Spontaneous transfer of Parahydrogen derived spin order to pyridine at low magnetic field

Article abstract of DOI:10.1021/ja903601p

The cationic iridium complex [Ir(COD)(PCy₃)(py)]BF₄ (1) is shown to react with dihydrogen in the presence of pyridine (py) to form the dihydride complex fac,cis-[Ir(PCy₃)(py)₃(H) ₂]BF₄ (2).

Full text of DOI:10.1021/ja903601p

Published on Web 09/01/2009
Spontaneous Transfer of Parahydrogen Derived Spin Order to
Pyridine at Low Magnetic Field
Kevin D. Atkinson, Michael J. Cowley, Paul I. P. Elliott, Simon B. Duckett,*
Gary G. R. Green,† Joaqu´ın Lo´pez-Serrano, and Adrian C. Whitwood
Department of Chemistry, UniVersity of York, Heslington, York, YO10 5DD, United Kingdom
Received May 4, 2009; E-mail: sbd3@york.ac.uk
Abstract: The cationic iridium complex [Ir(COD)(PCy3)(py)]BF4 (1) is shown to react with dihydrogen in
the presence of pyridine (py) to form the dihydride complex fac,cis-[Ir(PCy3)(py)3(H)2]BF4 (2). Complex 2
undergoes rapid exchange of the two bound pyridine ligands which are trans to hydride with free pyridine;
the activation parameters for this process in methanol are ∆Hq ) 97.4 ( 9 kJ mol-1 and ∆Sq ) 84 ( 31
J K-1 mol-1. When parahydrogen is employed as a source of nuclear spin polarization, spontaneous
magnetization transfer proceeds in low magnetic field from the two nascent hydride ligands of 2 to its other
NMR active nuclei. Upon interrogation by NMR spectroscopy in a second step, signal enhancements in
excess of 100 fold are observed for the 1H, 13C and 15N resonances of free pyridine after ligand exchange.
The degree of signal enhancement in the free substrate is increased by employing electronically rich and
sterically encumbered phosphine ligands such as PCy3, PCy2Ph, or PiPr3 and by optimizing the strength
of the magnetic field in which polarization transfer occurs.
Introduction
by a microwave source. When such samples are rapidly thawed
and transferred into an NMR tube, signal enhancements in
NMR spectroscopy has undoubtedly become the most im-
portant tool available to the scientist for the characterization of
molecules, as well as the study of their dynamic behavior and
reactivity in solution.2,3 This technique suffers, however, from
the limitation that it is inherently insensitive due to the small
population difference that exists between the energy levels that
it interrogates. Hence, at a magnetic field strength of 9.4 T, the
normally observed H NMR signal results from an effective
contribution of only 1 in every 31 200 molecules present in the
sample.
Several “hyperpolarization” techniques have been reported
that allow detected NMR signals to be enhanced through the
generation of non-Boltzmann spin state populations between
these energy levels. For instance, hyperpolarized 129Xe can be
generated by optical pumping of this gas in a magnetic field.4
A related and recently commercialized polarization technique
is dynamic nuclear polarization (DNP).5-7 Here, the NMR active
nuclei are polarized at 1.3 K in a glassed solvent matrix while
exposed to a magnetic field in conjunction with magnetization
transfer from the electron of an added radical which is irradiated
excess of 10 000 fold have been observed for 13C and fast two-
dimensional approaches are now available.8
A further chemical “hyperpolarization” method that has been
used extensively by our research group and others involves
parahydrogen induced polarization (PHIP) or more rigorously
PASADENA (parahydrogen and synthesis allow dramatically
enhanced nuclear alignment).9,10 There are two forms of H2,
orthohydrogen where the nuclei are described by one of the
three possible magnetic states, |Rꢀ〉 + |ꢀR〉, |RR〉 or |ꢀꢀ〉 and
parahydrogen where the nuclei are in the (|Rꢀ〉 - |ꢀR〉) or singlet
state. Parahydrogen is restricted to having even values of the
rotational quantum number J while orthohydrogen must have
odd values of J and they hence lie 120 cm-1 apart in energy.
The selective formation of parahydrogen at low temperatures
makes use of the fact that interchange between these two forms
is formally forbidden, as both the spin and rotational states much
change for interconversion. Consequently parahydrogen can be
prepared in an almost pure form at 20 K by employing a suitable
spin exchange catalyst.11 While parahydrogen, the nuclear
singlet, is itself NMR silent, reaction products derived from it
are often produced with non-Boltzmann nuclear spin state
populations and thus exhibit greatly enhanced NMR signals.
