Tuning the Reactivity of a Heterogeneous Catalyst using N-Heterocyclic Carbene Ligands for C?H Activation Reactions

Article abstract of DOI:10.1002/anie.202009258

We report the dramatic impact of the addition of N-heterocyclic carbenes (NHCs) on the reactivity and selectivity of heterogeneous Ru catalysts in the context of C?H activation reactions. Using a simple and robust method, we prepared a series of new air-stable catalysts starting from commercially available Ru on carbon (Ru/C) and differently substituted NHCs. Associated with C?H deuteration processes, depending on Ru/C-NHC ratios, the chemical outcome can be controlled to a large extent. Indeed, tuning the reactivity of the Ru catalyst with NHC enabled: 1) increased chemoselectivity and the regioselectivity for the deuteration of alcohols in organic media; 2) the synthesis of fragile pharmaceutically relevant deuterated heterocycles (azine, purine) that are otherwise completely reduced using unmodified commercial catalysts; 3) the discovery of a novel reactivity for such heterogeneous Ru catalysts, namely the selective C-1 deuteration of aldehydes.

Full text of DOI:10.1002/anie.202009258

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Tuning the Reactivity of a Heterogeneous Catalyst using N-
Heterocyclic Carbene Ligands for C-H Activation Reactions
Authors: Alberto Palazzolo, Timothée Naret, Marion Daniel-Bertrand,
David-Alexandre Buisson, Simon Tricard, Philippe Lesot,
Yannick Coppel, Bruno Chaudret, Sophie Feuillastre, and
Grégory Pieters
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202009258
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10.1002/anie.202009258
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COMMUNICATION
Tuning the Reactivity of a Heterogeneous Catalyst using N-
Heterocyclic Carbene Ligands for C-H Activation Reactions
Alberto Palazzolo,[a] Timothée Naret,[a] Marion Daniel-Bertrand,[a] David-Alexandre Buisson,[a] Simon
Tricard,[b] Philippe Lesot,[c] Yannick Coppel,[d] Bruno Chaudret,[b] Sophie Feuillastre[a] and Grégory
Pieters*,[a]
[a]
Dr. A. Palazzolo, Dr. T. Naret, Dr. M. Daniel-Bertrand, D-A Buisson, Dr. S. Feuillastre, Dr. G. Pieters
Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SCBM, F-91191, Gif-sur-Yvette, France
E-mail: gregory.pieters@cea.fr
[b]
[c]
[d]
Dr. S. Tricard, Dr. B. Chaudret
LPCNO, Université de Toulouse, UMR 5215 INSA-CNRS-UPS, 135, Avenue de Rangueil, F-31077 Toulouse, France
Dr. P. Lesot
ICMMO, RMN en Milieu Orienté, UMR CNRS 8182, Université Paris-Saclay, Bât. 410, F-91405 Orsay cedex, France
Dr. Y. Coppel
Laboratoire de Chimie de Coordination (LCC), CNRS, 205 route de Narbonne, BP44099, F-31077 Toulouse Cedex 4, France
Supporting information for this article is given via a link at the end of the document.
Abstract: We report in this communication the dramatic impact of the
addition of N-heterocyclic carbene (NHC) ligands on the reactivity and
selectivity of heterogeneous Ru catalysts in the context of C-H
activation reactions. Using a simple and robust protocol, we have
addition of NHCs allowed an important enhancement of
reactivity.8 In the same context, an NHC modified Pd-Au alloy was
reported to be active for the hydrogenation of alkynes and
nitroarenes.9 Nevertheless, to the best of our knowledge, ligand
induced reactivity modification of heterogeneous catalysts has
only been reported in the context of reduction processes and
cross coupling reactions. Herein we report the effect of NHC
ligands on the reactivity of a supported heterogeneous ruthenium
catalyst in the context of C-H functionalization.
prepared
a series of new air stable catalysts starting from
commercially available Ru on carbon (Ru/C) and differently
substituted NHCs. Associated with C-H deuteration processes,
depending on Ru/C-NHC ratios, the chemical outcome can be
controlled to a large extent. Indeed, tuning the reactivity of the Ru
catalyst with NHC has allowed: i) to increase the chemoselectivity and
the regioselectivity for the deuteration of alcohols in organic media; ii)
to synthesize fragile pharmaceutically relevant deuterated
heterocycles (azine, purine) otherwise completely reduced using
unmodified commercial catalysts; iii) to discover a novel reactivity for
such heterogeneous Ru catalysts: the selective C-1 deuteration of
aldehydes.
