Hyperpolarization of Pyridyl Fentalogues by Signal Amplification By Reversible Exchange (SABRE)

Article abstract of DOI:10.1002/open.201900273

Fentanyl, also known as ‘jackpot’, is a synthetic opiate that is 50–100 times more potent than morphine. Clandestine laboratories produce analogues of fentanyl, known as fentalogues to circumvent legislation regarding its production. Three pyridyl fentalogues were synthesized and then hyperpolarized by signal amplification by reversible exchange (SABRE) to appraise the forensic potential of the technique. A maximum enhancement of -168-fold at 1.4 T was recorded for the ortho pyridyl ¹H nuclei. Studies of the activation parameters for the three fentalogues revealed that the ratio of ligand loss trans to hydride and hydride loss in the complex [Ir(IMes)(L)₃(H)₂]⁺ (IMes=1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene) ranged from 0.52 to 1.83. The fentalogue possessing the ratio closest to unity produced the largest enhancement subsequent to performing SABRE at earth's magnetic field. It was possible to hyperpolarize a pyridyl fentalogue selectively from a matrix that consisted largely of heroin (97 : 3 heroin:fentalogue) to validate the use of SABRE as a forensic tool.

Full text of DOI:10.1002/open.201900273

DOI: 10.1002/open.201900273
Full Papers
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Hyperpolarization of Pyridyl Fentalogues by Signal
Amplification By Reversible Exchange (SABRE)
Thomas B. R. Robertson,[a] Lysbeth H. Antonides,[a, d] Nicolas Gilbert,[a, b] Sophie L. Benjamin,[c]
Stuart K. Langley,[a] Lindsey J. Munro,[a] Oliver B. Sutcliffe,*[a, b] and Ryan E. Mewis*[a]
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Fentanyl, also known as ‘jackpot’, is a synthetic opiate that is
50–100 times more potent than morphine. Clandestine labora-
tories produce analogues of fentanyl, known as fentalogues to
circumvent legislation regarding its production. Three pyridyl
fentalogues were synthesized and then hyperpolarized by
signal amplification by reversible exchange (SABRE) to appraise
three fentalogues revealed that the ratio of ligand loss trans to
hydride and hydride loss in the complex [Ir(IMes)(L)3(H)2]+
(IMes=1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene)
ranged from 0.52 to 1.83. The fentalogue possessing the ratio
closest to unity produced the largest enhancement subsequent
to performing SABRE at earth’s magnetic field. It was possible
to hyperpolarize a pyridyl fentalogue selectively from a matrix
that consisted largely of heroin (97:3 heroin:fentalogue) to
validate the use of SABRE as a forensic tool.
the forensic potential of the technique.
A
maximum
enhancement of -168-fold at 1.4 T was recorded for the ortho
1
pyridyl H nuclei. Studies of the activation parameters for the
1. Introduction
PHIP utilises parahydrogen, a nuclear singlet, as the source
of polarization. Polarization is transferred to a molecule of
interest through a hydrogenative process resulting in chemical
change. The result of polarization transfer creates a non-
Boltzmann distribution of nuclear spins in the analyte thus
meaning that the signals are noticeably enhanced in the 1H
NMR spectrum, for example. Precursors possessing the correct
functionality, therefore, need to be prepared in order for the
polarized molecule to be produced. A now established non-
hydrogenative parahydrogen-based technique is Signal Amplifi-
cation By Reversible Exchange (SABRE).[7] As this technique is
non-hydrogenative, the analyte molecule is chemically un-
changed during the polarization process. An iridium centred
catalyst is typically employed to propagate polarisation, via J-
coupling, between the parahydrogen derived hydrides and the
Hyperpolarization techniques are regularly employed to over-
come the inherent sensitivity issue that is associated with NMR,
and by extension, MRI. The inherent insensitivity arises due to
the small population differences of the energy states that it
probes. Dynamic nuclear polarization (DNP),[1] quantum-rotor
induced polarisation,[2] spin-exchange optical pumping
(SEOP)[1c,3] and parahydrogen induced polarization (PHIP)[1b,c] are
four hyperpolarization methods that lead to improved popula-
tion differences. Thus, these methods are extensively used for
the analysis and detection of metabolites or pharmaceuticals,[4]
catalytic intermediates[5] and for medical imaging purposes.[6]
spin-1= nuclei of the analyte molecule being polarised.[8] The
[a] T. B. R. Robertson, L. H. Antonides, N. Gilbert, Dr. S. K. Langley,
Dr. L. J. Munro, Dr. O. B. Sutcliffe, Dr. R. E. Mewis
Department of Natural Sciences
2
pre-catalyst,
[Ir(IMes)(COD)Cl]
(IMes=1,3-bis(2,4,6-trimeth-
ylphenyl)imidazole-2-ylidene, COD=cyclooctadiene) has been
shown to be an excellent catalyst, following activation, in this
regard for a number of substrates such as nicotinamide,[9]
quinazoline,[10] and niacin.[11] Manipulation of the spin-reservoir
of the substrate, such as deuteration, has been shown to be an
effective route by which polarization can be maximized. This
has been exemplified for methyl-4,6-d2-nicotinate which was
polarized to a level of 50%.[12]
Fentanyl (1, Figure 1), is regarded as a synthetic opiate,
despite the chemical structure differing significantly from
morphine, codeine and heroin (2a–2c), which are natural
opiates. 1 exhibits a strong affinity towards the μ-opioid
receptor, which is found across the central and peripheral
nervous system as well as the intestinal tract and thus acts in a
similar way to 2a–2c. Activation of the μ-opioid receptor leads
to analgesia and euphoria, but also physical dependence,
constipation and respiratory depression,[13] which can lead to
death in the case of an overdose.