For example, when the complex [Ru(dpae)(CO)2(H)2] (dpea )
1,2-(diphenylarsino)ethane) is generated from the tricarbonyl
parent by irradiation, the two hydride ligands exist in a magnetic
state that is indistinguishable from that of a pure singlet spin
1
† York Neuroimaging Centre, The Biocentre, York Science Park,
Innovation Way, Heslington, York, YO10 5DG, U.K.
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(3) Wuthrich, K. Angew. Chem., Int. Ed. 2003, 42 (29), 3340–3363.
(4) Navon, G.; Song, Y. Q.; Room, T.; Appelt, S.; Taylor, R. E.; Pines,
A. Science 1996, 271 (5257), 1848–1851.
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Reson. 2007, 187 (2), 216–224.
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13362 J. AM. CHEM. SOC. 2009, 131, 13362–13368
10.1021/ja903601p CCC: $40.75  2009 American Chemical Society

Parahydrogen Derived Spin Order to Pyridine
A R T I C L E S
state.12 This results in a 31 200 fold increase in the H NMR
signal strengths associated with the hydride ligands of this
species. Not surprisingly, PHIP has therefore served as a useful
tool for the study of catalytic reactions where H2 is a reactant.
Indeed, many low concentration intermediates would otherwise
be invisible, and their reactivities have been studied by this
approach.11
1
In recent years, PHIP has attracted wider interest because of
its potential to generate highly polarized organic molecules via
the hydrogenation of unsaturated organic substrates. Golman
et al. have exploited this phenomenon for the generation of PHIP
enhanced contrast agents for use in magnetic resonance imaging
(MRI).13 While this methodology has been taken up by others,
the formal hydrogenation step represents a distinct limitation
of the underlying method because a reactive unsaturated analog
of the desired material is required.14 Nonetheless, recent studies
employing succinic acid15 and propane16 and the development
of an automated polarizer17 continue to expand the horizons of
this approach.
In this paper, we detail a new approach to the generation of
PHIP sensitized materials. This method relies on bringing both
parahydrogen and the substrate to be polarized into temporary
contact via a suitable transition metal based host. Polarization
is shown to be spontaneously transferred from the parahydrogen
derived hydride ligands in this template to the bound substrate
under low magnetic field conditions over the period of a few
seconds. This approach is therefore related to that demonstrated
for hydrogenation products under ALTADENA conditions.18
Dissociation of the magnetically labeled substrate then enables
the build up of polarization in this chemically unmodified
material which is then interrogated in a second step by NMR
spectroscopic methods. The magnetic signals that are measured
during this process can be several orders of magnitude larger
than those which are normally obtained. This process corre-
sponds to the production of non-hydrogenative parahydrogen
induced polarization (NH-PHIP) or more usefully signal am-
plification by reversible exchange (SABRE) and is achieved
without any chemical modification of the substrate.
1
Figure 1. (a) Hydride region of a H24 NMR spectrum recorded during
the reaction of 1 with p-H2 in the presence of 15N-pyridine at 300 K, (b)
1
corresponding H NMR spectrum.
the parahydrogen spin order across the network of coupled spins
that exist within the template according to the difference in
chemical shifts between pairs of spins, the size of their scalar
couplings and the time spent on the template. Consequently,
varying and enhanced spin-state amplitudes result for magneti-
cally active nuclei within the template which upon dissociation
produce the magnetically polarized substrate.
