Parahydrogen-induced polarization transfer to 19F in perfluorocarbons for 19F NMR spectroscopy and MRI

Article abstract of DOI:10.1002/chem.201203455

Fluorinated substances are important in chemistry, industry, and the life sciences. In a new approach, parahydrogen-induced polarization (PHIP) is applied to enhance ¹⁹F MR signals of (perfluoro-n-hexyl)ethene and (perfluoro-n-hexyl)ethane. Unexpectedly, the end-standing CF₃ group exhibits the highest amount of polarization despite the negligible coupling to the added protons. To clarify this non-intuitive distribution of polarization, signal enhancements in deuterated chloroform and acetone were compared and ¹⁹F-¹⁹F NOESY spectra, as well as ¹⁹F T ₁ values were measured by NMR spectroscopy. By using the well separated and enhanced signal of the CF₃ group, first ¹⁹F MR images of hyperpolarized linear semifluorinated alkenes were recorded. Copyright

Full text of DOI:10.1002/chem.201203455

FULL PAPER
DOI: 10.1002/chem.201203455
19
Parahydrogen-Induced Polarization Transfer to F in Perfluorocarbons
19
for F NMR Spectroscopy and MRI**
Markus Plaumann,*[a] Ute Bommerich,[b] Thomas Trantzschel,[a] Denise Lego,[b]
Sonja Dillenberger,[c] Grit Sauer,[c] Joachim Bargon,[d] Gerd Buntkowsky,[c] and
Johannes Bernarding[a]
Abstract: Fluorinated substances are
important in chemistry, industry, and
the life sciences. In a new approach,
zation despite the negligible coupling
to the added protons. To clarify this
non-intuitive distribution of polariza-
tion, signal enhancements in deuterat-
ed chloroform and acetone were com-
pared and 19F–19F NOESY spectra, as
well as 19F T1 values were measured by
NMR spectroscopy. By using the well
separated and enhanced signal of the
CF3 group, first 19F MR images of hy-
perpolarized linear semifluorinated al-
kenes were recorded.
parahydrogen-induced
polarization
(PHIP) is applied to enhance 19F MR
signals of (perfluoro-n-hexyl)ethene
and (perfluoro-n-hexyl)ethane. Unex-
pectedly, the end-standing CF3 group
exhibits the highest amount of polari-
Keywords: fluorine
·
hydrogena-
tion · imaging agents · NMR spec-
troscopy · polarization transfer
Introduction
shift range of more than 300 ppm and no natural fluorine
background signal in biological organisms. Therefore, signals
can be attributed unambiguously. Similarly, 19F MRI has re-
cently become an important research topic in medicine with
a focus on molecular imaging applications, lung imaging,
and drug monitoring.[5] Although this shows that 19F MRI
has a high potential to serve as a new diagnostic tool, the in
vivo spin density of most substrates is rather small, leading
to low signal-to-noise ratios (SNRs). Hence, strong efforts
aim to increase the 19F SNR as the prerequisite to establish
MR in clinical and medical routine.
