Bimetallic palladium-platinum-on-carbon-catalyzed H-D exchange reaction: Synergistic effect on multiple deuterium incorporation

Article abstract of DOI:10.1055/s-0029-1216895

We prepared several activated carbon-supported bimetallic Pd-Pt catalysts (Pd-Pt/C) by using various reducing reagents, and examined their catalytic activities for the deuteration of alkylsubstituted aromatic compounds. Multiple deuterations catalyzed by

Full text of DOI:10.1055/s-0029-1216895

2674
PAPER
Bimetallic Palladium–Platinum-on-Carbon-Catalyzed H–D Exchange
Reaction: Synergistic Effect on Multiple Deuterium Incorporation
B
imetallic Pd–P
o
t/C-Catalyz
e
m
d
H
–D Exchange
Ro
eaction hiro Maegawa,a,1 Nobuhiro Ito,b Keiji Oono,b Yasunari Monguchi,a Hironao Sajiki*a
a
Laboratory of Organic Chemistry, Department of Organic and Medicinal Chemistry, Gifu Pharmaceutical University,
Gifu 502-8585, Japan
b
Chemical Products Research Laboratories, Wako Pure Chemical Industries, Ltd., Matoba, Kawagoe 350-1101, Japan
Fax +81(58)2375979; E-mail: sajiki@gifu-pu.ac.jp
Received 12 February 2009; revised 8 May 2009
ing various reducing agents, and we also report the
occurrence of synergistic effects in H–D exchange reac-
tions catalyzed by these bimetallic catalysts.
Abstract: We prepared several activated carbon-supported bime-
tallic Pd–Pt catalysts (Pd–Pt/C) by using various reducing reagents,
and examined their catalytic activities for the deuteration of alkyl-
substituted aromatic compounds. Multiple deuterations catalyzed
by Pt–Pd/C proceeded in D2O at 180 °C under a H2 atmosphere, and
a synergistic effect was observed in relation to the incorporation of
deuterium at sterically hindered positions on aromatic rings.
As an extension of our development of an effective multi-
deuteration method,7–10 we planned to prepare a Pd–Pt bi-
metallic catalysts that should promote efficient H–D ex-
change reactions through a synergistic effect. Pd/C is
usually prepared by the absorption of a palladium(II) salt
from solution into activated carbon, and subsequent re-
duction by using an appropriate reducing agent. We chose
dihydrogen, hydrazine, formaldehyde, and sodium boro-
hydride as reducing agents for the preparation of Pd–Pt bi-
metallic catalysts on the basis of known procedures for the
preparation of Pd/C catalysts.11 Each catalyst showed a
different catalytic activity toward the H–D exchange reac-
tion of 5-phenylpentanoic acid (Table 1). Pd/C was effi-
cient in catalyzing H–D exchange on the alkyl chain
(>94%), whereas the amount of deuteration of the aromat-
ic ring was moderate (entry 5). On the other hand, the use
of Pt/C alone led to high incorporation of deuterium on the
aromatic ring (80%), but a little incorporation on the alkyl
chain, except in the benzylic position (C1) (entry 6). Deu-
teration using bimetallic Pd–Pt/C catalysts, prepared by
various protocols, proceeded simultaneously on both the
alkyl chain and the aromatic ring with a high efficiency
(entries 1–4). Among the bimetallic catalysts, the one pre-
pared by reduction with sodium borohydride [5% Pt–Pd/
C(NaBH4)] showed a better catalytic activity toward mul-
tiple deuteration (entry 4), and the efficiency of deutera-
Key words: heterogeneous catalysis, palladium, platinum, H–D
exchange, synergy, bimetallic
The development of a variety of applications of deuteri-
um-labeled compounds in a number of scientific fields,
such as quantitative analyses using mass spectrometry,
mechanistic and metabolic studies, and material science,2
has led to interest in the development of efficient and con-
venient methods for synthesizing such compounds. Al-
though deuterium-labeled compounds can be obtained
either by multistep syntheses starting from deuterium-
labeled small-molecule synthons or by post-synthetic
H–D exchange reactions of target compounds, the latter
approach is more cost- and time-efficient than the former.
