NHC-Stabilized Iridium Nanoparticles as Catalysts in Hydrogen Isotope Exchange Reactions of Anilines

Article abstract of DOI:10.1002/anie.201914369

The preparation of N-heterocyclic carbene-stabilized iridium nanoparticles and their application in hydrogen isotope exchange reactions is reported. These air-stable and easy-to-handle iridium nanoparticles showed a unique catalytic activity, allowing selective and efficient hydrogen isotope incorporation on anilines using D₂ or T₂ as isotopic source. The usefulness of this transformation has been demonstrated by the deuterium and tritium labeling of diverse complex pharmaceuticals.

Full text of DOI:10.1002/anie.201914369

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: NHC-Stabilized Iridium Nanoparticles as Novel Catalysts in
Hydrogen Isotope Exchange Reactions of Anilines
Authors: Mégane Valero, Donia Bouzouita, Alberto Palazzolo,
Jens Atzrodt, Christophe Dugave, Simon Tricard, Sophie
Feuillastre, Grégory Pieters, Bruno Chaudret, and Volker
Derdau
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201914369
Angew. Chem. 10.1002/ange.201914369
Link to VoR: http://dx.doi.org/10.1002/anie.201914369
http://dx.doi.org/10.1002/ange.201914369

10.1002/anie.201914369
Angewandte Chemie International Edition
COMMUNICATION
NHC-Stabilized Iridium Nanoparticles as Novel Catalysts in
Hydrogen Isotope Exchange Reactions of Anilines
Mégane Valero,[a, $] Donia Bouzouita,[b,$] Alberto Palazzolo,[c,$] Jens Atzrodt,[a] Christophe Dugave,[c]
Simon Tricard,[b] Sophie Feuillastre,[c] Grégory Pieters,[c,*] Bruno Chaudret,[b,*] and Volker Derdau[a,*]
Abstract: The preparation of novel N-heterocyclic carbene-
stabilized iridium nanoparticles and their application in hydrogen
isotope exchange reactions is reported. These air-stable and easy to
handle iridium nanoparticles showed a unique catalytic activity,
allowing selective and efficient hydrogen isotope incorporation on
anilines using D2 or T2 as isotopic source. The usefulness of this
transformation has been demonstrated by the deuterium and tritium
labelling of diverse complex pharmaceuticals.
Metal nanoparticles (MNPs) possess unique physical and
chemical properties, crossing the barriers of homogeneous and
heterogeneous catalysis and paving the way to new applications
in life sciences and medicine.1 To enhance their performance in
catalysis, N-heterocyclic carbenes (NHCs) are employed as
ligands to stabilize the nanoparticles and to induce selectivity.2
These ligands were used for the preparation of Au,3 Pd,4 Ni,5
and also Ru6 nanoparticles. Recently Pieters and Chaudret et al.
demonstrated the usefulness of metal nanocatalysts (Ru) in the
context of Hydrogen Isotope Exchange (HIE),7 which is widely
known as the most fundamental of all C-H functionalization
processes.8 HIE has become the state-of-art strategy for the
incorporation of deuterium or tritium atoms into complex organic
molecules.9,10 In life sciences isotopically-labelled compounds11
are experiencing a renaissance due to the highly improved mass
spectrometry applications utilizing labelled mass spectrometry
(MS) standards12,13 and to the limitations of 14C-labeling, like high
cost and synthesis duration. In this context, we were interested
Scheme 1. Overview of the presented work
in the synthesis of new NHC-stabilized IrNPs and the study of
been successful. Regarding C(sp2)-H activation by HIE there are
their catalytic properties in HIE reactions.