Manchester Metropolitan University
John Dalton Building, Chester St., Manchester, M1 5GD, UK
E-mail: r.mewis@mmu.ac.uk
o.sutcliffe@mmu.ac.uk
[b] N. Gilbert, Dr. O. B. Sutcliffe
MANchester DRug Analysis and Knowledge Exchange (MANDRAKE)
Manchester Metropolitan University
John Dalton Building, Chester St., Manchester, M1 5GD, UK
E-mail: o.sutcliffe@mmu.ac.uk
[c] Dr. S. L. Benjamin
School of Science and Technology
Nottingham Trent University
Nottingham, NG11 8NS, UK
[d] L. H. Antonides
Leverhulme Research Centre for Forensic Science
University of Dundee
Dundee, DD1 5EH, UK
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/open.201900273
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macroelectrodes for amperometric detection has been devel-
oped for the simultaneous detection of 1, 2c and ten
fentalogues.[26] Furthermore, low-field (62 MHz) NMR spectro-
scopy has been used to differentiate 65 fentalogues in
conjunction with quantum mechanical spin system analysis of
spectra acquired at a frequency of 600 MHz to produce
comparison spectra.[27] Low-field NMR was selected in this
instance due to the cost saving attributes it possesses (smaller
footprint, no need for cryogens, cheaper instrument cost) over
high field instrumentation.
Given the low-threshold for overdose, we sought to employ
an NMR-based methodology for detecting fentanyl or its
pyridyl-analogues (5, 7 and 10), which are synthesized as part
of this work. Furthermore, we sought to demonstrate that a
fentalogue can be readily detected despite being in a matrix
consisting of largely of 2c (97% w/w). In order to detect the
fentalogue present in a single scan, thus avoiding the need for
extensive instrument time, whilst also overcoming the inherent
insensitivity associated with NMR, SABRE was employed to
significantly enhance the signal intensity observed for the
analogue of interest.
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Figure 1. Chemical structures of common opiates.
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1 attained widespread medical use due to its very strong
and fast action, estimated at around 50–100 times stronger
than 2a.[14] Because of its euphoria-inducing effects, resembling
those of 2c, fentanyl has been used recreationally and is often
referred to as ‘jackpot’. This poses a serious threat for public
health, as minute quantities of 1 (around 2 mg) can be enough
to induce overdose.[15] This problem has been exacerbated as
some heroin samples are contaminated with 1, unbeknown to
the end user[16] and as such, techniques have been developed
for its detection.[17] Illicit sources of 1 are obtained by diversion
of pharmaceutical supplies and via clandestine production.[18]
The first large outbreak of deaths happened in California 2. Results and Discussion
between 1979 and 1988, where 112 deaths were related to α-
methylfentanyl abuse, and frequent incidents have been
reported since then. From 2013 onward, however, abuse of 1
has grown significantly in the US, eventually reaching epidemic
levels.[19] Recently, in 2016, 63,632 people died in the USA from
a drug overdose, which is a 21% increase from the previous
year.[20] This was largely attributed to a rise in deaths associated
with pharmaceutical opioids, including 1 and its derivatives. In
Europe, the problem has remained entrenched in Estonia, but
cases have been observed in other countries,[18] including the
UK.[16,21] Indeed, a worrying trend is the appearance of new
fentanyl analogues, termed fentalogues, of which some are
even more potent than 1, on the international drug market
scene. Since 2009, 18 new fentalogues have been detected by
the European Monitoring Centre for Drugs and Drug Addiction
(EMCDDA), and that number keeps growing every year.[22]
A number of techniques have been employed for the
detection of fentanyl. Raman spectroscopy has been utilized in
combination with density-functional theory (DFT) towards
detection of trace samples. Surface-enhanced Raman spectro-
scopy proved to give an enhancement factor of �1.6×105,
which was endowed by proximity to silver or gold
nanoparticles.[23] Immunoassay has also been investigated as a
technique for the detection of fentalogues, but none of the
ELISA (Enzyme-Linked Immunosorbent Assay) kits evaluated
proved to have sufficient cross-reactivity towards the N-acyl
and piperidine-modified fentalogues studied.[24] LC-MS/MS
(Liquid Chromatography-Mass Spectrometry/ Mass Spectrome-
try) has been utilized to detect 24 fentanyl derivatives and
metabolites in whole blood in under 14 min screening time.[25]
As a number of fentalogues have been encountered, three
pyridyl-fentanyl analogues were also prepared to study along-
side 1 and its hydrochloride salt. Fentalogues can be easily
prepared through the replacement of the ethyl chain by
selecting the desired acyl chloride instead of propanoyl
chloride. Pyridine was one of the first compounds to be
polarized by SABRE,[7,28] due to the initial use of Crabtree’s
catalyst, [Ir(Py)(COD)PCy3]+ (Py=pyridine, PCy3 =tricyclohexyl-
phosphine), or its derivatives, as a polarization transfer catalyst.