Although a number of post-synthetic H–D exchange
methods have been reported that involve the use of transi-
tion-metal catalysts,3 supercritical conditions,4 microwave
irradiation,3q–s,5 or other methods,6 the vast majority of
these requires harsh conditions, expensive reagents (such
as D2 gas), and special (pressure-, acid-, or base-resistant)
equipment, and are therefore inefficient.3–6
We have developed several novel deuteration methods tion of the aromatic ring (91%) was obviously higher than
based on heterogeneously catalyzed H–D exchange reac- that of corresponding reaction catalyzed by Pt/C alone
tions of various organic compounds in D2O under an at- (entry 6).12 A mixture of Pd/C and Pt/C also gave an
mosphere of H2 in the presence of platinum group equivalent level of deuteration of the aromatic ring to 5%
catalysts such as palladium-on-carbon (Pd/C),7 platinum- Pt–Pd/C(NaBH4), but a somewhat lower level of deutera-
on-carbon (Pt/C),7g,l rhodium-on-carbon,8 or ruthenium- tion at the C4 position (entry 7). The mechanism of these
on-carbon.9 These methods are simple, efficient, cost-ef- synergistic effects is unclear, but we speculate that alloy-
fective, and can be applied in the deuteration of a wide va- ing of the palladium and platinum metals may affect their
riety of substrates. In our ongoing study of such H–D catalytic activity.13
exchange reactions, we identified a marked synergistic ef-
We next examined the use of Pd–Pt/C(NaBH4) for the
fect when mixtures of Pd/C and Pt/C catalysts were
deuteration of hexylbenzene (Table 2). The incorporation
of deuterium by the 5% Pd–Pt/C(NaBH4)-catalyzed reac-
used.10 Here, we report a method for the preparation of bi-
metallic platinum–palladium-on-carbon catalysts by us-
tion proceeded efficiently to give highly deuterated hexyl-
benzene-d18 in 85% isolated yield (entry 1); this reaction
SYNTHESIS 2009, No. 16, pp 2674–2678
x
x.
x
x
.
2
0
0
9
also proceeded efficiently with a mixture of 5% Pd/C and
5% Pt/C catalysts (entry 2), whereas the use of 10% Pd/C
alone gave disappointing deuteration efficiencies, espe-
Advanced online publication: 10.07.2009
DOI: 10.1055/s-0029-1216895; Art ID: F04009SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Bimetallic Pd–Pt/C-Catalyzed H–D Exchange Reaction
2675
Table 1 5% Pd–Pt/Carbon-Catalyzed Deuteration of 5-Phenylpentanoic Acid
D
D D
D
Ar
1
3
CO2H
CO2H
5% Pd–Pt/C (20 wt%)
2
4
D
H2, D2O, 180 °C, 6 h
sealed tube
D
D
D
D
Entry
Reducing Agent
Catalyst
D content (%)
Ar
Yield (%)
C1
97
97
97
96
96
96
96
C2 + C3
96
C4
97
94
76
88
95
25
77
1
2
3
4
5
6
7
H2
5% Pd–Pt/C
5% Pd–Pt/C
5% Pd–Pt/C
5% Pd–Pt/C
10% Pd/Ca
75
78
64
91
68
80
87
85
NH2NH2
95
95
HCHO
94
91
NaBH4
94
84
–
–
–
94
83
5% Pt/C
47
quant
92
5% Pd/C + 5% Pt/C
97
a 10 wt% of 10% Pd/C was used as the catalyst.
Table 2 5% Pd–Pt/C(NaBH4)-Catalyzed Deuteration of Hexylbenzene
D
D D D D D
Ar
1
3
5
D
D
catalyst (20 wt%)
6
2
4
D
H2, D2O, 180 °C, 24 h
sealed tube
D
D
D
D
D
Entry
Catalyst
D content (%)
Yield
(%)
Ar
97
94
35
C1
97
96
94
C2
93
94
94
C3–C5
89
C6
86
83
42
1
2
3
5% Pd–Pt/C(NaBH4)
5% Pd/C + 5% Pt/C
10% Pd/Ca
85
97
98
89
61
a 10 wt% of 10% Pd/C was used as the catalyst.
