Ruthenium-Catalyzed Dehydrogenation Through an Intermolecular Hydrogen Atom Transfer Mechanism

Article abstract of DOI:10.1002/anie.202015837

The direct dehydrogenation of alkanes is among the most efficient ways to access valuable alkene products. Although several catalysts have been designed to promote this transformation, they have unfortunately found limited applications in fine chemical synthesis. Here, we report a conceptually novel strategy for the catalytic, intermolecular dehydrogenation of alkanes using a ruthenium catalyst. The combination of a redox-active ligand and a sterically hindered aryl radical intermediate has unleashed this novel strategy. Importantly, mechanistic investigations have been performed to provide a conceptual framework for the further development of this new catalytic dehydrogenation system.

Full text of DOI:10.1002/anie.202015837

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 7290–7296
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Dehydrogenation Very Important Paper
Ruthenium-Catalyzed Dehydrogenation Through an Intermolecular
Hydrogen Atom Transfer Mechanism
Lin Huang, Alessandro Bismuto, Simon A. Rath, Nils Trapp, and Bill Morandi*
Abstract: The direct dehydrogenation of alkanes is among the
most efficient ways to access valuable alkene products.
Although several catalysts have been designed to promote this
transformation, they have unfortunately found limited appli-
cations in fine chemical synthesis. Here, we report a concep-
tually novel strategy for the catalytic, intermolecular dehydro-
genation of alkanes using a ruthenium catalyst. The combina-
tion of a redox-active ligand and a sterically hindered aryl
radical intermediate has unleashed this novel strategy. Impor-
tantly, mechanistic investigations have been performed to
provide a conceptual framework for the further development
of this new catalytic dehydrogenation system.
applicability. A novel approach has been inspired by the
exquisite reactivity achieved with desaturase enzymes, which
can dehydrogenate alkanes with high site-selectivity through
a stepwise process under mild reaction conditions.[7] To mimic
Introduction
Alkenes are important building blocks for a variety of
applications spanning petrochemistry to natural product
synthesis.[1] The direct, catalytic dehydrogenation of alkanes
offers the most versatile and efficient strategy to access
alkenes.[2] Indeed, industrially, alkenes are generally accessed
through a dehydrogenation process. However, the extremely
harsh reaction conditions have limited the possibility to
harness this reaction in fine chemical synthesis.[3] A seminal
report of dehydrogenation by Crabtree in 1979, in which tert-
butylethylene (TBE; 3,3-dimethyl-1-butene) served as a hy-
drogen acceptor to produce the corresponding alkene-IrIII-
complex from an IrI species, has spurred the development of
milder, Ir-catalyzed protocols for alkane dehydrogenation
(Scheme 1a).[4] The proposed mechanism of this reaction
À
features an oxidative addition of the inert C H bond,
mediated by noble metal complexes, followed by a b-hydride
elimination.[5] The same strategy has also been demonstrated
with Ru- and Os-pincer complexes,[6] however, with limited
[*] L. Huang, Prof. Dr. B. Morandi
Max-Planck-Institut für Kohlenforschung
Kaiser-Wihelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
L. Huang, Dr. A. Bismuto, S. A. Rath, Dr. N. Trapp,
Prof. Dr. B. Morandi
Laboratorium für Organische Chemie ETH Zürich
Vladimir-Prelog-Weg 3, HCI, 8093 Zürich (Switzerland)
E-mail: bill.morandi@org.chem.ethz.ch
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202015837.
ꢀ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution Non-Commercial
NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-
commercial and no modifications or adaptations are made.
Scheme 1. Previous works: a) Pincer-ligated metal catalytic dehydro-
genation, b) Intramolecular desaturation, c) Cooperative desaturation
(cHAT), and d) Our hypothesis and design.