still some challenges which still wait to be overcome. One of
While there have been numerous homogeneous iridium-
these examples is the labelling of anilines. Indeed, the best
catalysed-methods described in the last 40 years8,14 and some
results for unselective aniline labelling with deuterium were
HIE catalysts are commercially available, e.g. Crabtree's 15
,
described by Lautens or Jung using strong acids like DCl22 or
TFA 23 in large excess at temperatures above 100°C giving
access to 99%D labelled simple anilines. Junk described
complete exchange (99%D) for the synthesis of [D7]aniline in
D2O/NaOD at 400°C (600 bar) over 10h.24 Recently Bagley
reported an unselective deuteration of aniline and
aminopyridines in neutral D2O at 190°C (high pressure, 16 bar)
with up to 25%D of isotopic enrichment for all C(sp2)-H aniline
positions. 25 Unfortunately, all these methods are difficult to
transfer to tritium chemistry, yielding mainly low specific activity26
or are incompatible with some functional groups due to the
harsh conditions used. Another approach reported by Garnett
starting from nitrobenzene reacting over Raney nickel
(alternatively platinum or palladium) with D2 or D2O (or T2 or
HTO respectively) at a temperature lower than 75°C over days
allows the corresponding deuterated/tritiated anilines to be
obtained in low %D or %T unless a very large excess of isotope
source is used. 27 Alternatively Tashiro et al. started from
brominated anilines and exchanged the halogen by deuterium
with a raney copper-aluminium alloy in a basic D2O/THF
media. 28 However, both pathways might need an involved
precursor synthesis. A direct HIE approach for the ortho-
deuteration of anilines was studied using several transition
Kerr's16,17 or Burgess18 catalysts, heterogeneous HIE applications
with iridium are overall orphaned. To the best of our knowledge,
there is only one report on the stabilization of IrNPs using
imidazolium-based ionic liquids.19 An ongoing active research for
especially protocols with
deuterations in the vicinity of N-heteroatoms (e.g. primary,
secondary and tertiary amines or N-heterocycles) have already
20
, 21
C(sp3)-H activation by HIE,
[a]
[b]
M. Valero, Dr. J. Atzrodt, Dr. V. Derdau,
Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery
Industriepark Höchst, 65926 Frankfurt am Main, Germany
E-mail: Volker.Derdau@sanofi.com
Dr. D. Bouzouita, Dr. S. Tricard, Dr. B. Chaudret
LPCNO, Laboratoire de Physique et Chimie de Nano-Objets, UMR
5215 INSA-CNRS-UPS, Institut National des Sciences Appliquées,
135, Avenue de Rangueil, F-31077 Toulouse, France.
Dr. A. Palazzolo, Dr. C. Dugave, Dr. S. Feuillastre, Dr. G. Pieters
SCBM, JOLIOT Institute, CEA, Université Paris-Saclay, F-91191,
Gif-sur-Yvette, France.
M. Valero, D. Bouzouita, A. Palazzolo are participants in the EU
ISOTOPICS consortium. The ISOTOPICS project has received
funding from the European Union’s Horizon 2020 research and
innovation programme under the Marie Sklodowska-Curie grant
agreement N°675071
[c]
[#]
[$]
These authors contributed equally
This article is protected by copyright. All rights reserved.

10.1002/anie.201914369
Angewandte Chemie International Edition
COMMUNICATION
metals like Co, Ni or Pt leading up to 34%D at the ortho position
but requiring temperatures >300°C and along with the reduction
of the aromatic ring.29 Schou studied the synergistic effect of a
heterogeneous and homogeneous catalysts mixture such as
rhodium black and Crabtree catalyst (1 atm of D2, 4h , rt)
reaching 36%D in the ortho position of unsubstituted aniline.30
Furthermore Lockley et al. reported labelling of anilines with a
homogeneous iridium catalyst.31 Even though there are already
some examples published, there is still no simple and general
method for the deuteration/tritiation of complex anilines. This is
due to the fact that the conjugated amino-group may be a too
strong metal ligand or the pH can cause reactivity or solubility
issues. This motivated us to search for an easy to handle, mild
and generally applicable HIE method applying our newly
synthesized iridium nanoparticle (IrNP) catalysts. This way we
could notably improve the tritiated compound supply in a
compound class where moderately useful methods have been
developed for over the last 50 years.
you get consistent levels of deuterium incorporation from run to
run. The NPs can be isolated as a black powder and can be
redissolved in organic solvents, e.g. tetrahydrofuran (THF). The
metal content of the isolated powder depends upon the initial
ligand/metal ratio and was found between 40 and 90wt%.