We exemplify this polarization transfer process in this paper
for pyridine and employ inorganic templates of the type
fac,cis-[Ir(PCy3)(py)3(H)2]BF4 to achieve it. We recently re-
ported results from a related study on analogous aryl phosphine
complexes such as fac,cis-[Ir(PPh3)(py)3(H)2]BF4 and fac,cis-
[Ir(PPh3)2(py)2(H)2]BF4 that established the direct sensitization
of the 15N signal of free pyridine could be achieved through
ligand exchange in conjunction with a radio frequency based
polarization transfer procedure.20 Some of these results have
recently been communicated.21
Results and Discussion
Reaction of [Ir(COD)(PCy3)(py)]BF4 (1) with Parahydro-
gen and Pyridine. When a sample of [Ir(COD)(PCy3)(py)]BF4
(1), in methanol-d4, reacts with parahydrogen in the presence
of pyridine at 300 K a nonenhanced doublet is observed in the
1
hydride region of the corresponding H NMR spectrum at δ
It works by taking the nuclear singlet state of parahydrogen,
(sI1zI2z - I1xI2x - I1yI2y) and transferring this polarization
into a reaction product in low field under conditions where the
magnetic equivalence of the two metal hydrides, and hence
symmetry restrictions for spin-state interconversion, are re-
moved.19 In the template, the ensuing proton chemical shift
differences begin to match the frequencies associated with the
field invariant scalar coupling framework. In other words, the
resulting spin system, under these conditions, evolves to share
-23.52 (d, JPH ) 24.3 Hz). Upon repeating this procedure with
100% 15N-labeled pyridine, the hydride signal exhibits an extra
splitting of 20.4 Hz and is now strongly polarized through its
formation from parahydrogen (Figure 1) and the generation of
an [AX]2 spin system (neglecting 31P). It is the production of
magnetic inequivalence that leads to polarization with the 20.4
Hz splitting corresponding to |JNH(cis) + JNH(trans)|.22 Ad-
ditionally, the 31P resonance for 2 exhibits a trans 15N splitting
of 43.2 Hz under these conditions. When a 20% 15N, 80% 14
N
mixture of pyridine is employed, polarized hydride resonances
for the dihydride complex 2 are seen for the ABX spin system
isomer (neglecting 31P, hydride trans to 15N) [Ir(PCy3)(15N-
py)(14N-py)2(H)2]BF4] and through simulation we estimate that
JNH(trans) is of the order of |20.9| Hz while JNH(cis) is
approximately |0.5| Hz.23 The behavior of the δ -23.52 signal
(12) Blazina, D.; Duckett, S. B.; Halstead, T. K.; Kozak, C. M.; Taylor,
R. J. K.; Anwar, M. S.; Jones, J. A.; Carteret, H. A. Magn. Reson.
Chem. 2005, 43 (3), 200–208.
(13) Goldman, M.; Johannesson, H.; Axelsson, O.; Karlsson, M. Compt.
Rend. Chim. 2006, 9 (3-4), 357–363.
(14) Kuhn, L. T.; Bargon, J. In Situ NMR Methods Catal. 2007, 276, 25–
68.
(15) Chekmenev, E. Y.; Hovener, J.; Norton, V. A.; Harris, K.; Batchelder,
L. S.; Bhattacharya, P.; Ross, B. D.; Weitekamp, D. P. J. Am. Chem.
Soc. 2008, 130 (13), 4212–4213.
(20) Atkinson, K. D.; Cowley, M. J.; Duckett, S. B.; Elliott, P. I. P.; Green,
G. G. R.; Lopez-Serrano, J.; Khazal, I. G.; Whitwood, A. C. Inorg.
Chem. 2009, 48 (2), 663–670.
(16) Bouchard, L. S.; Burt, S. R.; Anwar, M. S.; Kovtunov, K. V.; Koptyug,
I. V.; Pines, A. Science 2008, 319 (5862), 442–445.
(17) Hovener, J. B.; Chekmenev, E. Y.; Harris, K. C.; Perman, W. H.;
Tran, T. T.; Ross, B. D.; Bhattacharya, P. Magn. Reson. Mater. Phys.
Biol. Med. 2009, 22 (2), 123–134.
(21) Adams, R. W.; Aguilar, J. A.; Atkinson, K. D.; Cowley, M. J.; Duckett,
S. B.; Green, G. G. R.; Khazal, I. G.; Lo´pez-Serrano, J.; Williamson,
D. C. Science 2009, (323), 1708–1711.
(22) Messerle, B. A.; Sleigh, C. J.; Partridge, M. G.; Duckett, S. B. Dalton
Trans. 1999, 1429–1435.
(18) Pravica, M. G.; Weitekamp, D. P. Chem. Phys. Let. 1988, 145 (4),
255–258.
(23) gNMR V5 Adept Scientific plc.
(19) Natterer, J.; Bargon, J. Prog. Nucl. Magnet Res. Spectrosc. 1997, 31,
293–315.
(24) Boehm, E. A.; Radda, G. K.; Tomlin, H.; Clark, J. F. Biochim. Biophys.
Acta, Bioenerg. 1996, 1274 (3), 119–128.
9
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A R T I C L E S
Atkinson et al.