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this reactivity with non-enzymatic catalytic systems, White
diimine ligands as their ability to adopt a monoanionic radical
and co-workers have managed to divert a non-heme iron
hydroxylation catalyst toward dehydrogenation.[8] However,
further oxidation of the double bond under the reaction
conditions could not be prevented, precluding the use of this
method for alkene synthesis from alkanes. Subsequently, the
Baran and Gevorgyan groups have developed alternative
strategies for the dehydrogenation reaction employing small
molecule-based reagents to prevent overoxidation.[9] In these
processes, highly reactive aryl radical intermediates are used
as controlling elements to mediate the desaturation of alkanes
by an intramolecular hydrogen atom transfer (HAT) process
(Scheme 1b).[9] While these methods offer practical solutions
for intramolecular dehydrogenation, they have not yet
demonstrated their applicability in more challenging inter-
molecular dehydrogenations.
character had been previously shown by Chirik and co-
workers in hydrofunctionalization reactions.[14] Interestingly,
the same set of ligands did not lead to any product formation
for our target dehydrogenation reaction (Supporting Infor-
mation, Tables S1, S2). We envisaged that adding phenyl rings
on the ligand backbone may further enhance the propensity
of this ligand to exhibit a non-innocent behavior owing to
a possible additional delocalization of the radical into a more
extended p-system. Gratifyingly, this strategy led to almost
full conversion of the starting material, especially when
bidentate diimine ligands were employed. Unfortunately, the
yield of cyclooctene was relatively low, and the coupling
product between the phenyl radical and the aromatic solvent
was observed (Supporting Information, Figure S1). Notably,
we reasoned that the lifetime of the aryl radical and
potentially the chemoselectivity of the HAT process could
be readily influenced by tuning the steric and electronic
properties of the aryl radical to favor an intermolecular HAT
process.[16] We decided to investigate the effect of introducing
substituents in the ortho position of the starting aryl iodide
(Supporting Information, Figure S1). This resulted in a sig-
nificant increase in the yield of cyclooctene when a mixture of
alkane (5 equiv), mesityl iodide (1 equiv), diimine ligand (L4,
18 mol%), and Ru3(CO)12 (3 mol%) were allowed to react at
1508C in chlorobenzene for 24 hours (see the Supporting
Information: optimization of the model reaction).
Next, we sought to explore the substrate scope of this
dehydrogenation protocol (Scheme 2). Generally, cycloal-
kanes with a larger ring size gave the corresponding alkenes in
a higher yield. Cyclooctane, cyclododecane, and cyclopenta-
decane afforded 3a in 84% yield, 3d as a mixture of E/Z (2/3)
isomers[17] in 82% yield, and 3e as an unidentified mixture of
E/Z isomers in 91% yield, respectively. By contrast, the
smaller ring size cycloalkanes gave the corresponding alkenes
in 45% (3b) and 72% (3c) yields. It should be noted that the
yields of these cycloalkenes seem to correlate with the lower
boiling points of the corresponding alkane substrates, possibly
hinting a material loss through evaporation. Unfunctionalized
linear alkanes also successfully underwent a dehydrogenation
reaction, giving the corresponding alkenes (3 f–i) as a mixture
of isomers in 52% to 67% yield. Furthermore, a mixture of
substituted cyclohexanes gave alkene regio-isomers (3j and
3j’) in 34% (17% of 3j + 17% of 3j’) yield. When the less
crowded 1-iodo-2-methylbenzene was used as an aryl radical
precursor, the alkene regio-isomers (3j and 3j’) were
obtained in 49% (17% of 3j + 32% of 3j’) yield. Interest-
ingly, the isomeric ratio of 3j/3j’ remained constant through-
out the reaction, ruling out the occurence of isomerization as
a side reaction when using the substituted cyclohexane
substrates (see the Supporting Information, control experi-
ments (2) and (3)). These results also indicate that the
selectivity obtained might reflect the kinetic selectivity of the
process. Next, we explored the reactivity toward ethers and
aliphatic amines. They all underwent successful dehydrogen-