Pyridine has been the focus of numerous studies,[29] and
therefore, the pyridyl derivative was produced (5). Given the
structural similarity of benzene and pyridine, two further
analogues of 1 were synthesized which exchanged one of the
benzene rings for pyridine (7 and 10). The addition of pyridyl
rings to a peptide chain resulted in successful polarization by
SABRE.[30] A similar approach has been used for the production
of hyperpolarizable NOS (nitric oxide synthase) substrates.[31]
An overview of the synthesis of fentanyl derivatives is
shown in Scheme 1. The synthesis of 1.HCl and 5 utilized a two-
step synthesis from 1-phenylethyl-4-piperidone (3) via the
intermediate N-[1-(2-phenylethyl)-4-piperidinyl]aniline (4, 4-
ANPP) which was synthesized according to
a procedure
reported by Valdez et al.[14] Yields for converting 4 to 1.HCl and
5 were 33 and 45% respectively.
Fentalogue 7, where the aniline group is substituted with a
N-4-pyridine moiety, was prepared from
3 via reductive
amination using 4-aminopyridine and NaBH4 to afford the
product (6) after purification in 22% yield. This compound was
then converted to 7 by reacting it with propionic anhydride
and isolated in 75% yield. The 2-furyl and 3-furyl derivatives of
7 have been produced by Bagley et al. in yields of 74% and
43% respectively,[32] in addition to substituting the chiral
In addition,
a dual HPLC-DAD (High-Performance Liquid
Chromatography Diode-Array Detector) and HPLC-AD (Ampero-
metric Detection) protocol that uses screen-printed graphite
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piperidine have shown that the chair is the more stable
conformer, similar to cyclohexane.[34] On inspection of the
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2
3
4
5
6
7
8
9
4
piperidine ring of 1.HCl, it was found to have C1 conformation
and possessed the ring puckering parameters[35] Q=0.589 Å,
°
°
q2 =0.025 Å, q3 =0.589, �2 =À 27 and θ=2.4 which were
calculated using triangular decomposition.[36] As q3 @q2, the ring
is a slightly distorted chair; the same observation was made for
the free-base[37] and the citrate toluene solvate[38] of 1.
A search of the Cambridge Structural Database (CSD)[39]
identified 26 other compounds with structural similarity to
1.HCl. This search revealed that three further fentanyl deriva-
tives have been crystallised that differ only in the length of a
carboxylic acid chain present.[40] In all of the X-ray structures of
these compounds, the piperidine ring is always in the chair
conformation. In addition, the packing of molecules in the unit
lattice shows a similar extended planar conformation as
observed for 1.HCl.
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Scheme 1. Synthesis of fentanyl (1) and its pyridyl derivatives (5, 7 and 10).
Conditions: (a) PhNH2, NaBH(OAc)3; (b) 4-aminopyridine, NaBH4; (c) EtCOCl,
NEt3; (d) 4-pyridinecarbonylchloride, NEt3; (e) for 1.HCl only: HCl (3 M in
CPME); (f) (EtCO)2O, toluene; (g) EtCOCl / iPr2NEt, DCM; (h) TFA-DCM (2:1); (i)
4-vinylpyridine, MeO(CH2)2OH
A hydrogen bond is present in 1.HCl between N2-H2 and
Cl1 and has a length of 2.12 Å. This value, along with the value
of D··· XÀ (3.046 Å), compare well with reported mean values for
this interaction.[41] Further parameters that detail this bond are
shown in Table 1.
hydrogen of the piperidine ring with CO2CH3 and CH2OCH3
groups to study the pharmacological activity of the derivatives
synthesized.[33]
In this study, [Ir(IMes)(COD)Cl] was utilized as the SABRE
pre-catalyst. Upon exposure to an excess of 5, the complex [Ir
(IMes)(5)3(H)2]+ was formed; this complex is responsible for
Pyridylfentanyl, 10, was synthesized by simple replacement
of the phenethyl side-chain of 1 with a 4-pyridylethyl moiety.