Reductive Deuteration
Hydrogen Isotope Exchange
The functionalization of non-activated C-H bonds is one of the
most studied topics in the current chemical research.1 This strong
interest is due to the numerous advantages of the direct
functionalization of such non-reactive bonds leading to
straightforward syntheses.2 A plethora of homogeneous transition
metal catalysts have been developed until now in the field of C-H
activation. Heterogeneous catalysts, despite their advantages
over homogeneous ones such as their higher robustness and
easier recyclability, are generally less employed to activate C-H
bonds on complex molecules. This fact is probably due to the
challenge related to the modulation of heterogeneous catalyst
reactivity by organic ligands.3 In contrast, for other types of
important chemical reactions such as hydrogenations, the
addition of ligands to influence the reactivity of heterogeneous
catalysts has been known for decades.4 In spite of the fact that N-
heterocyclic carbenes (NHCs) are widely applied as ligands in
homogeneous catalysis,5 only recently, Glorius et al. reported
their capability to tune the reactivity and selectivity of a
heterogeneous Ru catalyst (Ru/K-Al2O3).6 In this example, the
addition of several equivalents of NHCs to the catalyst permitted
the selective hydrogenation of the alkyne over the phenyl moiety
in phenylacetylene.7 Later, the same group described a Pd/Al2O3-
catalyzed Buchwald-Hartwig cross-coupling reaction in which the
Figure 1: Schematic preparation of the NHCs modified Ru on carbon catalysts
and examples of catalytic activity switches observed.
The addition of various amount of NHCs on commercially
available Ru/C allows to control the reaction outcome (see Figure
1). This includes the nature of the major product and the chemo/
regio-selectivity of C-H deuteration processes on various
substrates such as alcohols, pharmaceutically relevant
1
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10.1002/anie.202009258
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heterocycles and aldehydes. In most cases, the use of the
commercial Ru catalyst led to a mixture of products arising from
2.2 D incorporated, 90% of the labelling at the α position). Using
apolar solvents, such as cyclohexane or heptane led to efficient
both reductive deuteration and Hydrogen Isotope Exchange (HIE). but unselective deuteration of the aliphatic chain (entry 3). In
In contrast, the catalyst modification using NHCs promotes the
HIE over the reduction.
contrast with other results reported in the literature, using D2O as
solvent also led to unselective deuterium incorporation (4.1 D,
entry 5).10a Despite such promising preliminary results, this
approach did not allow a complete α regioselective deuteration of
1-dodecanol. As an alternative the potential effect of the addition
of NHCs at the surface of the catalyst on the regioselectivity of
this HIE reaction has been explored.12 The addition of one
equivalent of ICy on Ru/C (relative to Ru) totally suppressed the
deuterium uptake in 1-dodecanol (entry 6). This result suggested
the existence of a strong interaction between the ligand and the
catalyst. Decreasing the amount of ICy to 0.5 equivalent did not
significantly change the reaction outcome (see SI, Table S1).
Instead, a further decrease to 0.1 equivalent, led to a noticeably
higher deuteration (1.5 D, entry 7) of 1-dodecanol with a good
regioselectivity in favor of the α position and a deuterium uptake
in the same range as the one obtained using unmodified Ru/C. To
reach a complete deuteration along with a total regioselectivity
other NHC ligands were therefore screened (entries 8-10). Finally,
IAd(0.1 eq)@Ru/C13 gave the highest isotopic enrichment and α
regioselectivity for the deuteration of 1-dodecanol. We
investigated then the effect of some common additives like
Cs2CO3 and KOtBu on the reaction outcome. Although difficult to
rationalize, the use of the latter produced a quantitative
deuteration of 1-dodecanol 1 combined with a complete α
regioselectivity (Table 1, entry 11 and Figure 2).