Instead of increasing the external polarizing magnetic
field, less costly but very efficient non-standard polarization
methods offer a new way to acquire signals with higher
SNR. Hyperpolarization techniques such as dynamic nuclear
polarization (DNP), chemically induced dynamic nuclear
polarization (CIDNP), spin-exchange optical pumping
(SEOP), and parahydrogen-induced polarization (PHIP)
can be used to enhance the SNR in MR experiments up to
several orders of magnitude. In general, these methods gen-
erate populations of the Zeeman energy levels that differ
significantly from the limited thermal polarization.[6,7] PHIP
is advantageous because its implementation requires less
technological effort. PHIP signals depend on whether hy-
drogenation is performed in the presence of a strong mag-
netic field (PASADENA, parahydrogen and synthesis allow
dramatically enhanced nuclear alignment),[8] or whether hy-
drogenation occurs under low-field conditions (ALTADE-
NA, adiabatic longitudinal transfer after dissociation engen-
ders net alignment) followed by adiabatic transport into the
detection field.[9]
In the last few years, perfluorinated molecules have been
raising increasing interest. They are of great relevance in
technical, chemical, and life science applications due to their
manifold, excellent characteristics.[1] One of the most stud-
ied perfluorinated compounds in medicine is the linear per-
fluorooctylbromide (C8F15Br), also known as perflubron,
which can be used as a blood substitute as well as a contrast
agent in 19F magnetic resonance imaging (MRI).[2] In gener-
al, perfluorocarbons are well known from in vivo studies in
different applications, for example, artificial blood, liquid
breathing,[3] and in 19F MRI studies.[4]
19F NMR spectroscopy has a long-standing history in high-
resolution NMR spectroscopy as there is a high chemical-
[a] Dr. M. Plaumann, Dipl.-Phys. T. Trantzschel, Prof. Dr. J. Bernarding
Department of Biometry and Medical Informatics
Otto-von-Guericke University of Magdeburg
Leipziger Strasse 44, 39120 Magdeburg (Germany)
Fax : (+49)391-67-13536
E-mail: markus.plaumann@med.ovgu.de
[b] Dr. U. Bommerich, Dipl.-Ing. D. Lego
Leibniz-Institute for Neurobiology
39118 Magdeburg (Germany)
[c] Dipl.-Chem. S. Dillenberger, Dipl.-Chem. G. Sauer,
Prof. Dr. G. Buntkowsky
Eduard-Zintl-Institute for Inorganic Chemistry
Technical University Darmstadt
64287 Darmstadt (Germany)
[d] Prof. Dr. J. Bargon
Institute of Physical and Theoretical Chemistry
University Bonn, 53115 Bonn (Germany)
PHIP can be used, for example, for analyzing intermedi-
ates and products of catalytic reactions or, as recently re-
ported, also for biological and medical studies by polariza-
[**] MRI=magnetic resonance imaging.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203455.
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tion transfer to heteronuclei, mostly 13C.[10] The transfer of
proton hyperpolarization to heteronuclei such as 13C, 15N,
31P, or 19F through scalar couplings has been successfully
demonstrated. This enables the development of contrast
agents for MRI by using PHIP to hyperpolarize 13C or 19F in
these substrates.[7,11,12]
However, the transfer of PHIP to 19F is documented only
for a small class of closely related aromatic systems, which
are potentially harmful.[12,13]
In order to extend this method to biocompatible sub-
strates, we attempted to hyperpolarize the linear (perfluoro-
n-hexyl)ethene (PFE2) and (perfluoro-n-hexyl)ethane
(PFE1) through PHIP (Scheme 1). Both molecules have the
Figure 1. 1H NMR spectra measured in [D6]acetone. Hyperpolarized (per-
fluoro-n-hexyl)ethene (bottom) and its spectrum in thermal equilibrium
in eightfold magnification (top). Cycles indicate the transferred protons.
Scheme 1. Reaction scheme of the hydrogenation of PFE3 to PFE2 and
the further hydrogenation to PFE1.
same number of carbon atoms as the perfluorooctylbromide
previously mentioned; therefore, they should be applicable
for in vivo studies. The hyperpolarization of PFE1 is particu-
larly interesting because semifluorinated alkanes are physio-
logically inert.[14] In addition, they might be used for in vivo
monitoring of inflammatory processes.[15]
Figure 2. 1H NMR spectra measured in [D6]acetone. Hyperpolarized (per-
fluoro-n-hexyl)ethane (bottom) and its spectrum in thermal equilibrium
(top). Cycles indicate the transferred protons.
1
After the successful hydrogenation and H hyperpolariza-
tion of these model compounds, the polarization transfer to
fluorine was examined.