We hypothesized that inserting the pyridine ring further away
from the bulk of the molecule, when compared with 5 and 7,
would result in a more efficient ligation (due to reducing steric
interactions at the binding site) onto the iridium catalyst used
in SABRE, leading to a greater signal enhancement. 10 was thus
prepared in two steps from the BOC-protected precursor, 8, in
59% yield. To ensure authenticity of the materials utilized in
this study the synthesized materials were structurally charac-
terized (see Supplementary Information) by NMR, FTIR and GC-
EI-MS.
Slow evaporation of an acetone solution of 1.HCl led to
crystals suitable for X-ray crystallographic analysis. The salt
crystalizes in the monoclinic space group Cc; the Ortep diagram
of 1.HCl is shown in Figure 2. The asymmetric unit contains the
entire compound and a chloride counterion. The molecule
crystallises in an extended and relatively planar conformation
with only the N-phenyl ring deviating.
1
polarization transfer by SABRE, which is detailed later. The H
NMR spectrum of this complex possesses a main hydride signal
at À 23.17 ppm, which is indicative of chemically equivalent
hydride ligands. Two smaller hydrides are also seen at À 23.52
and À 25.56 ppm; these are due to inequivalent hydrides in [Ir
(IMes)(5)2(MeOH)(H)2]+. Relative integrals of the hydride signals
present indicate that the hydride signal for [Ir(IMes)(5)3(H)2]+
dominates as they are present in a ratio of 98:2 compared to
the hydride signals for [Ir(IMes)(5)2(MeOH)(H)2]+. A similar
observation has been made when pyridine is the analyte in that
[Ir(IMes)(Py)2(MeOH)(H)2]+ was detected.[29f] Due to the relative
size of the signals for [Ir(IMes)(5)2(MeOH)(H)2]+ compared to [Ir
(IMes)(5)3(H)2]+, characterization of the former complex was
impractical. Of the three fentanyl ligands in [Ir(IMes)(5)3(H)2]+,
two are trans to hydride whereas the remaining ligand is trans
to IMes. Due to the overlapping nature of the backbone of 5 for
the free and the two bound forms, NMR-based studies focused
largely on the pyridyl resonances which were sufficiently
resolved for structural characterization of the complexes. The
ortho proton signal of the pyridine ring of 5 trans to hydride is
observed at δ 7.69 whereas the meta proton signal is at δ 6.75.
The same signals for 5 trans to IMes are observed at δ 7.25 and
6.53 respectively. Using exchange spectroscopy (EXSY), the loss
of hydride from [Ir(IMes)(5)3(H)2]+ proved to be 5.6 sÀ 1 at 300 K.
This contrasts to 9 sÀ 1 when [Ir(IMes)(Py)3(H)2]+ was probed
under the same conditions.[29e] The loss of hydride is, therefore,
The piperidine ring present is in the chair conformation.
Conformational pathway analysis of the chair and boat forms of
°
Table 1. Hydrogen-bond geometry (Å, ) for 1.HCl.
DÀ H···XÀ
DÀ H
H·· XÀ
D·· XÀ
DÀ H·· XÀ
Figure 2. Ortep diagram of 1.HCl with all atoms shown. The thermal
ellipsoids for all non-H atoms are shown at the 50% level.
N2À H2···Cl1
0.93
2.12
3.046 (2)
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Table 2. Thermodynamic activation parameters and exchange rates of the complexes [Ir(IMes)(L)3(H)2]+ where L=5, 7, 10 or Py.
1
2
5
7
10
Pya
3
4
5
6
7
8
9
Hydride loss
ΔG300/kJmolÀ 1
ΔH/kJmolÀ 1
67.6�0.07
75.8�1.4
27.4�5.0
67.4�0.07
69.6�1.2
7.44�4.3
5.6
69.4�0.16
75.7�4.8
21.0�16.4
67.4�0.05
69.7�0.6
7.73�2.2
3.0
66.9�0.06
85.1�1.5
60.5�5.0
68.4�0.11
79.4�2.4
36.6�8.2
6.8
66.4�0.3
79 �1
41�3
64�2
93�3
97�9
9
ΔS/J molÀ 1 KÀ 1
ΔG300/kJmolÀ 1
ΔH/kJmolÀ 1
Loss of ligand trans to hydride
ΔS/J molÀ 1 KÀ 1
Loss of hydride at 300 K/sÀ 1
Loss of ligand at 300 K/sÀ 1
5.4
5.5
3.5
11.7
[a] Data taken from reference 29e.