The effect of the NHC modification on the reactivity was first
carried out using alcohols as substrates for which no deuteration
in organic media has been described so far using HIE.10 In this
context, we have recently reported the efficacy of ruthenium
nanoparticles (RuNps) to perform HIE on bioactive compounds.11
However here, the use of RuNp@PVP as catalyst (5, 10 and 20
mol%, see SI, Table S1, page 6) and deuterium gas (2 bar) as
isotopic source resulted in a very poor isotopic incorporation on
dodecanol 1 (Table 1, entry 1). Undecane, possibly coming from
the substrate’s decarbonylation, was actually observed by GC-
MS analysis. The subsequent CO poisoning of the catalysts
surface may thus be responsible for the low deuterium
incorporation observed. To overcome this problem other catalytic
systems were screened (see Table 1, entry 2 and Table S1).
Entry
Catalyst
Solvent
D
Total D
%labeled
Similar reactivity
compound
1
2
RuNp@PVP
Ru/C
THF
THF
-
0.05
0.7
4.8
2.2
4.1
0.05
1.5
0.8
0.8
1.7
1.9
8
0.7
1.7
1.8
2.0
-
46
99
92
99
26
91
87
61
92
95
Regioselectivity alteration
3
Ru/C
Heptane
MTBE
D2O
4
Ru/C
5
Ru/C
6
ICy(1 eq)@Ru/C
ICy(0.1 eq)@Ru/C
IMes(0.1 eq)@Ru/C
IPr(0.1 eq)@Ru/C
IAd(0.1 eq)@Ru/C
IAd(0.1 eq)@Ru/C
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
Chemoselectivity alteration
7
1.4
0.8
0.8
1.7
1.9
8
9
10
11*
Table 1: Initial screening of conditions, catalysts and ligands for the H/D
exchange on 1-dodecanol. αD: number of deuterium atoms incorporated at the
alpha position of the alcohol moiety. Total D: Total number of deuterium atoms
incorporated in 1-dodecanol.* Additive: t-BuOK (0.6 eq.)
Commercially available Ru/C (5 wt%) gave the highest deuterium
uptake per molecule (0.7 D) while Pd/C, Pt/C, Rh/C and Ir/CaCO3
all showed very poor reactivity in the same conditions (see SI
Table S1). Thus, optimization of the reactional conditions were
performed using Ru/C as catalyst. Regarding the solvent scope
(see Table 1, entries 2-5), the best compromise between the
maximum deuterium incorporation and the regioselectivity of the
labelling at the α-position was achieved by using MTBE (entry 4,
Figure 2: Illustration of catalytic activity switches in the context of the deuterium
labelling of aliphatic alcohols and N-heterocycles. Conditions: (a) IAd(0.1
eq)@Ru/C or Ru/C (20 mol%), 55°C, D2 (2 bar), 24 h, MTBE (0.1 M), KOtBu
(0.6 or 1.2 eq); (b) IAd(0.1 eq)@Ru/C or Ru/C (5 mol%), 55°C, D2 (1 bar), 24h,
THF (0.1 M). Isotopic enrichments are indicated in brackets.
2
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The expansion of the scope using different aliphatic alcohols as
substrates was systematically performed comparing results
obtained with modified and commercial ruthenium catalysts. No
significant difference was observed in the case of diol 2, contrary
to alcohols (3-5) where deuterium uptake occurred with a higher
regioselectivity using IAd(0.1 eq)@Ru/C. The regioselectivity of
the deuterium incorporation first determined by the analysis of 1H
NMR spectrum, was then confirmed using 2H-{1H} 1D NMR
spectroscopy @14.1 T (see SI), evidencing the substantial
enhancement of regioselectivity afforded by the presence of
NHCs at the surface of the Ru catalyst. Regarding the
chemoselectivity, activity switches have been first evidenced
using compounds 6 to 9 as substrates. Indeed, for those
molecules bearing reducible phenyl moieties, the use of Ru/C led
to the desired labelling but also to the reductive deuteration
whereas the use of IAd(0.1eq)@Ru/C led mainly to HIE. Puzzled
by the observed selectivity, we next compared the catalytic
activities of both ruthenium catalyst for the labelling of easily
reducible pharmaceutically relevant heterocycles. The differences
in terms of isolated yields between the use of native Ru/C and
IAd(0.1 eq)@Ru/C were rather small in the case of 2-phenyl
pyridine 10 (99% vs 80%) and 2-methyl benzoxazole 11 (92% vs
89%). More interestingly, in the case of 2,5-diphenyloxazole 12
the effect of the catalyst modification was much more important
as the isolated yield was five times higher (26% vs 5%). The effect
of the NHC-modification on the reactivity of Ru/C catalyst was
even more pronounced for compounds 13 to 16 for which a higher
ratio NHC/Ru had to be used to favor C-H deuteration processes
over the reduction of the aromatic rings (Figure 3).