Interestingly, the NPs 3 displaying a metal content of 90wt% are
stable which demonstrates the strong coordination of the NHC at
the surface of Ir. X-ray photoelectron spectroscopy (XPS)
(N(1s)) on NPs prepared with 0.125 eq ICy clearly showed two
signals corresponding respectively to free ICy ligand and to a
high energy shift which has been previously attributed to
coordinated ICy ligand in the case of Pd NPs.32
Trying to label aniline substructures using RuNps, 7 have led to
unsatisfactory results. Depending on the model substrate used
and the nature of the stabilizing agent very poor isotopic
enrichments or complete reduction of the aniline rings were
observed. In order to circumvent this issue we reasoned that the
use of metallic nanoparticles less prone to reduce aromatic rings
might allow developing a convenient approach to label aniline
substructure in complex molecules. In this context, we
hypothesized that Ir could be a good substitute to Ru since
ligated Ir complexes are very efficient for H/D exchange,8,9
presumably because of a low barrier for C-H activation.16,17 In
addition these catalysts are generally poor hydrogenation
catalysts.15 We therefore turned to synthesize novel IrNPs
stabilized by the same ligands found in RuNPs, namely NHCs
since these ligands have demonstrated their strong binding
abilities to various transition metal NPs. It is noteworthy that
there is no precedent for IrICy NPs although such NHC binding
to IrNPs has been proposed in ionic liquids to explain their
stabilization.19
Scheme 3. HIE reaction with various anilines 4-17. Conditions: substrate (22
µmol), IrICy 3 (4 mol%,1.5mg), solvent (3 mL), D2 (1 bar), 3h, 55°C, THF
After optimization and identification of the best HIE
conditions (solvent screening, catalyst, catalyst amount, time,
temperature; for details see supporting information) we observed
satisfactory to excellent isotopic enrichments (55-99%D) for
simple anilines 4–8 (scheme 3). Neither electron-withdrawing
functional groups (5,7,8) nor electron-donating ones (4,6)
seemed to have a significant influence on the outcome of the
HIE reaction. Instead we identified steric interactions as the
major driving force of the IrNP-catalyzed HIE reactions. For
example, we found no deuteration in ortho-position (7,8) of CF3-
groups at all, and in the HIE reaction of naphthalenes 9-12 we
Scheme 2. Synthesis of NHC stabilized iridium nanoparticles 3 (IrICy).
observed different %D for position
2 and 8 in 1-amino-
naphthalenes 9-11. Interestingly the C(sp2)-H is significantly
more reactive than the C(sp3)-H as shown by comparison of 1-
amino-naphthalenes 9 and 11. Furthermore we studied the
scope of this reaction with more complex anilines 13-17
containing other functional groups. The reaction conditions
tolerate halogens, phenols, indoles, esters and ketones without
any influence on selectivity or evidence of side reactions.
The reaction of the precursor [(COD)Ir(MeO)]2 (COD = 1,5
cyclooctadiene) 1 with 5 bar of H2 (scheme 2) over 15 hours in
the presence of N-heterocyclic carbene ligand 2 (ICy = 1,3-
dicyclohexyl-imidazol) produces very small NPs of 1.1 to 1.3 nm
mean size and of good size dispersity as observed by TEM
analysis. The NPs 3 adopt the face-centered cubic (fcc)
structure of bulk Ir as determined by X-ray diffraction (XRD)
analysis. For a detailed characterization of the NPs see the
supporting information (SI). We demonstrated also a high
reproducibility of different IrICy 3 batches with compound 4. The
NPs can be handled without the need for an inert atmosphere as
This article is protected by copyright. All rights reserved.

10.1002/anie.201914369
Angewandte Chemie International Edition
COMMUNICATION
Cl
[18]
HN
H2N
[28]
[25]
H2N
[15]
N
[30]
[99]
H2N
[53]
H2N
O
N
(C)
N
N
[0]
[10]
H
H2N
O
F3C
[0]
18 [0]
19 [0]
20 [0]
H2N
O
(D)
D2 (1 bar)
D2 (1 bar)
F3C
(B)
O
80°C,
[81]
[23]
O O
THF/D2O (1/1)
H2N
H2N
80°C,
THF/H2O (1/1)
No D2
!
