Mild and efficient H/D exchange of alkanes based on C-H activation catalyzed by rhodium on charcoal

Article abstract of DOI:10.1002/anie.200800941

(Chemical Equation Presented) Easy access: In the presence of Rh/C in D₂O under H₂ at 160°C the H/D exchange reaction of unfunctionalized alkanes can easily occur (see scheme). Inexpensive reagents and mild reaction conditions are used, and fully deuterated products can be obtained after a simple work up procedure.

Full text of DOI:10.1002/anie.200800941

Communications
DOI: 10.1002/anie.200800941
À
C H Activation
À
Mild and Efficient H/D Exchange of Alkanes Based on C H Activation
Catalyzed by Rhodium on Charcoal**
Tomohiro Maegawa, Yuta Fujiwara, Yuya Inagaki, Hiroyoshi Esaki, Yasunari Monguchi, and
Hironao Sajiki*
À
The C H bond activation of organic compounds is one of the
most useful synthetic methods for the fuctionalization of
simple molecules.[1] The activation of unsaturated compounds
can be achieved using transition-metal catalysts, and the
coordination of a metal center to the p bond plays an
important role in the reaction process.[1b] On the other
hand, alkanes (saturated organic compounds) are known to
of Pd/C (or Pt/C) in D2O under H2, which has led to efficient
H/D exchange for a variety of organic molecules such as
aromatic
compounds,[9,10]
ketones,
and
alcohols[11]
(Scheme 1). As part of an ongoing program for the develop-
ment of H/D exchange reactions induced by heterogeneous
À
catalysts, we have discovered a unique protocol for the C H
À
be much less reactive towards C H bond activation than
unsaturated compounds because alkanes possess no coordi-
nation sites for metals. Therefore only a few processes, such as
oxidation, H/D exchange, dehydrogenation, and radical
À
reactions, have been reported as being C H activation-
induced, even though extensive efforts to activate alkanes
have been made.[1] The H/D exchange reaction[2] is a basic
transformation of alkanes. Deuterated products have
received attention not only as useful tools for the investiga-
tion of human metabolism[3] or reaction mechanisms,[4] but
also as functional materials[5] like deuterated polymers as
components of optical fibers for high-speed telecommunica-
tions systems.[5a] Deuterated pesticides and pharmaceuticals
are also effective for quantitative analyses and bioanalytical
investigations as internal standards,[5b–d] while deuterated
alkanes are expected to be applied as marker molecules to
prevent the distribution of illegally mixed light diesel oil.[5e]
Owing to this increasing interest, it is important to develop an
efficient and facile H/D exchange method for alkanes. Since
the first H/D exchange of alkanes was reported by Shilov and
co-workers,[6] other H/D exchange reactions of alkanes have
been developed.[1] Recently, Bergman and co-workers
reported an efficient H/D exchange method for various
substrates, including alkanes, by using a homogeneous
cationic Ir hydride complex under mild conditions.[7] The
H/D exchange reaction with deuterium oxide catalyzed by
Pd/C under hydrothermal conditions has also been
reported.[8]
Scheme 1. Deuterium incorporation into alcohols, ketones, and aro-
matic compounds byusing Pd/C (or Pt/C) in D 2O under H2.
À
activation based deuteration of the C H bond of alkanes,
which do not possess functional groups. Herein we report
À
deuteration of the C H bond by the heterogeneous Rh/C-
catalyzed multi-H/D exchange of simple alkanes. The reac-
tion is carried out with D2O as a solvent and as a deuterium
source under nearly atmospheric pressure,[12] and the addition
of cyclohexane as a co-solvent improves the efficiency of
deuterium incorporation.
As an extension of our study, we examined the H/D
exchange reaction of n-dodecane, which possesses no func-
tional groups and thus cannot coordinate to metal catalysts.
Unexpectedly, deuterium incorporation was observed on all
the carbon atoms of n-dodecane with a 57–61% deuterium
incorporation in the presence of Pd/C in D2O under H2 at
1608C. Encouraged by this result, we screened the effect of
other Group VIII metal catalysts under the same reaction
conditions. Rh/C was found to be the most effective catalyst
for the deuteration of alkanes, where the deuterium incorpo-
ration increased to 81% (Table 1, entry 5). The hydrophobic
catalyst support is essential for the reaction to proceed
(Table 1, entries 6 and 7).