labelled with a high yield and a high isotopic enrichment (80% at
the α-position of the nitrogen atom) using IAd(1 eq)@Ru/C.
Interestingly, using 2 or 3 equivalents of IAd ligand did not
drastically change the reaction outcome while the use of 0.5
equivalent (or less) of IAd resulted in an increase of the amount
of reduced products formed (see SI page 70, Figure S94).
Thereafter, we demonstrated the synthetic usefulness related to
the use of such modified catalysts with the deuteration of fragile
pharmaceuticals. Chloroxine 15, a quinoline based antibiotic, was
also deuterated and isolated after HPLC purification with a good
yield (53%) while it was completely reduced using commercial
Ru/C. Finally, pentoxifylline 16, an easily reducible ketone-
containing drug, was isolated with an excellent yield and a high
deuterium incorporation (98% in position 8 of the heterocycle)
using IAd(1eq)@Ru/C, whereas the ketone moiety was totally
reduced and the compound unselectively deuterated employing
the unmodified catalyst. At this stage, the use of our new modified
catalysts significantly promoted the C-H deuteration over
reductive deuteration on different class of substrates possessing
aromatic rings and ketones.
The potential of such catalyst modification to discover novel C-H
activation processes has been demonstrated using aromatic
aldehydes as substrates (see Figure 4). Indeed, electron-rich
benzaldehydes (17-19) were efficiently labelled with IAd(1
eq)@Ru/C in acceptable yields whereas the use of commercial
Ru/C catalyzed the reductive deuteration of C=O along with the
C-H deuteration at the α position of the resulting alcohols.
Figure 4: Deuterium labelling of aldehydes. Conditions: IAd(1 eq)@Ru/C or
Figure 3: Illustration of the dramatic impact of the addition of NHC (1 eq) on the
chemical outcome in the context of the deuteration of easily reducible
compounds 13 to 16. Conditions: IAd(1 eq)@Ru/C or Ru/C (5 mol%), 55°C, D2
(1 bar), 24h, THF (0.1 M). [a] KOtBu (1 eq). [b] Room temperature instead of
55°C. [c] 16h instead of 24h.
Ru/C (5 mol%), 55°C, D2 (1 bar), 16h, THF (0.1 M).
Interestingly, only the C-1 proton was selectively exchanged (no
traces of side-labelling was detected in the aromatic parts even
using a 92.1 MHz 2H-{1H} NMR spectrometer equipped with a 2H
cryogenic probe) in contrast with the recently described method
using an homogeneous Ir catalyst.14 Electron-poor 4-
acetamidobenzaldehyde 20 was also labelled with a good
deuterium uptake and with limited reduced side-product. For 4-
Dimethylaminobenzaldehyde 21 only the C-1 proton was
exchanged using the NHC-modified catalyst while the use of the
native Ru/C has led to side-position labellings and the formation
of high amount of side products.