ation to the corresponding alkenes (3k–q) with good chemo-
selectivity. In the case of tertiary aliphatic amines, good
stereoselectivity was observed providing the corresponding
enamines (E) in moderate yield (3o–q). The chemo- and
Recently, Sorensen and co-workers reported the most
successful attempt so far to mimic enzymatic reactivity in an
intermolecular process, which generates alkenes from alkanes
through a radical pathway.[10] In this work (Scheme 1c), a dual
catalytic system composed of a tungsten photocatalyst, which
À
can initially abstract a hydrogen atom from a C H bond, and
a cobalt cocatalyst, which can generate alkenes from the
resulting carbon-centered radical, is used in a tandem fashion
to perform dehydrogenation of simple alkane substrates upon
release of hydrogen gas. Despite the low yield and limited
substrate scope reported, this reaction remains the state-of-
the-art in the area of catalytic intermolecular dehydrogen-
ation reactions based on a HAT process, clearly highlighting
the need for the development of new strategies.[10,11]
Herein, we report a conceptually new strategy for the
HAT-mediated intermolecular dehydrogenation reaction of
alkanes. We have used a redox-active ligand to facilitate the
Ru-catalyzed generation of highly reactive yet sterically
hindered aryl radicals, which can mediate a facile intermo-
lecular alkane dehydrogenation reaction (Scheme 1d).
Results and Discussion
Our key hypothesis to develop this new reaction relies on
the use of redox-active ligands[12] to enable an otherwise
challenging combination of one- and two-electron processes
at a Ru-center.[12d–f,13] In particular, aromatic diimine ligands
have often been shown to formally adopt a monoanionic,
monoradical character which could possibly help us to divert
the reactivity of Ru species toward radical pathways.[12d–f,13,14]
In theory, this could allow the generation, from a reaction
between a Ru-center and an aryl iodide,[15] of a highly reactive
aryl radical intermediate I, which could then participate in an
intermolecular HAT process; the newly generated carbon-
centered radical II can then react with the partially oxidized
Ru-intermediate to release the desired alkene and HI which
can subsequently be trapped by a base (Scheme 1d). In this
process, the aryl iodide formally plays the role of a mild
oxidant for the dehydrogenation process.
We started our investigation by selecting cyclooctane and
iodobenzene as benchmark substrates and Ru3(CO)12 as
precatalyst. We first focused our attention on conjugated
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Scheme 3. Intermolecular dehydrogenation scope of alkanes, ethers
and aliphatic amines. Reaction conditions: Ru3(CO)12 (3 mol%), L4
(18 mol%), 1 (0.6 mmol), 5n (0.5 mmol), Cs2CO3 (1 mmol), PhCl
(1 mL), 1508C, 16 h, isolated yields. [a] Ru3(CO)12 (5 mol%), L4
(30 mol%), 1 (1.1 mmol), 5n (0.5 mmol). [b] PhCl (0.1 mL), 18 h.
Functionalized aryl alkanes are rarely used as sub-
strates[21] in intermolecular dehydrogenation reactions, be-
cause of the high propensity of conjugated aryl alkenes to
participate in polymerization and other side reactions.
Interestingly, using our reaction conditions from Scheme 2,
we could obtain the desired product 9a in a low GC-yield
(11%) and the radical dimerization product 9b as a mixture
of diastereoisomers[22] (meso/DL = 1/1) in 18% GC-yield,
when propyl benzene was employed as a substrate. Then, we
started to optimize the conditions for propyl benzene
dehydrogenation using a selection of different redox-active
ligands[12,23] and phosphine ligands (Supporting Information,
Table S3). Finally, using a slightly modified version of our
original protocol (Scheme 4), the aryl alkanes bearing differ-
ent substituents (Cl, Br, phenyl, and methoxyl) gave the
desirable conjugated aryl alkenes in moderate to good yields
(9a–f, 9h, and 9h’). Compared to the previously reported
dehydrogenation of tetrahydronaphthalenes,[11e,24] we ob-
tained the aromatic product 9h’’ in a low yield (12%) and
the conjugated aryl alkene as a mixture of regioisomers[25]
(9h/9h’ = 1/1.2) in 47% (21% of 9h + 26% of 9h’) using 6-
methoxy-1,2,3,4-tetrahydronaphthalene as a substrate. Addi-
tionally, an aromatic heterocycle also gave the corresponding
dehydrogenated product (9g) in 32% yield.