H2N
S
F
F
F3C
O
80°C,
THF/D2O (1/1)
NH2
[99] [39]
[81]
S
F
[99]
[33]
(E)
[33]
22
O
O
H2N
O
[23]
23
[99]
[55]
H2N
O
H2N
O
[0]
21
(A)
H2 (1 bar)
D
2 (1 bar)
F3C
80°C
THF/D2O (1/1)
F3C
55°C, THF
[64]
O
F3C
8
H2N
[23]
[16]
O
H2N
O
H2N
O
OH
Scheme 5. HIE reaction with aniline 8. Conditions: substrate (22 µmol), IrICy
3 (4 mol%, 1.5mg), solvent (3 mL), 3h.
[99] [32]
[16]
[90]
OH
O
OH
NH2
[90]
[99]
H2N
[50]
H2N
[99]
H2N
[0]
[0]
24
25
26
H
N
O
[90]
S
N
[85]
[54]
[50]
S
O
O
N
N
[55]
O O
[99]
O
H2N
H2N
O
S
NH2
O
N
O
H2N
boc
[15]
H
HN
O
31
Sulfadimethoxine
32
Sulfamoxole
30
NH2
NH
OH
DL-Aminoglutethimide
[99]
[55]
[96]
[20]
[96]
[20]
O
O
O
O
O
O
O
27 [0]
28 [0]
29
O
O
HO
HO
H2N
[86]
conditions:
method A
method B
THF, 55°C
THF/D2O (1:1), 80°C
OH
OH
[35]
33
34
4-Aminophenyl ß-D-galactopyranoside
Menthyl anthranilate
Scheme 4. HIE reaction with various anilines 18-29. Conditions: substrate (22
µmol), IrICy 3 (4 mol%, 1.5mg), solvent (3 mL), D2 (1 bar), 3h, method A: 55°C,
THF; method B: 80°C, THF/D2O (1:1)
Scheme 6. HIE reaction with complex aniline compounds 30-34.
Conditions: substrate (22 µmol), IrICy 3 (4 mol%, 1.5mg), THF/D20 1:1 (3
mL), 80°C, 3h.
we observed 55% of isotopic enrichment whereas if the reaction
was performed in THF/D2O in the absence of H2 or D2, no
deuteration was found in 8 (B). However, if the deuteration was
carried out in the presence of D2 and in a THF/D2O mixture (C),
the deuterium introduction increased to 99%D. Thus, we
hypothesized that upon fast equilibrium for HIE between gas and
aqueous phase D2O may serve as kind of a reservoir to
replenish the consumed D2 in the gas phase. In order to verify
this assumption, we conducted two complementary experiments:
(D): THF/H2O under D2 and (E): THF/D2O under H2 resulting in
0 and 99 %D deuteration, respectively.33 We propose that the
HIE exchange between water and the catalyst is much faster
than the exchange of the catalyst with the substrate, resulting in
0%D (D) even though there is D2 in the system. Interestingly this
catalytic system does not require an additional supply of D2 gas
but can conveniently be carried out under H2 in D2O/THF
mixtures as well. And it is likely that similar conditions could be
also applied for other HIE reactions in D2O/ organic solvent
mixtures.34
Nevertheless, we observed for a group of anilines 18-29
that the prior optimized conditions yield low deuterium
incorporation (scheme 4). We concluded that due to the high
polarity of the amino moiety we would need a stronger donating
co-solvent like D2O, which would also allow us to run the
reaction at higher temperature. Thus, performing the HIE with a
THF/D2O 1:1 solvent mixture at 80°C permits successful
exchange for anilines 18-29 with high deuterium incorporation
and regioselectivity. However, in the case of N-heterocycles an
additional labelling takes place in ortho-position of the nitrogen
atom(16, 18, 19) as well and in three cases we have also
observed the labelling in the meta-position of aniline moieties
(22, 23, 29).
We questioned ourselves if the role of D2O is just as
simple polar co-solvent or if there are other effects we did not
understand so far. Therefore, we initiated
a series of
experiments to further investigate the role of the co-solvent.
Firstly, without substrate we placed a solution of IrICy in THF
containing ca. 1% water under an atmosphere of D2 (5 bar) and
monitored the reaction by 2H NMR. Initially, we only saw the
natural abundance signals of THF. Rapidly we observed both, a)
the fast appearance of a signal corresponding to D2O as well as
b) a signal for dissolved D2 confirming a very fast HIE between
gas phase D2 and water (likewise between H2 and D2O).