Results and Discussion
For the interpretation of the 19F PHIP NMR and MRI
At first, feasibility experiments for hydrogenation of (per-
fluoro-n-hexyl)ethyne (PFE3) in [D6]acetone were per-
data a correct signal assignment of the different fluorine
4
groups is essential. It is well known that J
(F,F) couplings in
3
5
formed in the presence of [Rh
G
N
perfluoroalkyl chains are generally larger than JACTHNGUETRNNU(G F,F) or J-
cyclooctadiene, dppb=1,4-bis(diphenylphosphino)butane)
(F,F) values.[17] These correlations, observable in
ACHTUNGTRENNUNG
1
as a catalytic system. The H NMR spectra show antiphase
19F–19F COSY spectra, were used to assign the signals (see
the Supporting Information). Figure 3 shows the 19F NMR
spectra of the three molecules discussed here with the corre-
sponding notations.
signals with signal-enhancement (SE) factors of 111 for the
CH group (C-2’) at d=6.26 ppm and 139 for the added
proton on the CH2 group (C-1’) of PFE2 at d=6.04 ppm
(Figure 1).
From comparison with proton-decoupled 19F NMR spec-
tra of PFE2 and PFE1 it can be concluded that only fluorine
atoms bound to C-3’, respectively C-3’’, exhibit a coupling to
the protons (Figures S7 and S8 in the Supporting Informa-
tion).
Additionally, hydrogenation from PFE2 to the saturated
1
PFE1 was measured. The corresponding H NMR spectrum
(Figure 2) shows signals with an SE of two for the newly
formed CH3 (C-1’’) at d=1.17 ppm and 1.5 for the CH2
group (C-2’’) at d=2.27 ppm. These smaller SE factors
might be caused by a small conversion rate of the double-
bond system.[16]
The 19F PHIP NMR spectrum measured directly after hy-
drogenation of PFE3 is shown in Figure 4. Except for C-5’
(d=ꢀ122.4 ppm) and C-6’ (d=ꢀ123.7 ppm), all other moi-
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Parahydrogen-Induced Polarization Transfer to 19
F
FULL PAPER
Figure 3. 19F NMR spectra and the corresponding signal assignments of
(perfluoro-n-hexyl)ethyne (PFE3; top), (perfluoro-n-hexyl)ethene
(PFE2; middel), and (perfluoro-n-hexyl)ethane (PFE1; bottom) meas-
ured in [D6]acetone.
Figure 5. 19F NMR spectrum taken directly after hydrogenation of PFE2
showing signals of hyperpolarized PFE1 (bottom) and the corresponding
spectrum detected at thermal equilibrium (top).
Unexpectedly, in both cases a large portion of polariza-
tion is transferred to the CF3 end groups, whereas the cen-
tral moieties exhibited no signal improvement.
To clarify whether the relaxation times of the individual
groups may explain this non-intuitive distribution of the po-
larization, T1 values were measured by inversion recovery
experiments for each fluorine group in PFE2 and PFE1
(Figure 6). The calculated longitudinal relaxation times
range from 4.2 to 6.6 s, which renders it improbable that dif-
Figure 4. 19F NMR spectrum taken directly after hydrogenation of PFE3
showing signals of hyperpolarized PFE2 (bottom) and the corresponding
spectrum detected at thermal equilibrium (top).
eties exhibit notable SE factors. Signals of fluorine bound to
C-3’ (d=ꢀ114.4 ppm, SE=11) and C-8’ (d=ꢀ82.0 ppm,
SE=15) show in-phase patterns, whereas emission phase
signals can be observed for fluorine bound to C-4’ (d =
ꢀ124.4 ppm, SE=26) and C-7’ (d=ꢀ127.1 ppm, SE=3).
For sake of clarity the calculation of the SE factors for
product signals (PFE2, PFE1) at d=ꢀ82.0 ppm has to be
explained. Because this signal interferes with the signals of
the starting material, the SE was determined by using the
SNR of the hyperpolarized signal at d=ꢀ82.0 ppm, on the
one hand, and the thermal SNR of the product CF3 assumed
from the separated thermal CF2 signal at d=ꢀ114.4 or
ꢀ117.8 ppm, on the other hand.