Table 1. NMR Data for 2 in CD3OD at 300 Ka
1H./δ
31P/δ
13Cb/δ
15Nc/δ
-23.52 (d, 2JPH ) 24.3 Hz, 2H, Ir-H)d
8.93 (d, br, J ) 4.42 Hz, 4 H, trans-Py, ortho)
8.61 (s, br, 2 H, cis-Py o)
7.99 (t, J ) 7.2 Hz, 2 H, trans-Py, para)
7.89 (m, cis-Py, p)
13.1 (JP N(trans) ) 43.2 Hz)
155.1 (trans-Py, o)
155.0 (cis-Py, o)
137.4 (trans-Py, p)
137.4 (cis-Py, p)
126.2 (trans-Py, m)
125.8 (cis-Py, m)
-58.4 (d, 2JN-P ) 50.9 Hz, cis-Py)
-48.3 (s, trans-Py)
15
7.49 (t, J ) 6.1 Hz, 4 H, trans-Py, meta)
7.28 (t, J ) 6.1 Hz, 2 H, cis-Py, m)
a δ in ppm, J in Hz. b Assigned via 13C-1H HMQC. c Relative to 15N-pyridine ) 0 ppm, assigned from 15N-1H HMQC experiments using 2
prepared with 15N-Py. d Appearance of the hydride resonance is complicated by slow H-D exchange in methanol-d4 and broadened due to pyridine and
hydrogen exchange processes; trans-Py ) py trans to H, cis-Py ) py cis to H.
Scheme 1. Reaction of 1 with H2 and Pyridine Yields 2
in the presence of the 15N label is therefore indicative of the
formation of fac,cis-[Ir(PCy3)(py)3(H)2]BF4 (2) and NMR data
for this material can be found in Table 1. Figure 1 illustrates
two NMR spectra which are differentiated according to the
presence of 31P decoupling. In the first, only a simplified doublet
multiplicity remains since the effect of 31P is removed while in
the second, the antiphase doublet appears with a pseudo triplet
multiplicity due to cis-31P-H, and the combination of cis- and
trans-H-15N couplings for a 100% 15N-labeled sample. The
chemical changes that take place during reaction of 1 with
parahydrogen in methanol-d4 are summarized in Scheme 1.
Single crystals of 2 were grown from methanol solution, and
an X-ray diffraction analysis confirmed the formulation of the
complex. The structure reveals that the phosphine ligand and
the pyridine trans to it bend slightly away from the two in-
plane pyridine ligands which lie trans to the two hydrides such
that the P(1)sIr(1)sN(1) angle is 168.63(6)°. The two in-plane
pyridine ligands that are trans to hydride also bend away from
the bulky PCy3 ligand, with the angle P(1)sIr(1)sN(2) being
105.12(5)°. Notably, the pyridine ligands trans to hydride have
relatively long Ir-N bond distances (Ir(1)sN(2), 2.2101(19)
Å; Ir(1)sN(3), 2.216(2) Å) which agrees with the later
observation that these pyridine ligands are labile in solution.
We note that the analogous distances in [Ir(PPh3)2(py)2(H)2]BF4
are 2.177(2) Å and 2.196(2) Å and that the corresponding ligand
exchange rate is much slower at 0.4 s-1 and 335 K.20
Figure 2. ORTEP diagram of the molecular structure of the cation 2.
Thermal ellipsoids at 50%. Selected bond distances (Å) and angles (deg).
Ir(1)sP(1), 2.4249(6); Ir(1)sN(1) to N(3), 2.144(2), 2.2101(19) and
2.216(2) respectively; P(1)sIr(1)sN(1), 168.63(6); P(1)sIr(1)sN(2),
105.12(5); P(1)sIr(1)sN(3), 98.85(5); N(1)sIr(1)sN(2), 84.61(8);
N(1)sIr(1)sN(3), 85.44(7).
Spontaneous Parahydrogen Polarization Transfer to the
1H Signals of Free Pyridine. The most noticeable features of
the NMR spectra of 2 in the presence of excess pyridine are
seen when the sample is first observed after the reaction with
parahydrogen takes place in a magnetic field of 0.5 × 10-4
T
(the earth’s magnetic field) outside the 9.4 T NMR magnet. This
observation is illustrated in Figure 3 which shows two single
1
scan H NMR spectra that only differ in the time of their
observation. Trace (a) corresponds to the situation after the
sample has been in the magnet for 10 min while trace (b) was
obtained immediately after the reaction and its introduction into
the spectrometer. In this trace, large signal enhancements are
observed for the three proton sites of free pyridine at δ 8.56,
7.88, and 7.46 the first two of which are in emission and the
latter absorption. Similar effects are seen regardless of whether
the pyridine is specifically 15N-labeled or not.