As shown in scheme 5, a second set of experiments were
conducted with 8 as substrate holding the reaction time,
temperature and gas pressure (if used) constant. If the reaction
was carried out in THF under D2 and in the absence of D2O (A),
We were able to show that the developed conditions could be
applied to more complex structures, like the drugs
aminoglutethimide 30, sulfadimethoxine 31, sulfamoxole 32,
menthyl anthranilate 33 (sunscreening agent) or saccharose 4-
aminophenyl-beta-D-galactopyranoside 34. In all examples
excellent selectivity and moderate to good HIE reactivity was
achieved.
Next, we demonstrated that the late-stage tritiation of complex
pharmaceuticals can be realized using this novel IrNp catalyzed
This article is protected by copyright. All rights reserved.

10.1002/anie.201914369
Angewandte Chemie International Edition
COMMUNICATION
to the EU ISOTOPICS project from the European Union’s Horizon 2020
research and innovation programme under the Marie Sklodowska-Curie
grant agreement N°675071
HIE. The use of T2 gas as an isotopic source is a clear
advantage because it is the cheapest and easiest raw material
to handle for tritium labelling. Typically, reactions involving T2
gas are conducted using a sub-atmospheric pressure of T2 in
order to minimize the risk of leakage and radioactivity release.
For these reasons, we have optimized our reaction conditions
using Volixibat 35 aniline pharmacophore as substrate (scheme
7).35 This complex molecule is a medication under development
for cholestatic liver disease. Using a catalytic loading of 80 mol%
of IrNps, the tritiated pharmacophore of Volixibat 35 was
obtained utilizing sub-atmospheric pressure of tritium gas (p=
0.8 bar, 10 Ci)36 within a relatively short reaction time (3 hours).
In terms of regioselectivity, the labelling of the less sterically
encumbered ortho position of the NH2 group was mainly
observed (as demonstrated by the isotope incorporation
observed for deuterium experiments and using 3H NMR
spectroscopy, see SI). Typically, a specific activity between 10–
20 Ci/mmol is considered as suitable for the use of tritiated
molecules in the context of absorption, distribution, metabolism
and excretion studies. The high specific activity of 25 Ci/mmol
obtained here (calculated by mass spectrometry) clearly
demonstrate the high potential of this novel method for late-
stage labelling of complex pharmaceuticals containing aniline
substructures.
Keywords: iridium nanoparticles • hydrogen isotope exchange •
C-H activation • C-H functionalization • heterogeneous catalysis
1
a) G. Schmid, Nanoparticles, From theory to applications, Weinheim, 2004.
b) A. Roucoux, J. Schulz and H. Patin, Chem. Rev. 2002, 102, 3757–3778.
M. N. Hopkinson, C. Richter, M. Schedler, F. Glorius, Nature 2014, 510,
2
485–496.
3
a) D. Canseco-Gonzalez, A. Petronilho, H. Mueller-Bunz, K. Ohmatsu, T.
Ooi, M. Albrecht, J. Am. Chem. Soc. 2013, 135, 13193–13203; b) E. C.
Hurst, K. Wilson, I. J. S. Fairlamb, V. Chechik, New J. Chem. 2009, 33,
1837–1840; c) A. V. Zhukhovitskiy, M. G. Mavros, T. Van Voorhis, J. A.
Johnson, J. Am. Chem. Soc. 2013, 135, 7418–7421; d) G. Wang, A.
Ruhling, S. Amirjalayer, M. Knor, J. B. Ernst, C. Richter, H.-J. Gao, A.
Timmer, H.-Y. Gao, N. L. Doltsinis, F. Glorius, H. Fuchs, Nat. Chem. 2017,
9, 152–156.
4
K. V. S. Ranganath, J. Kloesges, A. H. Schaefer, F. Glorius, Angew. Chem.,
Int. Ed. 2010, 49, 7786–7789.
M. Diaz de los Bernardos, S. Perez-Rodrıguez, A. Gual, C. Claver, C.
5
Godard, Chem. Commun. 2017, 53, 7894-7897; b) J.-F. Soule, H.
