Development of an anodic substitution reaction system using acoustic emulsification

Article abstract of DOI:10.1039/b713859h

The anodic substitution reaction proceeded smoothly without affecting the oxidation of the nucleophile in a one-step electrochemical operation using acoustic emulsification. The Royal Society of Chemistry.

Full text of DOI:10.1039/b713859h

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Development of an anodic substitution reaction system using acoustic
emulsification{
Ryosuke Asami, Toshio Fuchigami and Mahito Atobe*
Received (in Cambridge, UK) 10th September 2007, Accepted 16th October 2007
First published as an Advance Article on the web 24th October 2007
DOI: 10.1039/b713859h
The anodic substitution reaction proceeded smoothly without
affecting the oxidation of the nucleophile in a one-step
electrochemical operation using acoustic emulsification.
dispersed as submicrometre range droplets by ultrasonication. In
this situation, if the nucleophile droplet does not contain any
supporting electrolyte, it becomes electro-inactive, and therefore
the substrate is oxidized chemoselectively at the anode.
Consequently, the desired coupling-product would be formed if
the carbocation generated can be rapidly trapped by the coexisting
nucleophile droplet before its decomposition. Thus, this system
would realize the anodic substitution reaction to overcome the
restraints such as the oxidation potentials of nucleophiles and the
stability of carbocations.
The presence of several substrates in a single reactor often causes
interference with a desired reaction. To avoid this drawback,
chemo-selective reactions (which represent an elegant approach to
discriminate between substrates, allowing reaction of one in
preference to others) have been developed and they are extensively
used as an important tool in organic synthesis, catalysis, biological
1
chemistry, etc.
Herein we wish to report our results indicating that this concept
works. We chose the anodic substitution reaction of N-(methoxy-
carbonyl)pyrrolidine 1 (oxidation potential Eox = 1.91 V vs.
Ag/AgCl) with allyltrimethylsilane 2 (Eox = 1.75 V vs. Ag/AgCl) as
The nucleophilic substitution reaction using an anodically
generated carbocation has continued to be effectively utilized for
2
carbon–carbon bond formation. Since the carbocation is generally
4a
unstable, organic substrates and carbon nucleophiles need to
coexist in a reactor during the anodic oxidation so that the
nucleophile can trap the carbocation immediately as it is generated.
However, the oxidation potentials of the nucleophiles are usually
lower than those of organic substrates. Therefore, there is a
considerable difficulty in achieving oxidation of the organic
substrate preferentially in the presence of the nucleophile. In this
a model reaction (Scheme 1).
At first, we explored suitable electrolytic media which possess
solubilizing ability for a substrate, but should not exhibit
solubilizing ability for a nucleophile such as allyltrimethylsilane.
Among various electrolytic media, an ionic liquid like 1-ethyl-3-
methylimidazorium tetrafluoroborate (EMIM BF ) was found to
4
6
show the desired functions. Furthermore, the ionic liquid can be
used as an electrolytic medium on its own.
3
regard, introduction of the electro-auxiliary into substrates and
4
the ‘‘cation pool’’ method have been developed, but these
Subsequently, we measured linear sweep voltammograms of
compounds 1, 2 and a mixture of them. Since both 1 and 2 can be
dissolved in acetonitrile solution, 2 which has lower oxidation
potential was oxidized preferentially in acetonitrile solution as
shown in Fig. 2(a). In contrast, Fig. 2(b) indicates that the anodic
necessarily include laborious multi-step reactions.
Recently we have reported that direct electropolymerization of
water-insoluble monomers proceeded successfully in aqueous
5
electrolytes using acoustic emulsification. Ultrasonication of the
water-insoluble monomer–aqueous electrolyte mixtures allowed
the formation of very stable emulsions without added surfactants,
and smooth electropolymerization in the emulsions took place via
direct electron transfer between the electrode and the water-
insoluble monomer droplets. In this kind of biphasic electron-
transfer system, the supporting electrolyte should be dissolved not
only in the aqueous phase but also in the monomer droplets and
should contribute to the formation of an electric bilayer inside the
droplets. Hence, when the droplet did not contain any supporting
electrolytes, direct electron transfer was suppressed.
oxidation of 2 was hardly observed in EMIM BF because 2 was
4
These findings gave us the incentive to develop a novel
electrochemical system that would realize the anodic substitution
reaction without affecting the oxidation of the nucleophile in a
one-step electrochemical operation. In this system, illustrated in
Fig. 1, the nucleophile is insoluble in an electrolytic medium and is
Fig. 1 Schematic illustration of the anodic substitution reaction system
using acoustic emulsification.
Department of Electronic Chemistry, Tokyo Institute of Technology,
Yokohama, 226-8502, Japan. E-mail: atobe@echem.titech.ac.jp;
Fax: +81-45-924-5427; Tel: +81-45-924-5407
{ Electronic supplementary information (ESI) available: Chemicals and
experimental details. See DOI: 10.1039/b713859h
Scheme 1 Anodic substitution reaction of N-(methoxycarbonyl)pyrroli-
dine 1 with allyltrimethylsilane 2.