Analogous to the fluorine ALTADENA spectrum of
PFE2 (Figure 4), the 19F NMR spectrum of hyperpolarized
PFE1 (Figure 5) was detected under the same hydrogena-
tion conditions. For C-3’’ (d=ꢀ117.8 ppm, SE=10.5) and C-
8’’ (d=ꢀ82.0 ppm, SE=18.8) two enhanced in-phase signals
could be detected, whereas C-7’’ (d=ꢀ127.1 ppm) shows an
emission signal and C-4’’ (d=ꢀ124.5 ppm) an anti-phase
pattern, which were not enhanced.
Figure 6. T1 estimation from inversion recovery experiments. The fits for
PFE2 (top) and PFE1 (bottom) yield relaxation times in the range of
4.2–6.6 s.
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M. Plaumann et al.
ferences in T1 are the reason for the large variations in the
SE factors obtained.
To obtain further information about the polarization
transfer mechanism through the fluorinated alkyl chain and
the differences in the observed signal enhancements be-
tween the middle and the exterior CF2 or CF3 groups,
19F–19F NOE
measurements
were
performed.
19F–19F NOESY (nuclear Overhauser effect spectroscopy)
provides unambiguous assignment of the vicinal fluorine
atoms by showing through-space couplings.[18] Figure 7
shows the 19F–19F phase sensitive NOESY spectrum of PFE2
with a mixing time of 4 s (two scans, relaxation delay: 20 s).
In the 19F–19F NOESY spectrum of PFE2 in [D6]acetone
(Figure 7), two dominant pairs of cross peaks are observable
for the signal of CF3 (C-8’) at d=ꢀ82.0 ppm. These cross
peaks reflect correlations to the lines at d=ꢀ127.1 and
ꢀ123.6 ppm.
As known from 19F–19F COSY spectra, these signals corre-
spond to CF2 (C-7’, d=ꢀ127.1 ppm) and CF2 (C 6’, d=
ꢀ123.6 ppm) groups. This indicates interactions between
closely related fluorine atoms. The third smaller NOESY
connection corresponds to an interaction to the signal of
CF2 (C-5’, d=ꢀ122.4 ppm).
Similar results can be observed after closer examination
of the cross peaks corresponding to the signal of C-3’ at d=
ꢀ114.4 ppm. The strongest NOESY connections are as-
signed to the lines at d=ꢀ124.4 (C-4’) and ꢀ122.4 ppm (C-
5’). Additionally, an interaction is observed for the cross
peak at d=ꢀ123.6 ppm (C-6’).
Figure 7. Full 19F–19F NOESY spectrum (282.5 MHz) of PFE2 in
[D6]acetone (top) and expansion of the ppm region between d=ꢀ113.7
and ꢀ128.0 ppm, where in-phase cross peaks (in comparison to the diago-
nal peaks) between C-4’ and C-5’ and mixed phase patterns between C-4’
and C-6’ are in evidence (bottom).
There are remarkably strong in-phase cross peaks (same
phase as diagonal peaks) at d=ꢀ122.4/ꢀ124.4 and ꢀ124.4/
ꢀ122.4 ppm between the fluorine atoms on C-4’ and C-5’ in
the middle of the fluorine alkyl chain as well as mixed phase
signals at d=ꢀ123.6/ꢀ124.4 and ꢀ124.4/ꢀ123.6 ppm, respec-
tively, which reveal a special connection between C-4’ and
C-6’. No intensive cross peak can be measured for d=
ꢀ122.4/ꢀ123.6 ppm (C-5’/C-6’).
In contrast to PFE2, the correlations C-4/C-5 and C-4’’/C-
5’’, respectively, are in opposite phase to the diagonal (spec-
tra and values shown in the Supporting Information and
Table 1).
So far, only Battiste et al. mentioned fluorine signals in
19F–19F NOESY spectra with a mixed-phase character for
cyclic molecules.[19] Although signals with negative NOE
(same phase as diagonal) were observed in different
19F–19F NOESY spectra shown in the literature, they were
not interpreted.[17,20] These observations have not yet been
The recorded 19F–19F NOESY spectrum of PFE1 shows a
mixed-phase pattern between C-4“ and C-6” (see Figure S12
in the Supporting Information). In the spectrum of PFE3,
the corresponding cross peaks (C-4 and C-6) could not be
separated due to the absence of chemical shift differences.