Miyamura, S. Kobayashi, J. Am. Chem. Soc. 2013, 135, 10602–10605.
a) P. Lara, O. Rivada-Wheelaghan, S. Conejero, R. Poteau, K. Philippot, B.
6
Chaudret, Angew. Chem., Int. Ed. 2011, 50, 12080–12084; b) L. M.
Martinez-Prieto, A. Ferry, P. Lara, C. Richter, K. Philippot, F. Glorius, B.
Chaudret, Chem. Eur. J. 2015, 21, 17495–17502.
7
a) G. Pieters, C. Taglang, E. Bonnefille, T. Gutmann, C. Puente, J.-C.
Berthet, C. Dugave, B. Chaudret, B. Rousseau, Angew. Chem. Int. Ed.
2014, 53, 230-234; b) C. Taglang, L. M. Martinez-Prieto, I. del Rosal, L.
Maron, R. Poteau, K. Philippot, B. Chaudret, S. Perato, A. Sam Lone, C.
Puente, C. Dugave, B. Rousseau, G. Pieters, Angew. Chem., Int. Ed. 2015,
54, 10474–10477; c) L. Gao, S. Perato, S. Garcia-Argote, C. Taglang, L. M.
Martinez-Prieto, C. Chollet, D.-A. Buisson, V. Dauvois, P. Lesot, B.
Chaudret, B. Rousseau, S. Feuillastre, G. Pieters, Chem. Commun. 2018,
54, 2986–2989.
8
J. Atzrodt, V. Derdau, W. J. Kerr, M. Reid, Angew. Chem. Int. Ed. 2018, 57,
3022–3047.
9
J. Atzrodt, V. Derdau, T. Fey, J. Zimmermann, Angew. Chem. Int. Ed. 2007,
46, 7744–7765.
10
J. Atzrodt, V. Derdau, W. J. Kerr, M. Reid, Angew. Chem. Int. Ed. 2018, 57,
1758–1784.
11
For recent examples for labelling of drugs by HIE reactions, see: a) R. P.
Yu, D. Hesk, N. Rivera, I. Pelczer, P. J. Chirik. Nature 2016; 529, 195-199;
b) WJ. Kerr, RJ. Mudd, M. Reid, J. Atzrodt, V. Derdau. ACS Catal. 2018; 8,
11, 10895-10900; c) M. Valero, D. Becker, K. Jess, R. Weck, T.
Bannenberg, J. Atzrodt, V. Derdau, M. Tamm. Chem Eur. J. 2019; 25, 6517-
6522; d) H. Yang, P. G. Dormer, N. R. Rivera, A. J. Hoover Angew. Chem.
Int. Ed. 2018; 57: 1883-1887; e) Y. Y. Loh, K. Nagao, A. J. Hoover, D. Hesk,
N. R. Rivera, S. L. Coletti, I. W. Davies, D. W. C. MacMillan, Science 2017;
358, 1182-1187; f) M. Valero, A. Mishra, J. Blass, R. Weck, V. Derdau,
ChemistryOpen 2019, doi.org/10.1002/open.201900204.
Scheme 7. Tritiation of the pharmacophore of Volixibat 35 catalyzed by IrNps
3 in a 0.8 bar tritium atmosphere.
12
For selected reviews see: a) C. S. Elmore, R. A. Bragg, Bioorg. Med.
In conclusion, we have developed a new method for a
selective HIE of anilines. The method is fully adaptable to the
specific requirements of tritium chemistry, which is demonstrated
by direct tritium labelling of the volixibat pharmacophore with a
high selectivity and specific activity of 25 Ci/mmol. The new
IrNPs are simple to prepare, easy to handle and air stable. No
hydrogenation side products have been observed.
Chem. Lett. 2015, 25, 167–171; b) A. Krauser, J. Label Compd.
Radiopharm. 2013, 56, 441–446; c) W. J. S. Lockley, A. McEwen, R. Cooke,
J. Label. Compd. Radiopharm. 2012, 55, 235–257; d) A. E. Mutilib, Chem.
Res. Toxicol. 2008, 21, 1672–1689.
13
For selected reviews see: a) J. J. Maguire, R. E. Kuc, A. P. Davenport,
Methods Mol. Biol. 2012, 897, 31–77; b) E. C. Hulme, M. A. Trevethick, Br.