2
44 | Chem. Commun., 2008, 244–246
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solubility in the electrolytic medium (EMIM BF
quently allylated product 3 would be extracted from EMIM BF
into the nucleophile phase. To confirm this conjecture, we
measured the partition ratio of 1 and 3 between EMIM BF
and the nucleophile phase. As a result, it was found that about
5% of 3 was extracted into the nucleophile phase while only 16%
4
), and conse-
4
4
7
of 1 was dissolved in this phase (see the ESI{). From these facts, it
is likely that the allyl group serves as a ‘‘phase tag’’ for extraction
8
of the product from the electrolytic medium, and in situ extraction
results in reducing the chance for overoxidation.
Fig. 2 Linear sweep voltammograms of (i) 0.1 M N-(methoxycarbo-
nyl)pyrrolidine, (ii) 0.1 M allyltrimethylsilane and (iii) 0.1 M N-
In order to demonstrate the generality of this new methodology,
we also investigated the anodic substitution reactions of other
compounds with allyltrimethylsilane. As shown in Table 2, the
anodic substitution reactions of 6 and 8 were carried out to
provide the corresponding allylated products 7 and 9§ in reason-
able yields, but the yield of 4 was not so good. Fully exploring the
reason for this is beyond the scope of this short publication, but
the stability of the anodically generated carbocation would be
reflected in the yield of product.
(
methoxycarbonyl)pyrrolidine with 0.1 M allyltrimethylsilane in (a)
.1 M n-Bu NBF –acetonitrile solution and (b) EMIM BF under
ultrasonication. Scan rate was 0.1 V s
0
4
4
4
21
.
phase-separated from the electrolytic medium and moreover the
7
droplets of 2 did not contain EMIM BF electrolyte. Hence, the
4
droplet of 2 should be electro-inactive as mentioned above, and 1
was oxidized preferentially even in the presence of 2 in the same
reactor.
In summary, we have developed a novel electrosynthetic system
for an anodic substitution reaction using acoustic emulsification.
This new methodology has many practical advantages and
characteristics: (a) nucleophilic reaction by a one-step electro-
chemical operation in a single reactor; (b) the chemoselective
oxidation of substrates even in the presence of nucleophile; (c) the
smooth trapping of carbocations with submicrometre range
nucleophile droplets formed by ultrasonication; (d) a reduction
in the chance for overoxidation of products by the introduction of
a ‘‘phase tag’’ into them. It is hoped that this facile and novel
Next, we carried out the anodic substitution reaction on a
preparative scale (Scheme 1).{ 1 mmol of N-(methoxycarbonyl)-
pyrrolidine 1 was galvanostatically electrolyzed at 5 mA in the
2
1
presence of allyltrimethylsilane 2 by passing 2 F mol of charge
2
2
under ultrasonication with 150 W cm intensity. As shown in
entry 1 of Table 1, the desired carbon–carbon bond formation
product 3 was obtained in only 11% yield and 76% of substrate
was recovered in the acetonitrile solution. In this case, 2 was
probably oxidized preferentially.
In sharp contrast, the use of the emulsion system resulted in an
improvement of the conversion of 1 as shown in entry 2. However,
the low yield problem still remained. Probably this is ascribed to
the fact that the amount of 2 was insufficient to trap the
carbocations generated. In fact, the addition of further amounts of
Table 2 Anodic substitution reactions of various substrates with
allyltrime thylsilane 2 using acoustic emulsification
2
was effective for improving the yield and gave 3 in 70% yield
when 10 equivalents of 2 were added (entry 4). It should be noted
that the nucleophilic substitution reaction hardly proceeded under
mechanical stirring conditions, although the substrate was oxidized
smoothly as shown in entry 5. In this case, mechanical stirring
could not form an emulsion because of the high viscosity of the
21
a
Entry
1
Substrate
Electricity/F mol
2
Product
Yield (%)
70
4
EMIM BF .
The oxidation potential of product 3 (Eox = 1.90 V vs. Ag/AgCl)
was very close to that of substrate 1 implying that overoxidation of
2
3
2
3
43
50
4a
3
would be a problem for this reaction. However, in our case, the
overoxidized products were not detected at all. It can be considered
that introduction of an allyl group into 1 greatly decreases its
Table 1 Anodic substitution reaction of N-(methoxycarbonyl)pyrro-
lidine 1 with allyltrimethylsilane 2
Yield of Conversion
a
a
Entry Electrolytic media
2/mmol 3 (%)
of 1 (%)
b,c
4
4
66
1
2
3
4
5
a
0.1 M Bu NBF
4
4
–CH
3
CN 10
11
16
32
70 (62)
11
24
88
81
78
69
EMIM BF
EMIM BF
EMIM BF
EMIM BF
4
4
4
4
2
5
10
10
b
c
a
b
21
Determined by GC. After 2 F mol of electricity was passed,
b
Determined by GC. Isolated yield in parenthesis. Mechanical
c
c
10 equivalents of nucleophile were further added. Current density
22
was 0.08 mA cm .
stirring (1500 rpm) was used instead of ultrasonication.