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significantly slower in [Ir(IMes)(5)3(H)2]+ compared to [Ir(IMes)
(Py)3(H)2]+. An Eyring-Polanyi plot of hydride loss produced
values for ΔG (300 K), ΔH and ΔS of 67.6�0.07 kJmolÀ 1, 75.8�
1.4 kJmolÀ 1 and 27.4�5.0 JmolÀ 1 KÀ 1 respectively. The value of
ΔH suggests that the IrÀ H bond is relatively strong and
contrasts well to the same bond in [Ir(IMes)(Py)3(H)2]+ (79�
1 kJmolÀ 1).
investigated. In addition, loss of 10 results in the biggest gain in
entropy of all the fentalogues studied. This suggests that [Ir
(IMes)(10)3(H)2]+ is the most energetically stable of the com-
plexes investigated. Furthermore, the loss of hydride at 300 K
from [Ir(IMes)(10)3(H)2]+ is the quickest of all the fentalogues
investigated herein. It is noteworthy that the loss of 10 from [Ir
(IMes)(10)3(H)2]+ occurs much slower than hydride loss, which,
although unusual, has been reported for [Ir(SiPr)(Py)3(H)2]+.[29f]
Extension of this comparison to also consider the same values
for the rate of loss of either hydride or pyridine from [Ir(IMes)
(Py)3(H)2]+ revealed that loss of hydride from [Ir(IMes)(10)3(H)2]+
most closely resembled that of the former, whilst the loss of
either 5 or 7 from [Ir(IMes)(L)3(H)2]+ are similar to the value for
the latter. As part of our study, we wanted to probe the effect
of these exchange parameters on the extent of polarization
transfer via SABRE by obtaining 1H NMR hyperpolarized spectra.
Initial hyperpolarization studies were directed towards the
hyperpolarization of 1 and 1.HCl by SABRE. However, the lack of
suitable ligation groups/atoms to the SABRE catalyst meant that
conventional SABRE could not be employed, although it was
attempted to validate the change in approach (no
enhancement observed). Instead a combined SABRE-Relay[11]
CASH (catalyst separated hyperpolarization)-SABRE[42] approach
was utilized (see SI for details). However, this approach failed to
yield any detectable signal enhancement for either analyte
following polarization transfer in earth’s magnetic field and
subsequent detection in a 1.4 T field. This was again, perhaps,
expected, given that polarization of amines by SABRE-Relay has
only been exemplified for primary and secondary amines.[11,43]
To the best of our knowledge, polarization of tertiary amines
has not been reported. Focus therefore moved to the fentanyl
derivatives bearing pyridyl motifs (5, 7 and 10).
The loss of 5 from [Ir(IMes)(5)3(H)2]+ was also studied using
EXSY. For this process, the rate of loss of 5 was found to be
5.4 sÀ 1 at 300 K. Similar to the hydride loss rate, this process was
again much slower than pyridine in the analogous complex [Ir
(IMes)(Py)3(H)2]+ (11.7 sÀ 1). ΔG (300 K), ΔH and ΔS proved to be
67.4�0.07 kJmolÀ 1, 69.6�1.2 kJmolÀ 1 and 7.44�4.3 JmolÀ 1 KÀ 1
respectively for this process. Compared with [Ir(IMes)(Py)3(H)2]+,
the IrÀ N bond in [Ir(IMes)(5)3(H)2]+ is much weaker and also
there is far less entropic gain from reaching the transition state.
7 and 10 were treated similarly to 5. The complexes formed
were analogous to those formed for 5. Hydride resonances
were observed at À 22.70 and À 22.83 ppm for [Ir(IMes)(7)3(H)2]+
and [Ir(IMes)(10)3(H)2]+ respectively. Only a single hydride was
observed in both cases. The hydride and loss of fentanyl ligand
trans to hydride from the two complexes are shown in table 2.
Derivatives 5 and 7 result in very similar exchange rates for the
loss of ligand, whilst hydride loss is quicker for 5 than 7 at
300 K. The thermodynamic activation parameters for both 5
and 7 show significant similarity, despite the pyridine ring
involved in binding being bound through either the amide
nitrogen or the CO of the same amide.
When 10 is considered, relative to 5 and 7, we note that the
loss of 10 trans to hydride from [Ir(IMes)(10)3(H)2]+ requires a
considerable amount of energy, as reflected in the ΔH value
(79.4�2.4 kJmolÀ 1). The value of ΔH is ~10 kJmolÀ 1 higher
than the respective values for 5 and 7, implying that the IrÀ N
bond in [Ir(IMes)(10)3(H)2]+ is the strongest of the fentalogues
The incorporation of pyridyl rings in to the fentanyl
structure means that they are candidates for conventional
SABRE. To facilitate polarization transfer from parahydrogen
derived hydrides to the pyridyl fentanyl derivatives, the pre-
catalyst [Ir(IMes)(COD)Cl] was employed. Studies were con-
ducted using one equivalent of [Ir(IMes)(COD)Cl] to four
equivalents of fentanyl derivative (5, 7 and 10) in their free-base
forms.