J. Pharmacol. 2010, 161, 1219–1237; c) D. Harder, D. Fotiadis, Nat. Prot.
2012, 7, 1569–1578; d) J. Berry, M. Price-Jones, B. Killian, Methods Mol.
Biol. 2012, 897, 79–94; e) B. Buscher, S. Laakso, H. Mascher, K. Pusecker,
M. Doig, L. Dillen, W. Wagner-Redeker, T. Pfeifer, P. Delrat, P. Timmerman,
Bioanalysis 2014, 6, 673–682; f) E. G. Solon, Chem. Res. Toxicol. 2012, 25,
543–555; g) A. W. Harrell, C. Sychterz, M. Y. Ho, A. Weber, K. Valko, K.
Negash, Pharma Res. Per. 2015, 3, e00173; h) N. Penner, L. Xu, C.
Prakash, Chem. Res. Toxicol. 2012, 25, 513–531; i) E. M. Isin, C. S.
Elmore, G. N. Nilsson, R. A. Thompson, L. Weidolf, Chem. Res. Toxicol.
2012, 25, 532–542; j) A. Mullard, Rev. Drug Discov. 2017, 16, 305; k) R. D.
Tung, Future Med. Chem. 2016, 8, 491–494; l) A. Katsnelson, Nat. Med.
2013, 19, 656; m) G. S. Timmins, Expert Opin. Ther. Patents 2014, 24,
1067–1075; n) S. L. Harbeson, R. D. Tung, Med. Chem. News 2014, 2, 8–
22; o) T. G. Gant, J. Med. Chem. 2014, 57, 3595–3611.
Experimental Section
For experimental details, preparation and characterization of the IrNP
and the HIE experiments, see the Supporting Information.
14 a) K. Jess, V. Derdau, R. Weck, J. Atzrodt, M. Freytag, P. G. Jones, M.
Tamm, Adv. Synth. Catal. 2017, 359, 629–638; b) M. Valero, A. Burhop, K.
Jess, R. Weck, M. Tamm, J. Atzrodt, V. Derdau, J. Label. Comp.
Radiopharm. 2018, 16, 380–385.
Acknowledgements
15 R. Crabtree, Acc. Chem. Res. 1979, 12, 331–337.
16 a) J. A. Brown, S. Irvine, A. R. Kennedy, W. J. Kerr, S. Andersson and G. N.
Nilsson, Chem. Commun. 2008, 1115–1117.
The authors would like to thank Dr. Martin Sandvoss and Viktor Pfeifer
for analytical support. M. Valero, D. Bouzouita, A. Palazzolo are grateful
This article is protected by copyright. All rights reserved.

10.1002/anie.201914369
Angewandte Chemie International Edition
COMMUNICATION
17 a) W. J. Kerr, D. M. Lindsay, M. Reid, J. Atzrodt, V. Derdau, P. Rojahn, R.
Weck, Chem. Commun. 2016, 52, 6669–6672; b) J. Atzrodt, V. Derdau, W.
J. Kerr, M. Reid, P. Rojahn, R. Weck, Tetrahedron 2015, 71, 1924–1929; c)
J. A. Brown, A. R. Cochrane, S. Irvine, W. J. Kerr, B. Mondal, J. A.
Parkinson, L. C. Paterson, M. Reid, T. Tuttle, S. Andersson, G. N. Nilson,
Adv. Synth. Catal. 2014, 356, 3551–3562; d) A. R. Cochrane, C. Idziak, W.
J. Kerr, B. Mondal, L. C. Paterson, T. Tuttle, S. Andersson, G. N. Nilsson,
Org. Biomol. Chem. 2014, 12, 3598–3603.
18 a) A. Burhop, R. Weck, J. Atzrodt, V. Derdau, Eur. J. Org. Chem. 2017, 11,
1418–1424; b) A. Burhop, R. Prohaska, R. Weck, J. Atzrodt, V. Derdau, J.
Label. Compd. Radiopharm. 2017, 60, 343–348.
19
L. S. Ott, M. L. Cline, M. Deetlefs, K. R. Seddon and R. G. Finke, J. Am.
Chem. Soc. 2005, 127, 5758–5759.
20
For selected recent examples of C(sp3)labelling, see: a) L. Neubert, D.