To demonstrate the synthetic applicability of this proto-
col, we used dodecane, tetradecane, and cyclooctane as
substrates to perform gram-scale tandem reactions
(Scheme 5). Two terminal borylation products (10a and
10b) were isolated in 52% and 54% yields from one-pot
tandem reactions (Scheme 5a).[26] An epoxide product (10c)
was isolated in 67% yield proceeding through two separate
steps (Scheme 5b).[27] Overall, the results using this catalytic
system are synthetically relevant and are comparable to the
state-of-the-art in radical-based intermolecular dehydrogen-
ation reactions.
Scheme 2. Intermolecular dehydrogenation scope of alkanes, ethers
and aliphatic amines. Reaction conditions: Ru3(CO)12 (3 mol%), L4
(18 mol%), 1 (0.5 mmol), 2n (2.5 mmol), Cs2CO3 (1 mmol), PhCl
(1 mL), 1508C, 24 h, 1H-NMR yields using CH2Br2 as the internal
standard. [a] Ru3(CO)12 (6 mol%), L4 (36 mol%), 2n (10 mmol). [b]
Ru3(CO)12 (5 mol%), L4 (30 mol%). [c] Ru3(CO)12 (6 mol%), L4
(36 mol%), 2n (5 mmol). [d] Ru3(CO)12 (6 mol%), L4 (36 mol%), 2n
(5 mmol), 1-iodo-2-methylbenzene (1b, 0.5 mmol).
stereoselectivity of ether and aliphatic amine dehydrogen-
ations are similar to previous studies employing Ir-pincer
catalysts.[18]
This method also proved to be efficient toward aryl-
containing heterocycles (Scheme 3). Dehydrogenated prod-
ucts, such as indoles (6a–d), quinolines (6e and 6 f), isoquino-
lines (6g and 6h), lactone (6i), and arylimine (6j), were
isolated in moderate to good yield. In contrast to previously
reported methods,[19] a range of functional groups (F, Br,
methyl, methoxyl, and ester) (6b–d, 6 f, 6h, and 6i) were
tolerated. Harmine (6k), a potent alkaloid used in several
medical applications,[20] could also be obtained, showcasing
the synthetic potential of the new protocol. Next, we
evaluated the scope of intramolecular reactions using this
procedure with slightly modified conditions (using 0.1 mL of
PhCl as solvent). The corresponding unsaturated products
(7a–c) were isolated in good yield, similar to the previous
protocol.[9c]
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our reaction conditions [Scheme 6a, Eq. (1)]. Furthermore,
we observed the radical dimerization product 9b (18%) and
the radical alkyl-BHT trap product 10e (46%) during addi-
tional control reactions [Scheme 6a, Eqs. (2) and (3)]. Addi-
tionally, the dimer 9b (meso)[22] was isolated and structurally
characterized by 1H/13C-NMR and X-ray analysis (Supporting
Information, page 15, isolation of the dimer 9b). Moreover,
the radical trap product 10e was also isolated and structurally
1
characterized by H/13C-NMR (see the Supporting Informa-
tion, radical trap experiments). Alkyl-BHT adducts similar to
10e have been reported previously in the literature.[28,29]
Using TEMPO as another radical trap, 12% of 3a was
obtained while 84% of 1 was recovered from this experiment
[Scheme 6a, Eq. (4)]. Overall, these observations strongly
support the presence of both an aryl and alkyl radical in
accordance with our initial hypothesis (Scheme 1d). Finally,
we performed an intermolecular competition experiment and
observed a large primary kinetic isotope effect (Scheme 6b,
KIE: 6.5), a result comparable to literature values (KIE: 4.8–
À
11) for C H amination involving an intermolecular HAT
mechanism enabled by Ru-bis-imido complexes.[30]
Next, we performed mechanistic and organometallic
studies (Figure 1). First, we conducted preliminary stoichio-
metric experiments to isolate any potential reaction inter-
mediates. Stirring Ru3(CO)12 at 1108C in toluene for 24 hours
in the presence of two variations of the ligand gave both
complexes I and II in 61% and 42% yield, respectively
(Figure 1a) along with small amounts of diligated and
triligated species (see SI, X-ray analysis). In contrast to
previously reported Ru-diimine complexes, which were often
reported as dinuclear species,[31] the products of our reactions
were isolated as mononuclear ruthenium complexes. Single
crystal X-ray analysis of complex II showed the ruthenium
atom set in a square pyramidal geometry with the diimine
ligand placed in the same plane with a bite angle of 76.59(6)8.