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1
2
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This work was financially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan and Research Fellowships
of the Japan Society for the Promotion of Science for Young
Scientists.
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1
Notes and references
{ General procedure for the anodic substitution reaction: a divided H-type
glass cell with a glass frit diaphragm in a cooling bath was equipped with a
5
2
2
Pt mesh anode (ca. 25 cm ), a Pt mesh cathode (ca. 50 cm ), and an
ultrasonic stepped horn (3.2 mm diameter) connected with a 20 kHz
oscillator (SONIFIER-250D, Branson Ultrasonics Co.). The top of the
7
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horn was positioned
Methoxycarbonyl)pyrrolidine 1 and other compounds 4, 6, and 8 were
galvanostatically electrolyzed at 5 mA in 0.1 M n-Bu NBF acetonitrile
(12 cm ) in the presence of 2 by passing 2 F
3 cm apart from the cell bottom. N-
(
4
4
3
solution and EMIM BF
4
21
22
mol of charge under ultrasonication with 150 W cm intensity at a
solution temperature of 25 ¡ 1 uC unless otherwise stated. Mechanical
stirring at 1500 rpm (Magnestir, MGP-306 Sibata Scientific Technology
Ltd.) was also used instead of ultrasonication. After electrolysis, products 3,
1245–1248.
4
(a) J. Yoshida, S. Suga, S. Suzuki, N. Kinomura, A. Yamamoto and
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analyzed by gas chromatography (GC-2014 with Tween 80, 3m column,
Shimadzu Co., Japan).
10244–10245; (c) S. Suga, M. Okajima, K. Fujiwara and J. Yoshida,
§
divided H-type glass cell with a glass frit diaphragm in a cooling bath was
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T. Nishida, D. Yamada, A. Nagaki and J. Yoshida, J. Am. Chem. Soc.,
2
equipped with a Pt mesh anode (ca. 125 cm ), a Ag mesh cathode (ca.
2
00 cm ), and an ultrasonic stepped horn (3.2 mm diameter) connected
2
with a 20 kHz oscillator (SONIFIER-250D, Branson Ultrasonics Co.). The
top of the horn was positioned 3 cm apart from the cell bottom.
Compound 8 (0.10 g, 0.97 mmol) was galvanostatically electrolyzed at
2004, 126, 14338–14339; (h) T. Maruyama, S. Suga and J. Yoshida,
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3
10 mA in EMIM BF
under ultrasonication with 150 W cm intensity at a solution temperature
4
(12 cm ) in the presence of 2 (1.14 g, 9.98 mmol)
22
2
1
of 25 ¡ 1 uC. When 2 F mol of electricity was passed, 10 mmol of 2 was
21
further added. After 4 F mol
of electricity had been passed, the
electrolysis was stopped, and then the product was extracted with diethyl
ether (10 6 10 ml). Subsequently, the solvent was evaporated under
reduced pressure and the residue was purified with reversed-phase high-
performance liquid chromatography (HPLC) (SPD-10A with
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13160–13161; (b) R. Asami, T. Fuchigami and M. Atobe, Langmuir,
2006, 22, 10258–10263.
6 See ESI.
SUPERIOREX ODS, 25 cm column, SHISEIDO Co.) to obtain the title
1
compound (0.08 g, 56%). H NMR (270 MHz, CDCl
7 The boron atom of EMIM BF4 could not be detected from the
allyltrimethylsilane phase by inductively coupled plasma spectrometry
(ICP).
8 (a) D. P. Curran, Angew. Chem., Int. Ed., 1998, 37, 1174–1196; (b)
M. E. Bakkari, N. McClenaghan and J. M. Vincent, J. Am. Chem. Soc.,
2002, 124, 12942–12943; (c) J. Yoshida and K. Itami, Chem. Rev., 2002,
102, 3693–3716.
3
): d = 2.21–2.36 (m,
2
H), 2.84–2.97 (m, 3H), 3.23–3.45 (m, 2H), 3.69 (s, 3H), 4.98–5.17 (m, 2H),
13
5.67–5.86 (m, 1H); C NMR (68 MHz, CDCl ) d = 32.3, 34.4, 48.4, 52.5,
3
21
;
116.6, 135.1, 156.8; IR (KBr) n = 2926, 1705, 1485, 1396, 1217 cm
LRMS (EI) m/z 143 (M ), 102 (M 2 CH
+
+
2
LCHCH
2
); HRMS (EI) calcd
+
for C H13NO (M ): 143.0946, found: 143.0946.
7 2
2
46 | Chem. Commun., 2008, 244–246
This journal is ß The Royal Society of Chemistry 2008