1
Figure 3. (a) Single scan H NMR spectrum of the aromatic region of a
sample of 2 showing resonances for free pyridine that were obtained prior
to polarization, (b) 1H NMR spectrum recorded immediately after polariza-
tion in a 0.5 × 10-4 T field revealing the newly enhanced hydrogen atom
signals for free pyridine.
read pulse is employed. This demonstrates that the observed
proton polarization at pyridine is not generated by a process
that occurs while the sample is in the high magnetic field
These enhanced signals persist for a few scans with low tip
angle pulses but can be seen optimally only once when a 90°
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Parahydrogen Derived Spin Order to Pyridine
A R T I C L E S
environment of the observation magnet but instead is generated
during the period when the sample is in the lower 0.5 × 10-4
T field. This effect can be observed again if the sample is
removed, shaken to dissolve fresh parahydrogen in solution for
a period of five seconds, and then reinterrogated.
In addition to the enhanced signals for free pyridine, smaller
signals at δ 8.93 and 7.99 corresponding to the ortho- and para-
protons positions of the pyridine ligands in 2 that are trans to
hydride in 2 also show this effect. It would therefore seem that
the transfer of parahydrogen induced polarization into the free
pyridine proton resonances is mediated by 2 and the prerequisite
ligand exchange; repeating this process without the metal
complex results in no pyridine signal enhancement.
Mechanism of Polarization Transfer. Evidence that the
aforementioned NMR polarization does not build up when such
a process occurs within the 9.4 T magnetic field of the
spectrometer was indicated first by the fact the polarized
magnetization can only be read effectively by a single 90 degree
pulse, with a second scan resulting in substantially less visible
magnetization. To further confirm this point, a fresh sample was
prepared at -78 °C before being shaken to dissolve the
parahydrogen and immediately transferred into the spectrometer
1
at 330 K. A series of single acquisition H NMR spectra were
then recorded. In the first of these spectra, no hydride signals
were observed nor any polarization seen in the proton signals
for pyridine. In the second and subsequent spectra, as the sample
had warmed and hence reacted, the hydride signals of 2 are
observed to increase in intensity before reaching a steady state.
At no point are signal enhancements observed for the free
pyridine resonances as described earlier. When this sample was
removed, shaken to ensure the solution contains fresh parahy-
Figure 4. (a) 1H EXSY NMR trace for the situation where the δ 8.91
signal of 2 was selected which reveals exchange into the free pyridine signal
at δ 8.56, (b) plot of the change in peak intensities (percentage) for the
pyridine trans to hydride (9), free pyridine (b), and bound pyridine trans
to phosphine (2) at 313 K as a function of the exchange or reaction time.
polarization arises from the spontaneous and sequential transfer
of polarization from the parahydrogen derived hydride ligands
of 2 in low magnetic field. Exchange of bound and free pyridine
would then be necessary to build up a concentration of free
pyridine that is polarized.
1
drogen, and immediately reintroduced, the resultant H NMR
spectrum now shows enhanced proton signals for pyridine.
Furthermore, when this sample is removed, recooled to -78
°C, and reexamined, no pyridine signal enhancements are seen.
These data confirm therefore the need for a low magnetic field
step in the life of the sample to facilitate the polarization transfer
step and the need for a reaction that is kinetically significant
on the NMR time scale.
Pyridine Ligand Exchange by 2. A series of 1H EXSY
experiments were recorded in order to establish whether 2
undergoes pyridine exchange on the necessary time scale. When
the ligated pyridine signal at δ 8.93, due the pyridine trans to
hydride, was selected magnetization transfer into the corre-
sponding position of free pyridine at δ 8.56 was observed with
limited exchange into the signal for the unique pyridine ligand
of 2 at δ 8.61 also being seen. Representative data obtained via
these studies are presented in Figure 4 which shows how the
location of the magnetization varies with reaction time. The
extraction of variable temperature based kinetic data allowed
activation parameters of ∆Hq ) 97.4 ( 9 kJ mol-1 and ∆Sq )
84 ( 31 J K-1 mol-1 to be determined for pyridine dissociation
in 2 from the site trans to hydride. The associated rate constant
is 0.45 s-1 at 295 K and hence consistent with the ligand based
exchange hypothesis.