Indeed, benzylic alcohol 13 was completely reduced using Ru/C
(see SI, page 63). By contrast, using a NHC:Ru ratio of 1:1
(IAd(1 eq)@Ru/C) allowed the labelling of such fragile compound
with a good deuterium incorporation (1.3 D) and an acceptable
yield (77%). Inspired by this result, we applied the same catalyst
for the deuteration of the easily reducible quinoline 14. The
compound was totally reduced with the Ru/C catalyst but only
3
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In order to confirm the coordination of the NHC IAd to the surface
of the catalyst, the synthesis of 13C-labelled IAd ligand has been
performed (see SI page 108 for experimental details). Using this
isotopically labelled carbene, modified catalysts with 0.1 and 1.0
eq of NHC has been prepared and solid-state 13C NMR analyses
performed. Through 13C Hahn-echo experiment with short
relaxation delay (see Figures 5a-b and SI), a broad signal
centered at ca. 160 ppm was detected for the two modified
catalysts. This signal correspond in fact to the sum of two signals:
one at ca. 184 ppm that can be attributed to the NHC carbene
coordinated at the surface of the Ru catalyst and the second one
at ca. 154 ppm associated to the Ru/C catalyst itself (see SI).
Their relaxation behaviors characterized by short T2 is very likely
related to the presence of conduction electrons on the Ru
particles that can also lead to small Knight shifts.15
28% for the NHC and 72% for the imidazolium. Instead, for IAd(1
eq)@Ru/C the contribution were respectively 15% for NHC and
85% for imidazolium (Figure 5d). In IAd(0.1 eq)@Ru/C, there is
thus 0.1  0.28 = 0.03 eq of NHC bound to the surface, while in
IAd(1 eq)@Ru/C, there is 1  0.15 = 0.15 eq of NHC at the surface,
namely 5 times more. The switch in reactivity between IAd(0.1
eq)@Ru/C and IAd(1 eq)@Ru/C could therefore be explained by
an increased competition between the substrate coordination and
the one of the NHC ligands, in addition to possible
physicochemical interactions of the imidazolium in excess notably
when a base is added as additive (t-BuOK in case of the labelling
of aliphatic alcohols). We propose that the regio- and chemo-
selectivity switches can be explained by structural effects due to
the coordination of the NHC and the bulkiness of the IAd
substituents.18 Indeed, reduction of an aromatic ring requires a flat
π-coordination of the substrate on a dense facet of the Ru particle,
so an easily available free surface. The strong NHC coordination
at the surface of the Ru catalyst can prevent this π-coordination
of aromatic rings of the substrate but not a side-on approach and
coordination of a nitrogen or an oxygen atom directing the C-H
activation processes. Control experiments (see SI page 117)
show that the presence of NHCs decreased the rate of the
reductive deuteration pathway (probably occurring on the faces of
the Ru particles19a) whereas the rate of C-H deuteration one
(which can be catalyzed at edges and corners of the metallic
cluster) is less affected.19b
d
c
In conclusion, we have demonstrated for the first time in the
context of C-H activation reactions, that the addition of NHCs to a
heterogeneous catalyst can have a dramatic impact on its
reactivity. Depending on the nature of the substrate, the amount
of NHC can be adjusted in order to favor selective C-H deuteration
over reductive deuteration. The modified catalysts showed
enhanced regio- and chemo-selectivity for the H/D exchange
process and gave access to the first general method for the
selective labelling of α-positions on aliphatic alcohols using
organic solvents. Moreover, the use of NHC@Ru/C permit to
synthesize deuterated pharmaceutically relevant compounds that
cannot be obtained using the commercially available unmodified
catalyst due to reduction side reactions. Finally, the potential of
such strategy to discover novel C-H activation reactions has been
highlighted by the deuteration of aromatic aldehydes (a type of
HIE scarcely reported in the literature until now using D2 as
isotopic source). As the catalyst modification is simple to
implement, and diverse metallic clusters (Pd, Ni, Ir, Pt, …) can be
modified using this strategy, we think that this work could have a
great impact on future developments for C-H activation processes
using heterogeneous catalysis.