We have recently established a method for deuterium
incorporation into organic molecules by using a combination
[*] Dr. T. Maegawa, Y. Fujiwara, Y. Inagaki, Dr. H. Esaki, Dr. Y. Monguchi,
Prof. Dr. H. Sajiki
Laboratoryof Medicinal Chemistry
Gifu Pharmaceutical University
5-6-1 Mitahora-higashi Gifu 502-8585 (Japan)
Fax: (+81)58-237-5979
E-mail: sajiki@gifu-pu.ac.jp
Homepage: http://www.gifu-pu.ac.jp/lab/yakuhin/index.html
[**] We are grateful to N.E. Chemcat for providing catalysts.
Next, several commercial Rh/C catalysts, obtained from
different suppliers, were used for the H/D exchange reaction
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Examination of Group VIII metal catalysts.[a]
Table 3: H/D exchange of linear alkanes.[a]
[b]
stEntryCataly
D content [%]
CD3(CD2)10CD3
EntrySubstrate
D content [%]
Yield [%]
1
n-dodecane (C12H26)
CD3(CD2)10CD3
91 90 91
CD3(CD2)10CD3
76
76
1
2
3
4
5
6
7
10% Pd/C (10 wt%)
10% Ru/C (10 wt%)
10% Ir/C (10 wt%)
5% Pt/C (20 wt%)
10% Rh/C (10 wt%)
5% Rh/Al2O3 (20 wt%)
RhCl3 3H2O (1.6 mol%)[c]
57 61 57
12 14 12
45 34 45
18 18 18
80 81 80
2[b]
3
n-dodecane (C12H26)
n-pentadecane (C15H32)
n-eicosane (C20H42)
0
0
0
CD3(CD2)13CD3
92 92 92
CD3(CD2)18CD3
87 90 87
93
0
0
0
0
0
0
4
93
5
n-octacosane (C28H58)
n-hexatriacontane (C36H74)
CD3(CD2)26CD3
96 92 96
CD3(CD2)34CD3
59 52 59
100
96
[a] The reaction was carried out with the given catalyst in D2O (2 mL)
under H2 at 1608C. [b] Catalysts were provided by N.E. Chemcat, except
for Pt/C (Aldrich). Amount of catalyst used is shown in parentheses.
[c] The amount of Rh metal used in the reaction was the same as for
entry5.
6[c]
[a] The reaction was carried out with the substrate (0.25 mmol) and 5%
Rh/C (20 wt%) in D2O (2 mL) under H2 at 1608C. [b] Under argon.
[c] 24 h.
because it is known that the activity of supported metal
catalysts is variable depending on the commercial source[13]
(Table 2). The 5% Rh/C provided by Aldrich had a better
catalyst activity, and nearly fully deuterated n-dodecane was
obtained (Table 2, entry 3). The reason for the varied out-
methyl groups within the branched alkanes proceeded
smoothly with high deuteration efficiencies (Table 4,
entries 1–4). Cyclic alkanes, such as cyclopentadecane and
pentadecylcyclohexane, were also deuterated with moderate
to excellent efficiencies (Table 4, entries 5–7). In contrast a-
cholestane, possessing a rigid cholesterol skeleton, had a
lower deuterium incorporation ratio (Table 4, entry 8). The
deuterated products were spectroscopically pure and did not
require chromatographic purification.
Table 2: Effect of catalyst obtained from different suppliers.
EntrySupplier
1
D content [%]
CD3(CD2)10CD3
For the H/D exchange reaction of alkanes, the oxidative
N.E. Chemcat (10% Rh/C, 10 wt%)
80 81 80
81 80 81
96 92 96
50 52 50
À
insertion of Rh into the C H bonds should be the key step.
2
3
4
Wako Chemical (5% Rh/C, 20 wt%)
Aldrich (5% Rh/C, 20 wt%)
Merck (5% Rh/C, 20 wt%)
Since H2 at atmospheric pressure is essential for the deutera-
tion reaction (Table 3, entry 2) it might act as an activator of
the Rh catalyst (as a so-called mild ligand). There are two
plausible mechanisms (Scheme 2).[9g] Firstly, the H2-and D2O-
[a] The reaction was carried out with the catalyst in D2O (2 mL) under H2
at 1608C.
À
activated Rh species A could insert into the C H bond of the
alkane followed by H/D exchange with D2O to form B’. Then
reductive elimination from B’ gives the corresponding
deuterated alkane (path a). Alternatively, the Rh–substrate
complex B could undergo b-hydride elimination to produce
an alkene, which can react with A to form the Rh–p-allyl
complex C. Subsequent H/D exchange, reductive elimination,
come of the reaction (depending on the source of catalyst) is
still unclear. This inconsistency might be caused by the quality
of the activated carbon in the catalyst, by the remaining acid
(a contaminant from the process purification of catalyst) on
the activated carbon, or by the valence of Rh on the activated
carbon.