Effect of the Ratio of 1 to Pyridine on the Extent of
Polarization Transfer in a 0.5 × 10-4 T Magnetic Field. A series
of samples were prepared that contained 1 and pyridine
(concentration always 103 milli-molar) in methanol-d4. The ratio
of 1 to pyridine was varied from 1:1000 to 1:5, beyond which
the catalyst precipitated from solution. These samples were then
filled with parahydrogen and warmed to 318 K before being
shaken for approximately 5 s in the earth’s magnetic field. After
this point, following a 5 s delay for sample insertion, 1H NMR
spectra were recorded to assess the degree of signal enhancement
shown by the three pyridine proton sites. These data are
illustrated pictorially in Figure 5 and reveal that the degree of
To rule out the possibility that the 1H NMR signals of pyridine
were being enhanced by the iridium catalyzed incorporation of
parahydrogen through a CH bond activation pathway, a series
of control experiments were performed.25 In the first of these
experiments, 1 was reacted with parahydrogen and d5-pyridine
in methanol and the formation of d15-2 was found to take place
as expected. Under these conditions, however, the intensity of
1
1
the enhanced H NMR signals that result from the residual H
label in the d5-pyridine were very small. We further note that
2H-labeling studies, in conjunction with GC-MS analysis, failed
2
1
to detect any H incorporation into the H-pyridine substrate
either on the time scale of polarization buildup or over a further
24 h period.
It has been shown by others that when unsaturated substrates
are hydrogenated by parahydrogen under low magnetic field
conditions, spontaneous sharing of the polarization with directly
coupled heteronuclei such as 13C that are located within the
hydrogenation product results.14 In the results discussed here,
however, the polarized substrate is actually chemically identical
to that which is present at the start, and the hydride ligands do
not visibly couple to all of the sites within 2 where polarization
is observed. Nonetheless, we conclude that the observed
(25) Crabtree, R. Acc. Chem. Res. 1979, 12 (9), 331–338.
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J. AM. CHEM. SOC. VOL. 131, NO. 37, 2009 13365

A R T I C L E S
Atkinson et al.
1
Table 2. Effect of Temperature and Polarization Field on the H
and 13C Magnetization Observed at the ortho, para and meta Sites
of Pyridine
polarization
temperature relative enhancement
pyridine 1H signals
pyridine 13C1 signals
relative amplitudes
(ortho:meta:para)
polarization field strength
(Tesla)
(K)
level (ortho:para:meta)
0.5 × 10-4
0.5 × 10-3 to 1 × 10-2
0.5 × 10-3 to 1 × 10-2
298
353
298
353
-144:-47:+220
-84:-5:+182
-0.5:-0.44:3.22
16.8:7.5:4.4
-
0.5 × 10-4
15:5:-8
-
-6:15:43
studies establish a route to explain how the free pyridine res-
onances become polarized in turn.
Effect of the Strength of the Polarization Field on the
Free Pyridine Magnetization Profile. We prepared a series of
samples of 2 and pyridine to test how the magnetization seen
through the proton and 13C resonances of free pyridine depends
on the strength of the polarization field. The concentration of 2
in solution in these samples was 4.46 mM and a 24 fold excess
of pyridine was employed; the results are summarized in Table
2. These experimental results revealed the relative amplitudes
of the signals seen for the ortho, para and meta sites of free
pyridine were -144:-47:+220 when compared to the corre-
sponding unpolarized signals of 2:1:2; the signal enhancement
for the meta site is therefore 110.
Figure 5. Effect of the ratio of 1 to pyridine on the extent of the 1H NMR
spectral signal enhancement for the three proton sites of pyridine when
magnetization transfer is completed at 318 K in a 0.5 × 10-4 T magnetic
field.
When the spectrometer was used to record matching 13C
spectra, IzSz magnetization proved to be created at the three 13
C
sites of pyridine, as evidenced by the observation of antiphase
IxSz product terms (where S is 1H and I now 13C) in the
corresponding spectra. 13C data were then recorded after leaving
a delay of 1/2JHC between the 90 degree 13C observation pulse
and starting free induction decay storage in order to refocus
the magnetization prior to decoupling (Figure 7a). The signals
for the three ortho, para and meta 13C sites then exhibited a
polarization profile of 15:5:-8 (relative phase); the 13C signal
intensity gain for the ortho site is, however, greater than 50
fold.
Figure 6. Single scan 15N spectrum of a sample charged with 1 and 15N-
pyridine dissolved in CD3OD the two inset traces correspond to expansions
of the two polarized resonances for free pyridine (left) and the pyridine
site in 2 which is trans to hydride.
enhancement is maximized at the 1:5 loading level where the
ortho proton signal is 94 times stronger than normal when
polarization transfer is undertaken at 318 K. When the same
process is repeated for samples where the absolute concentra-
tions of 1 and pyridine are halved, the signal gain is reduced to
66 fold. We therefore conclude that there is a concentration
dependence on the efficiency of the enhancement process which
would be expected given the bimolecular nature of the H2
addition step, even if the pyridine dissociation step is dissociative
in character in accordance with the larger positive value
of ∆Sq .