The mononuclear nature and the vacant coordination site
resulted in a high air- and moisture-sensitive behavior, with
the compound decomposing within seconds when exposed to
air. Interestingly, the influence of the redox-active ligand
scaffold resulted in unusual bond lengths for the carbon–
nitrogen and the amino–ruthenium bonds, a result consistent
with our initial hypothesis. The Ru–N1 and Ru–N2 distances
are within the range of values reported for anionic nitrogen-
based ligands (2.03 Š complex II vs. 1.97 Š literature).[32]
Scheme 4. Intermolecular dehydrogenation scope of aryl alkanes. Re-
action conditions: Ru3(CO)12 (3 mol%), dppp (10 mol%), L13
(30 mol%), 1 (0.5 mmol), 8n (7.5 mmol), Cs2CO3 (1 mmol), PhCl
(1 mL), 1508C, 24 h, 1H-NMR yields using CH2Br2 as the internal
standard. [a] reaction conditions from Scheme 2. [b] 8n (2.5 mmol).
À
Accordingly, we observe elongation of the C N bonds
(1.28 Š literature vs. 1.36 Š complex II) when compared to
Scheme 5. Applicability and scalability of our dehydrogenation proto-
col.
À
imine bond lengths, as well as the shortening of the C C bond
(1.51 Š literature vs. 1.40 Š complex II) towards a range more
typical for an alkene bond. The solid-state structure of
complex I and II clearly supports an ambiguous oxidation
state at the Ru-center (Supporting Information, Figures S2,
S3). By analogy with similar species previously reported,[33] it
could be regarded as a RuI species supported by a mono-
anionic, radical ligand.[34]
Gratifyingly, performing the reaction using isolated com-
plex I and II as catalyst led to 42% and 32% yields
(Figure 1a, below) of product formation, respectively, and
showed a similar initial rate and kinetic profile when
compared with the normal reaction conditions involving the
We were particularly interested to confirm both the
involvement of radical species (see the Supporting Informa-
tion, control experiments (1)) and the implication of redox
non-innocence in enabling this novel reactivity. First, we
conducted radical coupling and trapping experiments under
optimum conditions (Scheme 6a). While the preceding,
highly reactive aryl radical (Scheme 1d, intermediate I) could
not be trapped directly by BHT/TEMPO, we were never-
theless able to detect it through reaction with a more
nucleophilic aromatic solvent (34% of coupling product
10d), thus indicating that this species is likely generated under
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Scheme 6. Radical coupling and trap reactions and kinetic isotope effect
study. Reactions were performed under optimum conditions (0.5 mmol
scales). GC yield using dodecane as the internal standard. 1H NMR yields
using CH2Br2 as the internal standard.
in situ generated catalyst, supporting the kinetic competency
of these complexes. Unfortunately, catalysts I and II seem to
be completely deactivated after reaching the fourth turnover,
a result which explains the lower yield observed in this case
(Supporting Information, Table S4). Recently, Bures[35] and
Blackmond[36] described a new method to determine catalyst
deactivation and product inhibition by carrying out a set of
three simple experiments, where the concentration of the
reagents is varied while keeping the concentration of the
catalyst constant (Figure 1b, top). It was evident from these
experiments that after the fifth turnover, the rate of the
reaction clearly decreased because of a possible catalyst
deactivation, which involved no product inhibition. Unfortu-
nately, even using the approach of the initial rate, we could
Figure 1. Mechanistic and organometallic studies. For more details,
see the Supporting Information.
not gather further information as the low homogeneity of the
reaction hampered the collection of reproducible data.