Figure 5: 13C Hahn-echo MAS NMR spectra (relaxation delay of 0.5 s) of 13C-
labelled along with the signals deconvolution and the 13C chemical shifts: (a)
IAd(0.1 eq)@Ru/C and (b) IAd(1 eq)@Ru/C. XPS spectra at the N1s edge of:
(c) IAd(0.1 eq)@Ru/C and (d) IAd(1 eq)@Ru/C
Furthermore, for 0.1 eq of NHC, 13C signals at 120 ppm, 58 and
17 ppm were observed, corresponding to the sp2-hybridized
carbons and to carbons of residual solvent (THF and t-BuOH). For
1 eq of NHC, 13C signals can be seen at 128 and in the 40-20 ppm
area. Through a NMR investigation (see SI, page 111-115), the
128 ppm signal was assigned to the protonated NHC
(imidazolium) and the 40-20 ppm ones to adamantane.16 The
modified catalysts were also characterized using X-ray
photoelectron spectroscopy (XPS). The XPS spectra showed two
superimposed peaks in the N1s area (see Figures 5c-d). The first
peak at 399 eV corresponds to a carbenic nitrogen species while
the second one at 402 eV can be attributed to imidazolium
species.17 The presence of imidazolium can be explained by the
reprotonation of the carbene ligand: considering that the Ru/C
surface is rapidly saturated with NHC, the unreacted fraction is
then reprotonated under air to give back the imidazolium. Peaks
deconvolution for IAd(0.1 eq)@Ru/C showed a contribution of
Acknowledgements
The authors acknowledge the European Union’s Horizon 2020
research and innovation program under the Marie Sklodowska-
Curie grant agreement no. 675071 for funding AP. GP thanks
ANR for funding TN (Carb2zyme, ANR-17-CE11-0014). CEA and
CNRS are also thanked for financial support. We also thank Dr.
Bernard Rousseau for helpful discussion, Dr. Edmond Gravel for
4
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COMMUNICATION
[12] Deuteration experiments with other ligands notably phosphines have
been performed. Using same experimental conditions, the best results
were obtained with 0.025 eq of dppb ligand leading to an isotopic
enrichment of 28% at the α-position of the alcohol moiety along with
traces of labelling on the aliphatic chain. Those results are far below the
results obtained using NHC ligands especially IAd (92 % of isotopic
enrichment at the α-position and no side labelling).
the help in TGA measurements, Dr. Donia Bouzouita for the help
in TEM analysis, Dr. Valérie Geertsen and Elodie Barruet for ICP-
MS measurements. We acknowledge Dr. Karen Hinsinger, Dr.
Emilie Nehlig and Dr. Christophe Dugave for their support in
managing the ISOTOPICS project. We thank Jérôme Esvan
(CIRIMAT, CNRS, Université de Toulouse) for XPS
measurements. PL thanks the CNRS for the recurrent funding of
fundamental research. We would like to warmly thank the
reviewers for their suggestions, which resulted in considerable
improvements to our manuscript and to the SI.
[13] Loadings of both catalysts IAd(1eq)@Ru/C and IAd(0.1 eq)@Ru/C have
been estimated by TGA measurements (see SI page 116 Figure S156).
[14] W. J. Kerr, M. Reid, T. Tuttle, Angew. Chem. Int. Ed. 2017, 56, 7808.
[15] P.-K. Wang, J.-P. Ansermet, S. L. Rudaz, Z. Wang, S. Shore, C. P.
Slichter, J. H. Sinfelt, Science 1986, 234, 35.
[16] According to NMR investigations (see SI, page 111-115) the sharp peak
at 158 ppm might be attributed to the presence of NHC fragments coming
from the degradation of the free NHC ligand.
Keywords: C-H activation • Heterogeneous catalysis • Isotopic
exchange • N-heterocyclic carbene • Deuterium
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[18] Numerous control experiments with various substrates have been
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modification (see SI page 115 Figure S155).
[5]
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10.1002/anie.202009258
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Hydrogen Isotope Exchange
Hydrogen Isotope Exchange
Reductive deuteration
« NHC induced Catalytic activity switch »
Regio- and chemo-selectivties increased
Discovery of novel reactivity
We demonstrate that the addition of N-Heterocyclic carbene ligands on Ru/C induces an important catalytic activity switch, favoring
Hydrogen Isotope Exchange over reductive deuteration. This type of catalyst modification has allowed to increase the regio- and chemo-
selectivities in the context of the C-H deuteration of pharmaceutically relevant substructures but also to discover a novel reactivity for
such heterogeneous Ru catalysts: the selective C-1 deuteration of aldehydes.
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