These data also reveal that when the same process is
completed in a polarization field of between 0.5 × 10-3 and 1
× 10-2 T the magnetization that is created changes. (The
Spontaneous Parahydrogen Spin Order Transfer to the
13C and 15N Signals of Free Pyridine. Since we observe strong
polarization for the hydrogen atoms of free pyridine after contact
with parahydrogen in low magnetic field, we reasoned that a
similar process might be occurring at both the 13C and 15N
nuclei. A single scan 15N spectrum is illustrated in Figure 6
which confirms this to be the case. Based on S/N arguments
we have seen a 128 fold increase in signal strengths available
at 15N when compared to that obtained without the polarization
step. We discuss below how substantial polarizations are also
present at the three 13C sites of free pyridine. In both cases,
weakly enhanced signals are seen for the corresponding 13C and
15N nuclei in the pyridine ligands of 2 that are trans to hydride.
This method therefore leads to the spontaneous transfer of
polarization located in parahydrogen to magnetically active
ligand-based sites that originate in 2. The ligand exchange
Figure 7. Single scan refocused 13C1 NMR spectra of a sample comprising
of 2, parahydrogen and 5 µL of pyridine; a) sample polarized in an external
0.5 × 10-4 T field (earths field); b) sample polarized in an external field
that varied between 5 × 10-3 T and 1 × 10-2 T (i.e., in the stray field of
a 9.4 T magnet).
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Parahydrogen Derived Spin Order to Pyridine
A R T I C L E S
electron rich and most sterically demanding phosphine PCy2Ph
was the most successful in achieving polarization transfer to
the hydrogen atoms in pyridine. It can also be seen from the
data, that the single para-proton consistently shows the largest
signal gain with the resultant intensities for the PCy2Ph system
be close to 1:1:1 and can therefore be integrated.
Experimental Section
NMR measurements were made on a Bruker Avance III series
400 MHz NMR spectrometer (1H at 400.13 MHz, 31P at 161 MHz,
15N at 40 MHz). NMR samples were made up in 5 mm Young’s
tapped NMR tubes. Typical samples contained 2 mg of the iridium
complex dissolved in CD3OD (600 µL) with the pyridine being
added by microsyringe. Samples were degassed at -78 °C and then
pressurized with 3.5 bar p-H2 before appropriate NMR measure-
ments were recorded. p-H2 was prepared by cooling the gas to 20
K over activated charcoal as described previously.27
X-ray data were obtained for a crystal of 2 at 110 K using a
Bruker Smart Apex diffractometer with Mo KR radiation (ν )
0.71073 Å) in conjunction with a SMART CCD camera. Diffrac-
tometer control, data collection and initial unit cell determination
was performed using “SMART” (v5.625 Bruker-AXS). Frame
integration and unit-cell refinement software was carried out with
the “SAINT+” (v6.22, Bruker AXS) package. Absorption correc-
tions were applied by SADABS (v2.03, Sheldrick). The structure
was solved via a Patterson map using ShelXS (Sheldrick, 1997)
and refined using ShelXL (Sheldrick, 1997). Crystals were grown
from a methanol solution of 1 which contained H2 and pyridine.
Syntheses: Tri(cyclohexyl)phosphine was secured from Aldrich,
pyridine (Aldrich) and 15N-pyridine (Cambridge Isotopes) were used
as supplied and stored under N2. [Ir(COD)(PCy3)py]BF4 (1) and
[Ir(COD)(py)2]BF4 (3) were prepared by literature methods.28,25
The remaining phosphines were sourced from STREM.
Figure 8. Plot of the relative absolute signals strengths for the three pyridine
proton sites (relative to signals for free pyridine at equilibrium). Results
represent an average of five measurements, each recorded immediately after
shaking the NMR tube in a 0.5 × 10-4 T field (these methanol-d4 based
samples contained [Ir(COD)(py)2]BF4, one equivalent of PR3 and pyridine).
indicated variation in polarization field simply reflects the fact
that we are shaking the sample in the stray field of the main
NMR magnet and consequently the sample experiences a
varying magnetic field during this process.) Under these
conditions, the 1H sites magnetization amplitudes is dramatically
reduced and hence so is the efficiency of polarization transfer.