In a study on the deuteration of several organic com-
pounds, we found that H–D exchange reactions at sterical-
ly hindered positions, such as the aromatic positions ortho
to carbon substituents, were highly inefficient when Pd/C
or Pt/C was used as a sole catalyst. The use of a mixture
of 5% Pd/C and 5% Pt/C as the catalyst provided effective
incorporation of deuterium at such positions. We there-
fore used the bimetallic 5% Pd–Pt/C(NaBH4) catalyst for
the deuteration of 1,2,4,5-tetramethylbenzene (durene), in
which the aromatic hydrogens at the 3- and 6-positions
(C1 positions in Table 3) are highly hindered by the
neighboring methyl groups. Deuteration catalyzed solely
by 5% Pt/C, an effective catalyst for deuteration of aro-
matic nuclei,7g,l,10 resulted in moderately efficient deuter-
ation (75%) at the aromatic C1 positions (entry 4),
whereas the average deuteration efficiency at the C1 posi-
tions was only 13% when 10% Pd/C was used (entry 3).
Deuteration with a mixed catalyst of 5% Pd/C and 5%
Pt/C gave a result similar to that of the reaction catalyzed
solely by 5% Pt/C, and no synergistic effect was observed
in this particular case (entry 2). On the other hand, the use
of the bimetallic 5% Pd–Pt/C(NaBH4) catalyst showed a
Table 3 5% Pd–Pt/C(NaBH4)-Catalyzed Deuteration of 1,2,4,5-
Tetramethylbenzene
D
1
2
D3C
D3C
CD3
catalyst (20 wt%), H2
D2O, 180 °C, 24 h
sealed tube
CD3
D
Entry Catalyst
D content (%)
Yield
C1
94
75
13
75
C2
(%)
quant
76
1
2
3
4
5% Pd–Pt/C(NaBH4)
95
96
97
93
5% Pd/C + 5% Pt/C
10% Pd/Ca
96
5% Pt/C
92
a 10 wt% of 10% Pd/C was used as the catalyst.
cially at the aromatic ring and the C3–C6 positions (entry
3).
Synthesis 2009, No. 16, 2674–2678 © Thieme Stuttgart · New York

2676
T. Maegawa et al.
PAPER
Table 4 5% Pd–Pt/C(NaBH4) Catalyzed Deuteration of 4-Propylbenzoic Acid
D
D
D
D
2
3
5
D
D
catalyst (20 wt%), H2
1
4
D
D
D
D
D2O, 180 °C, 24 h
sealed tube
HO2C
HO2C
D
Entry
Catalyst
D content (%)
Yield
C1
74
94
3
C2
83
92
4
C3
C4
96
96
93
12
C5
93
95
92
11
(%)
98
92
1
2
3
4
5% Pd–Pt/C(NaBH4)
5% Pd/C + 5% Pt/C
10% Pd/Ca
96
96
96
15
64
5% Pt/C
62
17
84
a 10 wt% of 10% Pd/C was used as the catalyst.
mixture of compounds with different degrees of deuteration that ap-
pear as a distribution on the MS chart.)
notable synergistic effect, and produced an excellent deu-
teration efficiency (95%), even at the C1 positions (entry
1).
Preparation of 5% Pd–Pt on Carbon
Each catalyst was prepared by using H2, NH2NH2, NaBH4, and
HCHO in turn as reducing agents.
Next, we attempted the deuteration of 4-propylbenzoic
acid. The deuteration efficiencies at the positions on the
aromatic ring ortho to the the alkyl substituent (C2) and to
the carboxylic acid (C1) were equally poor when Pd/C or
Pt/C was used alone (Table 4, entries 3 and 4, respective-
ly). A significant enhancement in deuterium incorporation
at the C1 and C2 positions was achieved by using 5% Pd–
Pt/C(NaBH4) (entry 1), whereas a mixture of 5% Pd/C and
5% Pt/C gave an even better deuteration efficiency (C1:
94%, C2: 92%; entry 2). It is therefore obvious that quan-
titative and multiple deuteration might be achieved by
complementary use of the bimetallic 5% Pd–Pt/C(NaBH4)
catalyst or a mixture of 5% Pd/C and 5% Pt/C catalysts,
depending on the substrate.
Pretreatment of the Activated Carbon11a
The activated carbon (Norit SX-3) was pretreated with 10% aq
HNO3 to remove residual metals. A sample of Norit SX-3 (3.0 g)
was suspended in 10% aq HNO3 (30 mL) and heated at 60 °C for 3
h then filtered and washed with ion-exchanged H2O until the filtrate
was neutral. The resulting activated carbon was dried initially under
atmospheric conditions and then at reduced pressure at r.t. to 100
°C.