Table 1. Chemical shifts (d), spin-lattice-relaxation times (T1), signal enhancements (SE), observed couplings from 19F–19F COSY and NOESY spectra
for PFE1 and PFE2 in degassed [D6]acetone solution.
PFE2
PFE1
C-3’
C-4’
C-5’
C-6’
C-7’
C-8’
C-3’’
C-4’’
C-5’’
C-6’’
C-7’’
C-8’’
d [ppm]
T1 [s]
SE
ꢀ114.4
5.0
11
ꢀ124.4
4.8
26
ꢀ122.4
ꢀ123.7
ꢀ127.1
ꢀ82.0
5.4
15
ꢀ117.8
4.8
10.5
ꢀ124.5
ꢀ122.9
ꢀ123.8
ꢀ127.1
5.5
1.2
ꢀ82.0
6.6
18.8
4.2
–
4.2
–
4.5
3
5.1
–
4.9
–
4.9
–
strong spin–spin
coupling to
C-5’
C-6’
C-3’
C-7’
C-4’
C-8’
C-5’
C-6’
C-5’’
C-6’’
C-3’’
C-7’’
C-4’’
C-8’’
C-5’’
C-6’’
strong NOE to
C-4’
C-5’
C-3’
C-5’
C-6’
C-3’
C-4’
C-6’
C-7’
C-4’
C-5’
C-7’
C-8’
C-5’
C-6’
C-8’
C-6’
C-7’
C-4’’
C-5’’
C-3’’
C-5’’
C-6’’
C-3’’
C-4’’
C-6’’
C-7’’
C-4’’
C-5’’
C-7’’
C-8’’
C-5’’
C-6’’
C-8’’
C-6’’
C-7’’
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Parahydrogen-Induced Polarization Transfer to 19
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FULL PAPER
clarified in detail. Strong coupling effects or cross-correlated
dipole chemical shifts anisotropies are postulated as explan-
ations for such phase changes.
which can be measured at higher magnetic field, and numer-
ical simulations should help to clarify the mechanism under-
lying the polarization distribution.
To clarify whether the in-phase cross peaks in our case
are based on this effects a 2D NOESY build-up curve was
measured (Figure S14 in the Supporting Information). The
results do not confirm an indirect NOE (no NOE build-up).
The opposite cross-peak phases of C4/C5 in the NOESY
spectra of PFE2 and PFE1 do not explain the unexpected
distribution of polarization in our PHIP data.
Therefore, intermolecular interactions were considered as
an explanation of the polarization transfer to the end-stand-
ing CF3 group. As those interactions (e.g., dipolar) should
be a function of solvent polarity and/or substrate concentra-
tion, additional PHIP experiments with PFE3 in acetone
and chloroform were performed by using varying concentra-
tions. In Figure 8, the calculated SE factors for C-8’ and C-3’
are plotted. The diagrams clearly show a linear correlation
between the SE factors of the two moieties, which does not
change significantly for either solvents. Variations in the SE
factors for certain concentrations result from the manual ex-
perimental procedure.
This is the first time that PHIP has been used to generate
19F hyperpolarization for an important biocompatible sub-
strate. With regard to the use of clinically relevant perfluo-
rocarbons, the observed polarization pattern qualifies the
use of PFEs as interesting marker substances for MRI. For-
tunately, the major part of the signal enhancement in PFE2
is located at d=ꢀ82.0 ppm, allowing the selection of the ter-
minal CF3 group for 19F MRI. Figure 9 (left) shows an MR
image of a phantom-containing hyperpolarized PFE2, which
was acquired after hydrogenation of 0.075 mL PFE3 in ace-
tone (c=0.071m).
The benefit of PHIP is clearly demonstrated by compari-
son with the image detected at thermal equilibrium
(Figure 9, right).