In contrast, the efficiency of polarization transfer to 13C increases
as shown in Figure 7b. We also note, that no magnetization
transfer is observed when the polarizing field strength exceeds
1 T. These data therefore confirm that the user must be wary of
the effects of both the polarization field and the associated
temperature on the strength of the NMR signals that can be
observed later. We interpret these effects to relate both to the
lifetime of the complex and the interplay between the chemical
shift difference of these resonances and the spin-spin couplings
that connect them while bound to the template. Such effects
are expected and have been rationalized for hydrogenation
products previously.26
Conclusions
We have illustrated here an alternative method for the
generation of non-Boltzmann spin state populations in organic
substrates by utilizing parahydrogen as a polarization reservoir.
Unlike previous approaches, it does not involve a formal
hydrogenation reaction. Instead, the substrate and parahydrogen
are brought into temporary association through a transition metal
complex. Spontaneous sharing of spin polarization occurs from
the hydride ligands of this template to the substrate over seconds
while they are located in a low magnetic field regime. Ligand
exchange then results in the free and chemically unmodified
substrate achieving a non-Boltzmann spin state population for
its NMR active nuclei. This route has been shown to lead to
Effect of the Phosphine’s Identity on the Iridium
Template’s Ability to Polarize Pyridine. Others have shown,
that related complexes [Ir(COD)(PR3)(py)]BF4 can be prepared
in situ by the simple addition of the appropriate phosphine to a
solution of [Ir(COD)(py)2]BF4 (3).25 This complex therefore
serves as an ideal precursor for the screening of the phosphines
influence on this process by the collection of comparative data.
A series of samples, containing equimolar amounts of 3 and a
phosphine from the list PCy3, PPhCy2, PPh2Cy, PEt3, PiPr3,
PnBu3, PtBu3 and P(1-naphthyl)3 were therefore prepared. Figure
8 reveals how the signal enhancements for the three free pyridine
resonances (quoted relative to the intensity of the same sites
pyridine signal recorded under equilibrium conditions) change
with phosphine for polarization transfer in an external magnetic
field of strength 0.5 × 10-4 T. On this basis, we conclude that
the identity of the phosphine has a dramatic effect on the
efficiency of polarization, presumably as a consequence of
changing the ligand exchange rates. We further note that the
1
magnetization transfer to H, 13C and 15N nuclei by reference
to pyridine with the resultant magnetization profile that is created
being critically dependent on the strength of the magnetic field
the sample is in during the polarization transfer step. When
samples of polarized pyridine were interrogated by NMR
1
spectroscopy, the observed H signal strengths were found to
exceed those normally available by up to 110 fold. Such signal
improvements are of great significance since the signal-to-noise
ratio varies with the square of the number of observations. In
the case of one 13C measurement, the 116 fold signal gain
requires a 13450 scan average to match the signal-to-noise ratios
when normal magnetization is employed. If there is a 15 s delay
between measurements, 56 h of spectrometer time would be
(27) Blazina, D.; Duckett, S. B.; Dunne, J. P.; Godard, C. Dalton Trans.
2004, (17), 2601–2609.
(28) Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Organomet. Chem. 1977,
141 (2), 205–215.
(26) Ivanov, K. L.; Yurkovskaya, A. V.; Vieth, H. M. J. Chem. Phys. 2008,
128, 154701.
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J. AM. CHEM. SOC. VOL. 131, NO. 37, 2009 13367

A R T I C L E S
Atkinson et al.
Acknowledgment. We thank the University of York, a York
based White Rose Healthcare Innovation Programme, the EPSRC,
and Bruker Bio-Spin for contributing to the funding of this work.
Other financial support from the Spanish MEC (Project Consolider
ORFEO (CSD 2007-00006)) and the MRC (KDA) are also
acknowledged. We are grateful to staff at Bruker BioSpin, M.
Mortimer, K. Armour, R. Adams, J. Aguilar, I. Khazal, R. Green
and D. Williamson for helpful discussions.
needed to achieve this rather than the 3 s necessary for the
polarized measurement.
This simple method of achieving magnetic polarization has
clear advantages over earlier approaches with parahydrogen
since there is no longer a need to incorporate parahydrogen
derived nuclei into the product. Consequently, the nuclear
polarization of materials is now possible where no dehydro-
analogues of the substrate are available. Thus, the method
presented here has the potential to polarize a range of substrates
that are not amenable to polarization by the more traditional
hydrogenative route, and we believe there is clear potential for
utilization of this approach in both routine high-resolution NMR
experiments and medical imaging applications.
Supporting Information Available: X-ray data, sample prepa-
ration and signal enhancement methods. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA903601P
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13368 J. AM. CHEM. SOC. VOL. 131, NO. 37, 2009