The above Rh/C-catalyzed H/D exchange
method was applied to the deuteration of
various linear alkanes (Table 3).[14] Linear
alkanes bearing less than 28 carbon atoms
underwent H/D exchange at all of the carbon
centers with over 90% deuterium incorpora-
tion and with high to quantitative yields of each
isolated product (Table 3, entries 1 and 3–5). In
the case of n-hexatriacontane (36 carbon
atoms), however, deuterium incorporation
was moderate (up to 59%, Table 3, entry 6).
No H/D exchange was observed under the H2-
free reaction conditions (Table 3, entry 2).
Branched and cyclic alkanes were also
deuterated under the same reaction conditions.
The H/D exchange of secondary and tertiary Scheme 2. Plausible mechanisms.
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Table 4: H/D exchange of branched and cyclic alkanes.[a]
Table 5: The effect of co-solvent.[a]
EntrySubstrate
t [h] D content [%]
Yield [%]
90
EntryCo-solvent
D content [%]
CD3(CD2)34CD3
1
2-methylundecane
12
1
2
3
4
5
none
cyclohexane
CHCl3
1,2-dichloroethane
toluene
43 41 43
93 94 93
13 25 13
37 40 37
28 30 28
CD3 92; CD2 93; CD 96
2,2,4,6,6-penta-
methylheptane
2
3
12
24
96
60
CD3 85; CD2 80; CD 91
CD3 88; CD2 90; CD 90
2,2,4,4,6,8,8-hepta-
methylnonane
[a] The reaction was carried out with the substrate (0.1 mmol) and 5%
Rh/C (20 wt%) in D2O (1 mL) and co-solvent (0.1 mL) under H2 at
1608C.
4
squalane
24
92
entry 2); in contrast, other solvents such as CHCl3, 1,2-
dichloromethane, and toluene all decreased the deuterium
efficiency (Table 5, entries 3–5). We also carried out H/D
exchange reactions on a branched alkane and a cyclic alkane
using cyclohexane as the co-solvent. Consequently, the
deuterium incorporated onto the substrates was significantly
improved (Scheme 3; for comparison see Table 4, entries 5
and 8).
CD3 99; CD2 99; CD 100
5
6
7
cyclododecane
24
24
66
78
88
CD2 84
cyclopentadecane
CD2 94
pentadecylcyclohexane 24
a 69; b 82; c 77
8
a-cholestane
24
97
Scheme 3. The H/D exchange reaction using cyclohexane as the co-
solvent.
D 36(average)
[a] The reaction was carried out with 5% Rh/C (20 wt%) in D2O (2 mL) under H2
at 1608C.
In conclusion, we have developed an efficient Rh/C-
catalyzed H/D exchange reaction of alkanes under nearly
À
and hydrogenation gives the deuterated alkane (path b).
Further deuterium incorporation may occur by repetition of
the processes described as paths a and b. The reaction may
occur on the Rh metal interface of the support, as the
activated carbon plays an important role in the reaction
progress (Table 1).
atmospheric conditions based on the C H activation process.
This method can be applied to diverse alkanes with good to
high deuterium incorporation. The addition of cyclohexane as
a co-solvent significantly improves the deuteration efficiency.
Notably, the H/D exchange reaction of alkanes described
herein efficiently proceeds in D2O even though alkanes are
only slightly soluble in D2O. It is likely that the activated
carbon helps to dissolve and/or concentrate the alkanes into
the carbon micropores (enrichment effect of the substrate),
and therefore the alkanes can easily come into contact with
the Rh catalyst. We envisioned that a co-solvent for dissolving
alkanes would improve the efficiency of the deuteration
process. Several solvents for the deuteration of n-hexatria-
contane were explored. Interestingly, only cyclohexane
enhanced the deuterium efficiencies up to 94% (Table 5,
Experimental Section
In a hydrogen atmosphere, a suspension of D2O (2 mL), 5% Rh/C
(20 wt%), and substrate (0.25–0.5 mmol) was stirred at 1608C for 12–
24 h. After the reaction was complete, the mixture was extracted with
Et2O and the ethereal layer was washed with brine, dried over
MgSO4, and concentrated in vacuo to give the deuterated product.
The deuterium content of the product was calculated by using
1H NMR spectra with 1,4-dimethoxybenzene as an internal standard.
The deuterium incorporation was confirmed by 2H NMR spectros-
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copy and the amount of deuterium incorporated was also determined
by mass spectrometry.
[9] Pd/C-catalyzed H/D exchange reactions: a) H. Sajiki, K. Hattori,
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Received: February 27, 2008
Published online: June 13, 2008
À
Keywords: alkanes · C H activation · H/D exchange ·
heterogeneous catalysis · rhodium
.
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