11b
Reduction with H2
A soln of PdCl2 (44 mg) in hot 5.5 M aq HCl (0.5 mL) was poured
into a soln of NaOAc (750 mg) in H2O (5 mL). H2PtCl6 (52.5 mg)
and pretreated Norit SX-3 (500 mg) were added, and the soln was
stirred at r.t. under H2 (3 atm) for 2 h. The catalyst was collected by
filtration, washed with H2O until the filtrate was neutral then dried,
initially under atmospheric conditions and finally at reduced pres-
sure at r.t.
In conclusion, we have developed a novel 5% Pd–Pt/
C(NaBH4) catalyst for efficient multiple deuteration reac-
tions, and we observed a significant synergy in H–D ex-
change reactions of sterically-hindered aromatic
hydrogens that is related to the bimetallic nature of the
catalyst. The 5% Pd–Pt/C(NaBH4) and a mixture of 5%
Pd/C and 5% Pt/C offer can serve as efficient and comple-
ICP-AES: Pd, 4.1%; Pt, 2.7%.
11c
Reduction with NH2NH2
Pretreated Norit SX-3 (250 mg) was added to a soln of PdCl2 (20.9
mentary catalysts for the polydeuteration of substrates mg) and H2PtCl6 (26.3 mg) in H2O (5 mL), and the suspension was
stirred at 50 °C for 4 h, then cooled to r.t. The resulting suspension
with hindered aromatic positions.
was adjusted to a pH of 10–12 with sat. aq Na2CO3, and NH2NH2
(0.5 mL) was added dropwise. The mixture was warmed at 50 °C
The 1H, 2H, and 13C NMR spectra were recorded on a JEOL AL-400
for 2 h to complete the reduction, and then filtered. The residue was
or EX-400 spectrometer (1H: 400 MHz; H: 61 MHz; 13C: 100
2
washed with H2O until the filtrate was neutral then dried, initially
under atmospheric conditions and finally at reduced pressure at r.t.
ICP-AES: Pd, 4.1%; Pt, 2.8%.
MHz). The chemical shifts d are given in ppm referred to TMS or
residual 1H peaks of the deuterated solvent. The deuterium contents
were determined by using an internal standard (4-methoxybenzoic
acid). The mass spectra and high-resolution mass spectra were re-
corded on a JEOL JMS-SX 102A spectrometer. Inductively coupled
plasma-atomic emission spectrometry (ICP-AES) analyses were
performed on an SPS 3100 [Seiko Instruments Inc. (Chiba, Japan)].
All reagents were obtained from commercial sources and used with-
out further purification. The deuteration efficiency was calculated
by the comparison of the integration for the deuterated product and
that of an internal standard in the 1H NMR, and confirmed from the
isotope distribution in the MS. (The deuterated product consists of
Reduced with HCHO11b
A suspension of pretreated Norit SX-3 (250 mg) in H2O (3.5 mL)
was heated to 80 °C and solns of PdCl2 (20.9 mg) in dil HCl (0.08
mL of concd HCl and 0.12 mL of H2O) and H2PtCl6 (26.3 mg) in
H2O (0.25 mL) were added. A 37% aq soln of HCHO (0.1 mL) was
added to the suspension, followed by the addition of 30% aq NaOH
to give a slightly alkaline suspension that was stirred at 80 °C for 5
min. The resulting catalyst was collected on a filter and washed with
Synthesis 2009, No. 16, 2674–2678 © Thieme Stuttgart · New York

PAPER
Bimetallic Pd–Pt/C-Catalyzed H–D Exchange Reaction
2677
H2O until the filtrate was neutral, then dried, initially under atmo-
spheric conditions and then at reduced pressure at r.t.
Acknowledgment
This work was partially supported by a Grant-in-Aid for Young
Scientists (B) (17790016) and by the Research Foundation of Gifu
Pharmaceutical University.
ICP-AES: Pd, 3.9%; Pt 2.7%.
11d,e
Reduced with NaBH4
Pretreated Norit SX-3 (250 mg) was added to a soln of K2PdCl4 and
K2PtCl4 in H2O (4 mL), and the mixture was stirred at r.t. for 2 h. A
soln of NaBH4 (137 mg) in H2O (1.5 mL) was added to the suspen-
sion and the mixture was vigorously stirred at r.t. for 12 h. The cat-
alyst was collected by filtration and washed with H2O until the
filtrate was neutral then dried, initially under atmospheric condi-
tions and finally at reduced pressure at r.t.
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Synthesis 2009, No. 16, 2674–2678 © Thieme Stuttgart · New York