a 2-necked flask
with
a rubber septum on a short way distillation apparatus. The
trichloroacetic acid was dried under reduced pressure (7 mbar) for 3 h.
Then the flask was flushed with nitrogen and 10 mL of trimethyl
orthoacetate (8.56 g, 71.3 mmol, CAS: 78-39-7, TCI GmbH) was added.
The reaction mixture was heated to 90°C and 3 mL of 2-chloroethanol
Conclusion
5
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(CAS: 107-07-3, Merck) was added to the flask. The pressure was
carefully reduced to 500 mbar and further 2-chloroethanol (3 ml) was
added every 0.5 h for 2.5 h until a total of 15 ml was reached (17.0 g,
220 mmol). The reaction mixture was heated to 90°C for 3 h. During this
time 7.12 g of methanol was distilled from the reaction mixture. The
heating bath was then removed and replaced with an ice bath. 400 mg of
potassium tert-butoxide (CAS: 865-47-4, TCI GmbH) dissolved in 5 ml dry
methanol (CAS: 67-56-1, Merck) was added to quench the reaction. The
product was obtained by distillation from the reaction mixture as a
colourless oil (6.84g, 43.80 mmol, bp. 155°C at 7 mbar). This corresponds
to a yield of 62 % relative to the trimethyl orthoacetate deployed.
μm internal diameter, 360 μm outer diameter) was glued with instant 2-
component adhesive (Loctite 3090, Henkel) to the end of the capillary and
inserted into the NMR tube and solution. The used hollow fiber is resistant to
aggressive media and does not cause magnetic field distortion: the increase of
FWHM after field shimming is below 1 Hz. The pressure was set to about 1.2
bar (0.2 bar overpressure to atmospheric pressure) and adjusted to achieve a
steady bubbling. For the experiments, pH2 was supplied (bubbled) to the sample
solution for 10-30 s to generate PASADENA. Next, the bubbling was stopped
and the system was allowed to settle down for another 2 s. After that, a
PASADENA spectrum was recorded after 45o excitation. All NMR experiments
were carried out at 25°C and ambient pressure.
Synthesis of trivinyl orthoacetate (TVOA). Sodium hydride (60 %
suspension in mineral oil) (2.20 g, 54.32 mmol, CAS: 7646-69-7, Acros)
was mixed with 5 mL 1,2-dimethoxyethane (CAS: 110-71-4, ABCR) under
a nitrogen atmosphere in a 3-neck flask with a rubber septum. Then
tert-butanol (234 mg, 3.16 mmol, CAS: 75-65-0, Grüssing) was added at
room temperature and the suspension was stirred for 5 min.
Tris(chloroethyl)orthoacetate (4.41 g, 15.09 mmol) was carefully added to
the solution, which was heated under reflux for 5 h. The solvent was
removed under reduced pressure (50 mbar, 40°C). The residue was
treated with 30 mL of diethyl ether (CAS: 60-29-7, Walter-CMP) and 20 mL
of distilled water. The phases were separated and the organic phase was
washed three times with 20 ml of water and dried over magnesium sulfate
(CAS: 7487-88-9, Grüssing). The solvent was removed under reduced
pressure and the remaining liquid was distilled two times at reduced
pressure yielding TVOA (358 mg, 2.28 mmol, 80°C at 30 mbar) with a
Mass spectrometric analysis. Using the same H2 bubbling setup, the PHIP
samples were flushed with pH2 at room temperature for 5-10 minutes in 5 ml
amber glass vials. Using a Jeol AccuTOF GCv 4G spectrometer with electron
ionisation (EI), mass spectra of the blank samples (before hydrogenation) and
corresponding samples after hydrogenation were acquired (cf. SI). No stable
products of direct TVOA hydrogenation, namely DVEOA or TEOA were found.
Acknowledgements
We acknowledge support by the Emmy Noether Program
“metabolic and molecular MR” (HO 4604/2-2), the research
training circle “materials for brain” (GRK 2154/1-2019), DFG -
RFBR grant (HO 4604/3-1, № 19-53-12013), the German Federal
Ministry of Education and Research (BMBF) within the framework
of the e:Med research and funding concept (01ZX1915C), cluster
of Excellence “precision medicine in inflammation” (PMI 1267).
Kiel University and the Medical Faculty are acknowledged for
supporting the Molecular Imaging North Competence Center
(MOIN CC) as a core facility for imaging in vivo. MOIN CC was
founded by a grant from the European Regional Development
Fund (ERDF) and the Zukunftsprogramm Wirtschaft of
Schleswig-Holstein (Project no. 122-09-053).
purity of 90 %. This corresponds to
a yield of 15 % based on
tris(chloroethyl)orthoacetate. Possible impurities and side products are
bisvinyl(chloroethyl)orthoacetate, 2-chloroethanol (Figure 8).
Figure 7. Trivinyl orthoacetate (TVOA) synthesis. Step 1: the methyl ethers
of trimethyl orthoacetate (TMOA) are replaced by chloroethyl under acidic
conditions to give the tris(chloroethyl)orthoacetate (TCOA). Step 2: sodium
hydride is used as a base in an elimination reaction to obtain TVOA.
Keywords: acetate • geminal hydrogenation • homogeneous
catalysis • hyperpolarization • parahydrogen • PASADENA • PHIP
• sidearm hydrogenation • vinyl
Abbreviations:
TVOA – trivinyl orthoacetate
DVEOA – divinyl ethyl orthoacetate
TEOA – triethyl orthoacetate
TCA – trichlor acetic acid
TMOA – trimethyl orthoacetate
TCOA – tri(chloroethyl) orthoacetate
VA – vinyl acetate
Figure 8. High-resolution 1H NMR spectra of chloroform-d (1), vinyl acetate
(VA, 2) and trivinyl orthoacetate (TVOA, 3) in chloroform-d. Red arrows
indicate side products of synthesis (presumably it is bisvinyl(chloroethyl)-
orthoacetate). 2-chloroethanol (2-CE) and some other residues from the
synthesis are also present. The estimated purity of TVOA is about 90%.
EA – ethyl acetate
AD – acetaldehyde
CE – chloroethanol
PHIP – parahydrogen induced polarization
PHIP-SAH – PHIP-side arm hydrogenation
PHIP-HOT – PHIP by hydrogenation of three side arms
III.
Experimental routines
PASADENA experiments. pH2 was prepared using a liquid nitrogen setup that
provides pH2 fraction of 50 %.[45] All experiments were carried out on a 600 MHz
NMR spectrometer (Bruker Avance II) with a cryogenically cooled probe (TCI)
and 5 mm screw-cap NMR tubes (Wilmad). The gas was delivered into the
ORCID:
Andrey Pravdivtsev https://orcid.org/0000-0002-8763-617X
spectrometer by
a 1/16” polytetrafluoroethylene (PTFE) capillary (0.023”
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Entry for the Table of Contents
In an attempt to use multiple parahydrogen molecules to hyperpolarize one molecule, homogeneous catalytic hydrogenation of trivinyl
orthoacetate (TVOA) was studied. Hydrogenation of TVOA is accompanied by a fast decomposition of the semihydrogenated reagent.
Ethyl acetate, vinyl acetate, acetaldehyde and ethanol are final products. Utilization of parahydrogen and PASADENA NMR
spectroscopy together with the expected hydrogenation of vinyl sites revealed also unexpected geminal and vicinal hydrogen exchange.
Institute and/or researcher Twitter usernames: @theMOINCC
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