5 was successfully polarized by SABRE following polarization
transfer at earth’s magnetic field (Figure 3). The ortho- and
meta-1H NMR signal of the pyridyl ring are observed as emission
and absorption signals respectively (indicated as α and β
Table 3. 1H NMR signal enhancements for the ortho pyridyl protons of 5, 7
or 10 (L) hyperpolarised using [Ir(IMes)(COD)Cl] (ratio of L:Ir(IMes)(COD)Cl]
is 4:1)
Enhancement value obtained after transfer of
polarization in the field indicated
Fentanyl derivative (L) Earth’s magnetic field
6.5 mT
5
7
10
À 168
À 38
À 50
À 79
À 2
À 14
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7 was also polarized by SABRE following polarization
transfer at earth’s magnetic field. The ortho- and meta-1H NMR
signal of the pyridyl ring are again observed as emission and
absorption signals respectively. In comparison to 5, the
1
2
3
4
5
6
7
8
9
1
enhancement observed was far lower (40-fold for both H NMR
sites of the pyridyl ring). The reductive elimination of hydride in
[Ir(IMes)(7)2(H)2]+ may result in slower polarization reservoir
replenishment, thus leading to
enhancement.
a
smaller observed
Hyperpolarization of 10 by SABRE produced 1H NMR spectra
that mirrored that of 5 and 7. The ortho-pyridyl protons of 10
were enhanced by 50-fold. Unlike, 5 and 7, it is not just the
pyridyl ring protons that were hyperpolarized. The ethylene
chain that connects the pyridine ring to that of the piperidine
ring also show a small enhancement (small emissive peak at
2.65 ppm, see SI). 4-picoline, an analyte that is structurally
similar to that of the ethylpyridine moiety has been inves-
10
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Figure 3. 1H NMR spectra of 5 and [Ir(IMes)(COD)Cl] in the ratio of 4:1 in the
presence of parahydrogen in CD3OD. Spectrum 1 is the thermal spectrum
whereas spectra 2 and 3 are hyperpolarized following polarization transfer in
earth’s magnetic field or at 6.5 mT respectively. Multiplication factors
indicate scaling of the vertical axis. Spectra collected at 60 MHz. α and β
refer to the ortho- and meta-pyridyl protons respectively of 5. * indicates
bound 5 of [Ir(IMes)(5)3(H)2]+.
1
tigated using SABRE, but the focus was on 15N rather than H
polarization; no comment was made about the transfer to the
methyl protons.[49] Compared with the enhancement of the
ortho- and meta-pyridyl protons, the enhancement of the
ethylene protons is significantly lower.
Comparison of the enhancement data for the fentalogues 5,
7 and 10 to the thermodynamic activation parameters reported
in table 2, reveals a number of interesting observations. 5 has
the highest enhancement and the ratio of ligand loss trans to
hydride to rate of hydride loss from [Ir(IMes)(5)3(H)2]+ is 0.96.
The rates of ligand loss trans to hydride and hydride loss are
the most commensurate of the three fentalogues investigated;
the corresponding ratios for 7 and 10 are 1.83 and 0.52
respectively. This gives the order 10<5<7. Similarly, if the
fentalogues are ordered in terms of their enhancements at
earth’s magnetic field, then the order is 5>10>7. Thus, for
pyridyl fentalogues 5, 7 and 10, the more commensurate the
loss of ligand trans to hydride to loss of hydride is, the higher
the enhancement. A similar trend is observed when polarization
transfer is conducted in a magnetic field of 6.5 mT, although
the values here are more susceptible to error due to the
significant changes in magnetic field during transfer to the
magnet when contrasted to performing the same experiment
but shaking the tube in earth’s magnetic field. A �20%
variation in enhancement values has been reported for the
same sample when analyzed by different experimenters.[9b]
T1 data was also collected for 5, 7 and 10 (table 4). These
data show there is little difference in the T1s of 5, 7 and 10 at
the concentration investigated in the presence of [Ir(IMes)
(L)3(H)2]+ when L:[Ir(IMes)(L)3(H)2]+ is 1:1. It is particularly
noteworthy that in terms of the timescale of the experiment, in
that following polarization transfer in the stated field to the
application of a RF pulse inside the magnet, a whole T1 is likely
to have transpired resulting in significant loss of enhancement.