Hence, intermolecular polarization transfer could not be
proven and the assumption and analysis of the intramolecu-
lar processes did not yield an explanation for the unexpect-
ed distribution of hyperpolarization. A complete theoretical
analysis of these highly interesting systems is currently lack-
ing. The read-out of all coupling constants from spectra,
Figure 9. 19F MR images of a PHIP experiment that uses a 0.071m solu-
tion of PFE3 in [D6]acetone. PFE2 after hyperpolarization (left) and in
thermal equilibrium (right). Images were acquired at 4.7 T with a single
scan by using a fast spin echo sequence (RARE: TE=14 ms, FOV=80ꢁ
40, voxel size 0.625ꢁ0.625ꢁ1 mm3, RARE factor: 16, zero filling acceler-
ation of two and acquisition time taq =465 ms).
Conclusion
In summary, the analysis of the SE showed an unexpected
degree of polarization transfer to the end-standing CF3
group of the reaction products PFE2 and PFE1, respectively.
Further investigation of this finding excluded intermolecular
interactions as an explanation of this transfer of polarization
over the rather long distance. However, the mechanism of
the alternative intramolecular transfer could not yet be com-
pletely clarified. As the transfer only occurs in a low mag-
netic field, that is, in the strong coupling regime, the process
seems to be driven by a J-coupling mechanism where the
4
strong J interactions may play a major role.
However, due to the strong SE and the notably well sepa-
rated signal at d=ꢀ82.0 ppm, the end-standing CF3 group is
particularly well suited for 19F imaging.
Future experiments at higher magnetic fields and corre-
sponding simulations are necessary to elucidate the details
of the polarization transfer along the fluorinated chain. A
complete analysis of the relevant factors controlling this
transfer will further improve the SE, thus enhancing the
Figure 8. Calculated SE of the CF2 group at d=ꢀ114.6 ppm plotted
against the SE of the CF3-group at d=ꢀ82.0 ppm for different concentra-
tions (vol%) of PFE2 in [D6]acetone (top) and [D1]chloroform (bottom).
As can be seen, all measurements show a stable ratio between the SEs
for these groups.
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M. Plaumann et al.
SNR of corresponding MR spectra and images. The 19F MR
images of hyperpolarized PFE2 demonstrate that the spatial
distribution of these biologically relevant semifluorinated al-
kenes should be detectable with mm concentration by using
a single MR scan.
This qualifies the PHIP technique for a new class of po-
tential biocompatible substances that do exhibit sufficient
SE to allow background-free 19F MRI as well as 19F NMR
spectroscopy.
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10312.
Experimental Section
Materials: (Perfluoro-n-hexyl) acetylene (PFE3) and 1H,1H,2H-per-
fluoro-1-octene (PFE2) were purchased from ABCR, whereas (per-
fluoro-n-hexyl)ethane (PFE1) was delivered from Santa Cruz Biotechnol-
ogy. The [RhI
ACHTUNGTRENNUNG(1,4-bis(diphenylphosphino)-butane) (1,5-cyclooctadie-
ne)]BF4 catalyst was obtained from STREM Chemicals Inc. and the deu-
terated acetone from Deutero GmbH and euriso-top.
Hydrogenation and NMR measurements: Enriched para-H2 (50%) was
achieved at temperatures of liquid nitrogen over activated charcoal.[21]
The samples consisted of PFE3/PFE2/PFE1 (0.2 mL), [D6]acetone
(1.8 mL), and the catalyst (0.014 mmol). Furthermore, the solutions were
degassed under an argon atmosphere to remove oxygen. Then the para-
hydrogen (6.2 bar) was piped into a 10 mm NMR tube containing the
prepared reaction solutions. The hydrogenations were performed under
ALTADENA conditions by shaking the sample for about 10 s in the
magnetic field of the earth. Then the tubes were transported into a 7 T
Bruker WB 300 ultrashield NMR spectrometer. When the sample was
locked (approximately 1–2 s after arriving at the lift-down position) data
acquisition was started.
In the case of 1H, a regular ALTADENA single-shot experiment with a
458 radio frequency pulse was performed (P1=14.5 ms, PL1=14.997 W).