In an attempt to shed light on the deactivation pathway,
we next performed another stoichiometric experiment in-
volving aryl iodide reagents. Interestingly, in the absence of
the diimine ligand, no reaction was observed even at elevated
temperatures, supporting the role of the ligand in promoting
the activation of the iodide oxidant. Instead, the addition of
mesityl iodide to pre-formed complex I or II led to a full
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conversion to a new complex. In contrast to what has been
arship. Open access funding enabled and organized by
reported with other classes of diimine ligands bearing alkyl
substituents on the backbone instead of aryl groups, it was not
possible to observe or isolate any of the oxidative addition
products.[37] Instead, the trans carbonyl insertion complex III
was obtained (Figure 1b, bottom) along with the diiodo
ruthenium complex IV. In contrast to complex I, these two
Projekt DEAL.
Conflict of interest
The authors declare no conflict of interest.
À
complexes both exhibit an octahedral geometry, with Ru N
II
À
and C N bond lengths and angles within the range of a Ru
Keywords: alkenes ·aryl radicals ·dehydrogenation ·
hydrogenation atom transfer ·redox-active ligands
complex with dative nitrogen coordination, indicating a more
classical behavior of the neutral diimine ligand in this
oxidized state. We then set out to evaluate the catalytic and
kinetic competence of all the isolated ruthenium complexes
for the dehydrogenation of cyclooctane. Complexes III and
IV only gave trace amounts of the product (Supporting
Information, Table S4), suggesting that these species are
possible deactivation products. More importantly, the di-iodo
species IV could be observed by 19F NMR spectroscopy under
catalytic conditions and its concentration steadily increased
over the course of the reaction (Supporting Information,
Figure S4). This observation, when combined with the
catalytic incompetence observed above, clearly suggests that
the formation of the di-iodo species is the major deactivation
pathway under the reaction conditions. This result provides
critical information for the design of second-generation
catalysts for this transformation.
While the detailed mechanism remains unclear at this
stage, the observed unusual bond lengths in the solid state, the
indirect detection of the two proposed carbon-centered
radical intermediates and the large primary KIE strongly
support a redox-active ligand assisted HAT pathway[30] for
this intermolecular dehydrogenation reaction, similar to the
one postulated in Scheme 1d.
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Conclusion
The use of Ru3(CO)12 and a diimine ligand (L4)/diketone
ligand (L13) has unlocked the challenging intermolecular
dehydrogenation of alkanes. The combination of a redox-
active ligand and a sterically hindered aryl radical intermedi-
ate has enabled this novel strategy, which can be used to
synthesize a wide variety of alkene products. Mechanistic
studies have shed light on crucial aspects of this conceptually
novel catalytic system. We thus believe that the results
reported herein will serve as a platform to develop a com-
pletely new family of dehydrogenation catalysts.
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We thank the Max-Planck-Society and ETH Zürich (ETH
Research Grant ETH-45 19-2) for generous funding. We
thank Prof. B. List for sharing analytical equipment, and the
NMR, MS, and X-ray departments of the MPI für Kohlen-
forschung and ETH Zürich for technical assistance. We also
thank Dr. Shin for the analysis of oligomers/polymers by
GPC. L.H. thanks the China Scholarship Council for a schol-
Angew. Chem. Int. Ed. 2021, 60, 7290 –7296
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7295

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Manuscript received: November 27, 2020
Accepted manuscript online: January 5, 2021
Version of record online: February 25, 2021
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