Thus, elongating the T1 of these molecules would significantly
boost signal intensity. We note that compared to pyridine, in
the presence of [Ir(IMes)(Py)3(H)2]+ these T1 values are 9 seconds
shorter, which corresponds to a reduction of 75% of the T1. The
quicker relaxation of 5, 7 and 10 is expected due to their
increased molecular size compared to pyridine. Thus, the
respectively in Figure 3). The ortho 1H NMR signal (α) is
enhanced by À 168-fold. Due to the overlap of the phenyl ring
protons with the meta-pyridyl protons (β), an enhancement for
the latter cannot be calculated accurately. When the polar-
ization transfer field was changed to 6.5 mT, the enhancement
of the ortho-pyridyl protons fell to only À 79-fold. A similar
observation was made for NOS substrates bearing 4-substituted
pyridyl-tethers.[31] The continuous re-hyperpolarization of nu-
clear spins has been explored theoretically, which has been
shown to be dependent on the lifetime of the complex, as well
as the magnetic field in which polarization is conducted.[44] The
role of level-anti-crossings in the transfer of polarization has
also been explored, and has been shown to be the most
efficient at low magnetic fields.[45] Recently, a more simplified
approach has been investigated, that takes in to account non-
linear and chemical and physical dynamics to produce a master
equation to provide insight in to the SABRE mechanism.[46]
No transfer is observed in to the piperidine ring of 5. This
was expected due to the vanishingly small size of the JHH
-
couplings between the meta-pyridyl ring protons and the
nearest piperidine ring protons.
We note here that the experiment is far from optimized.
Critically, only 50% parahydrogen is employed. By utilizing
100% parahydrogen a further factor of three could be obtained
for the enhancement values, as described by Shchepin and co-
workers.[47] Furthermore, the magnetic field for polarization
transfer was not optimized; only earth’s field and a magnetic
field of 6.5 mT were arbitrarily chosen for polarization transfer.
As polarization occurs optimally when a level anti-crossing
(LAC) condition is met,[45a,48] optimizing this parameter would
yield even better enhancement values due to more efficient
spin mixing. However, our goal was to simply demonstrate that
the pyridyl fentalogues could be hyperpolarized, via SABRE, to
obtain hyperpolarized 1H NMR spectra.
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Table 4. T1 values at 298 K for ortho and meta pyridyl 1H nuclei of free 5, 7
or 10 in the presence or absence of [Ir(IMes)(L)3(H)2]+ in d4-MeOH and
under a H2 atmosphere, vacuum or in air. The concentration of L in all
samples was 0.02 M. aPeak forms part of multiplet along with all the phenyl
proton nuclei. T1 listed is the value for all these different environments.
1
2
3
4
T1 in the
T1 (air)/s
T1 under
vacuum/s
5
6
7
presence of [Ir
(IMes)(L)3(H)2]+
and H2/ s
Fentanyl
derivative
(L)
Ortho
Meta
Ortho
1H
nuclei
Fentanyl
derivative
(L)
Ortho
1H
nuclei
Meta
1H
nuclei
8
9
1H
1H
nuclei
nuclei
10
11
12
13
14
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5
7
10
3.1
2.9
3.3
3.5
3.2a
2.1
2.6
2.0
2.3
5
7
10
3.1
2.9
3.3
3.5
3.2a
2.1
Figure 4. 1H NMR spectra of 5 and heroin (3:97) [Ir(IMes)(COD)Cl] in the ratio
of 4:1 in the presence of p-H2 in CD3OD. Spectrum 1 is the thermal spectrum
whereas spectra 2 and 3 are hyperpolarized following polarization transfer in
earth’s magnetic field, with 3 being collected subsequent to 2. Spectra
collected at 60 MHz. α and β refer to the ortho- and meta-pyridyl protons
respectively of 5. * indicates bound 5 of [Ir(IMes)(5)3(H)2]+.
enhancements reported for 5, 7 and 10 are significantly
reduced by relaxation processes. To overcome these short T1s,
other nuclei such as 15N, could be utilized, especially when
combined with a heterogeneous approach.[50] Recent studies
have shown that 15N-based polarization can be detected at
high-field via spin lock induced crossing (SLIC)-SABRE, which
has been exemplified for pyridine and nicotinamide,[51] as well
as dalfampridine, a drug which is used in the treatment of
multiple sclerosis.[52] The pyridyl nitrogen of dalfampridine was
enhanced by over 32,000-fold. Metronidazole, an antibiotic has
been polarized to a level of 15%, which persists for tens of
minutes at 1.4 T.[53] However, our focus here was to study the 1H
polarization, and lifetimes, only.
1
iridium species in solution. The meta pyridyl H NMR resonance
of free 5 also showed enhancement, but due to the overlapping
1
nature of this H NMR signal and the phenyl rings of 5 and
those of heroin, an accurate enhancement could not be
calculated.