For 19F PHIP experiments a 908 flip angle was used (P1=32.5 ms, PL1=
17 W).
Signal enhancements: Signal enhancements specified in this work were
calculated from the signal-to-noise ratios of the thermal and the hyperpo-
larized spectra by using Equation (1):
signalðHPÞ ꢁ stdðnoiseðthermalÞÞ
ð1Þ
SE ¼
stdðnoiseðHPÞÞ ꢁ signalðthermalÞ
[13] a) L. T. Kuhn, U. Bommerich, J. Bargon, J. Phys. Chem. A 2006, 110,
3521–3526; b) U. Bommerich, S. Mulla-Osman, J. Bargon, J. Ber-
narding, Proc. Intl. Soc. Mag. Reson. Med. 2009, 17, 2460.
[14] H. Meinert, T. Roy, Eur. J. Ophthalmol. 2000, 10, 189–197.
[15] Hendrik Hardung, PhD Thesis, Freiburg (Germany), 2008.
[16] a) E. Wiberg, N. Wiberg, Lehrbuch der anorganischen Chemie, de
Gruyter, Berlin, 1995; b) N. S. Isaacs, Physical Organic Chemistry,
Wiley, New York, 1995.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG BE 1824/8-1, BO 3055/2-1, BU 911/15-1. We thank the working
group of Prof. Dr. Peter Spiteller, particularly Dipl.-Chem.-Ing. Johannes
Stelten, for the opportunity to measure the proton-decoupled fluorine
spectra.
[17] G. W. Buchanan, E. Munteanu, B. A. Dawson, D. Hodgson, Magn.
Reson. Chem. 2005, 43, 528–534.
[18] J. L. Battiste, N. Jing, R. A. Newmark, J. Fluorine Chem. 2004, 125,
1331–1337.
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plications; Wiley-VCH, Weinheim, 2004.
[19] J. Battiste, R. A. Newmark, Prog. NMR Spectroscopy 2006, 48, 1–
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[2] C. Giraudeau, J. Flament, B. Marty, F. Boumezbeur, S. Mꢂriaux, C.
Robic, M. Port, N. Tsapis, E. Fattal, E. Giacomini, F. Lethimonnier,
D. Le Bihan, J. Valette, Magn. Reson. Med. 2010, 63, 1119–1124.
[3] K. C. Lowe, J. Mater. Chem. 2006, 16, 4189.
[20] S. Sato, J. Jida, K. Suzuki, M. Kawano, T. Ozeki, M. Fujita, Science
2006, 313, 1273–1276.
[21] K. F. Bonhoeffer, P. Harteck, Z. Phys. Chem. 1929, 4, 113–141.
[4] R. P. Mason, P. P. Antich, E. E. Babcock, J. L. Gerberich, R. L. Nun-
nally, Magn. Reson. Imaging 1989, 7, 475–485.
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Wꢃlchli, M. Shirakawa, K. Kikuchi, J. Am. Chem. Soc. 2008, 130,
Received: September 27, 2012
Revised: February 19, 2013
Published online: && &&, 0000
&
6
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www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Parahydrogen-Induced Polarization Transfer to 19
F
FULL PAPER
Hyperpolarized Fluorine
M. Plaumann,* U. Bommerich,
T. Trantzschel, D. Lego,
S. Dillenberger, G. Sauer, J. Bargon,
G. Buntkowsky,
J. Bernarding .................. &&&& — &&&&
Fluorinated substances are important
in chemistry and the life sciences. In a
new approach, parahydrogen-induced
polarization (PHIP) is applied to
of hyperpolarized linear semifluori-
nated alkenes (see picture). Unexpect-
edly, the end-standing CF3 group
exhibits the highest amount of polari-
zation despite the negligible coupling
to the added protons.
Parahydrogen-Induced Polarization
Transfer to 19F in Perfluorocarbons for
19F NMR Spectroscopy and MRI
enhance 19F MR signals of (perfluoro-
n-hexyl)ethene and (perfluoro-n-hex-
yl)ethane. This allows 19F MR imaging
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
7
&
ÞÞ
These are not the final page numbers!