Michalik, S. Bähn, S. Imm, H. Neumann, J. Atzrodt, V. Derdau, W. Holla, M.
Beller, J. Am. Chem. Soc. 2012, 134, 12239–12244; b) L. V. A. Hale, N. K.
Szymczak, J. Am. Chem. Soc., 2016, 138, 13489–13492, c) W. N. Palmer,
P. J. Chirik ACS Catal. 2017, 7, 5674–5678; d) Y. Y. Loh, K. Nagao, A. J.
Hoover, D. Hesk, N. R. Rivera, S. L. Coletti, I. W. Davies, D. W. C.
MacMillan, Science 2017, 358, 1182–1187; e) M. Valero, R. Weck, S.
Guessregen, J. Atzrodt, V. Derdau Angew. Chem. Int. Ed. 2018, 57, 8159–
8163.
For
21
a recent review, see: M. Valero, V. Derdau, J. Label. Compd.
Radiopharm. 2019, https://doi.org/10.1002/jlcr.3783.
22 A. Martens, M. Lautens Org. Lett. 2008, 10, 4351-4353.
23 R. Giles, A. Lee, E. Jung, A. Kang, K. W. Jung, Tetrahedron Lett. 2015, 56,
747-749.
24 T. Junk, W. J. Catallo, L. D. Civils, J. Labelled Compd. Radiopharm. 1997,
39, 625–630.
25 M. C. Bagley, A. Alnomsy, H. I. Sharhan, Synlett 2016, 27, 2467–2472.
26 G. Ayrey and R.W. Dunlop, J. Label Compd. Radiopharm 1980, 17, 21-33.
27 J. L. Garnett, M. A. Long, C.Than, P. G. Williamst J. Chem. Soc. Faraday
Trans. 1990, 86, 875-879.
28
M. Tashiro, H. Tsuzuki, T. Tsukinoki, S. Mataka, K. Nakayama, T.
Yonemitsu, J. Label Compd. Radiopharm. 1990, 28, 703-712.
29 a) G.E.Calf, J. L. Garnett, V.A. Pickles, Aust. J. Chem. 1968, 21, 961-972.
b) H. Hagiwara, E. Echigoya, Bull. Chem. Soc. Jp 1966, 39(8), 1683-1689;
c) C. G.Macdonald, J.S. Shannon, Tetrahedron Lett. 1964, 45, 3351-3354.
30 Søren Christian Schou J. Label Compd. Radiopharm 2009, 52, 376–381.
31 W. J. S. Lockley, J. Label Compd. Radiopharm 2010, 53, 668-673.
32 A. Rühling, K. Schaepe, L. Rakers, B. Vonhören, P. Tegeder, B. J. Ravoo,
F. Glorius, Angew.Chem. Intl Ed. 2016, 55, 5856 5860.
–
33 The deuterium molarity of 1.5 mL heavy water is 0.166 mol, that of 20 mL D2
gas, 1.78.10-3 mol.
34 This in in line with research done by Sajiki et al. on metal surface activation
by hydrogen gas: T. Maegawa, N. Ito, K. Oono,Y Monguchi,H. Sajiki
Synthesis 2009; 2674-2678.
35 International Nonproprietary Names for Pharmaceutical Substances (INN).
Recommended International Nonproprietary Names: List 75. World Health
Organization. p. 166. Retrieved 21 January 2017.
36
It is worth pointing out that in general tritium manifold reaction port
connections are also designed for sub-atmospheric tritium pressures.
This article is protected by copyright. All rights reserved.

10.1002/anie.201914369
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Novel Iridium
Mégane Valero, Donia
Nanoparticles as
catalysts in Hydrogen
Isotope Exchange
Reactions – a new
powerful tool for
deuterium or tritium
labelling of complex drug
candidates.
Bouzouita, Alberto
Palazzolo,Jens Atzrodt,
Christophe Dugave,
Simon Tricard, Sophie
Feuillastre, Grégory
Pieters, Bruno Chaudret,
and Volker Derdau
Page No. – Page No.
NHC-Ligated Iridium
Nanoparticles as Novel
Catalysts in Hydrogen
Isotope Exchange
Reactions of Anilines
This article is protected by copyright. All rights reserved.