We also wanted to test the selectivity of the SABRE catalyst
for the fentanyl derivatives described herein in the presence of 3. Conclusions
heroin, given that they have similar pharmacological actions,
yet fentanyl has a far lower LD50, and hence is more potent,
than heroin. Hyperpolarization of 2c using [Ir(IMes)(COD)Cl]
revealed no evidence for polarization transfer. This is despite 2a
having been polarized previously, albeit using the catalyst [Ir
(COD)(PCy3)(py)][PF6].[54] It is proposed that 2c did not polarize
under the conditions employed here are most likely due to
heroin lacking a suitable donor to ligate to the catalyst in order
to become hyperpolarized and / or steric hindrance preventing
This paper describes the successful synthesis of fentanyl
derivatives that possess pyridine rings (5, 7 and 10) that are
polarized by SABRE. Enhancements of À 168-fold, À 38-fold and
À 50-fold are reported for the ortho pyridyl protons of 5, 7 and
10 respectively despite the T1s of these environments being in
the region of 2.9–3.3 s, which are significantly shorter than
pyridine. The thermodynamic activation parameters of ligand
loss trans to hydride, where L=5, 7 or 10, and hydride loss
from [Ir(IMes)(L)3(H)2]+ were obtained. The ratio of rate of ligand
loss trans to hydride, to rate of hydride loss was calculated (5=
0.96, 7=1.83 and 10=0.52) and the order 10<5<7 was
established. The trend observed for the enhancement observed
at earth’s magnetic field was 5>10>7, thus highlighting that
for 5, 7 and 10, the more commensurate the loss of ligand trans
to hydride to loss of hydride is, the higher the enhancement.
SABRE was employed to hyperpolarize one of the fentanyl
derivatives, 5, which represents an easily accessible fentalogue,
based on the synthesis described herein, that could be
produced by a clandestine laboratory. A matrix that largely
consisted of heroin (ratio 97:3 heroin:5) resulted in the ortho
pyridyl protons of 5 being enhanced by 47-fold, which fell to
24-fold in subsequent polarization-based experiments. It was
not possible to polarize heroin using the pre-catalyst [Ir(IMes)
(COD)Cl] under the conditions employed herein. However, the
selective hyperpolarization of 5 showcases the potential for
SABRE as a forensic tool in order to validate the presence of
1
successful binding; no hydride signal was detected in the H
NMR spectra collected (see SI). 5 was selected as the fentalogue
to test given the number of other derivatives that have been
encountered that have been derivatized similarly by replacing
the ethyl attached to the amide for other moieties, such as
methoxyacetyl, isobutyl and isovaleryl, along with many
others.[24–26] We have also evidenced that 5 shows the most
significant enhancement by SABRE of the three fentalogues
synthesized herein. A solution consisting of 5 and heroin (ratio
3:97 w/w) were subjected to SABRE. The amount of 5 present
relative to [Ir(IMes)(COD)Cl] was 4:1. The resulting 1H NMR
spectrum (figure 4) provided evidence for 5 being polarized,
1
namely the ortho H NMR signal (indicated as α in figure 4) of
free 5 at δ 8.25. Initially, the signal enhancement was 47-fold,
but then fell to 24-fold in subsequent experiments. We note
that this is a reduction of ~100-fold compared to the sample
without heroin present, and this reduction represents the
complexity of the matrix affecting effective ligation of 5 to the
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Acknowledgements
REM is grateful to Manchester Metropolitan University for a Vice
Chancellor studentship for TBRR. The Natural Sciences and
Engineering Research Council of Canada (396154510) and Fonds
de Recherche du Québec - Nature et Technologie (206375) are
thanked for funding for NG. Oxford Instruments, especially Hetal
Patel, are thanked for their technical support.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: NMR · fentanyl · fentalogues · hyperpolarisation ·
exchange dynamics
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Manuscript received: September 9, 2019
Revised manuscript received: September 24, 2019
ChemistryOpen 2019, 8, 1–9
www.chemistryopen.org
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Full Papers
FULL PAPERS
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No more hiding for pyridyl fenta-
logues! The hyperpolarization
technique SABRE (signal amplifica-
tion by reversible exchange) is
utilised for the successful
T. B. R. Robertson, L. H. Antonides, N.
Gilbert, Dr. S. L. Benjamin, Dr. S. K.
Langley, Dr. L. J. Munro, Dr. O. B.
Sutcliffe*, Dr. R. E. Mewis*
enhancement of 1H NMR signals of
pyridyl functionalised fentalogues.
We further demonstrate the success-
ful selective polarization of one the
fentalogues against a strong back-
ground-signal of heroin.
1 – 9
Hyperpolarization of Pyridyl Fenta-
logues by Signal Amplification By
Reversible Exchange (SABRE)
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