Electroorganic synthesis in oil-in-water nanoemulsion: TEMPO-mediated electrooxidation of amphiphilic alcohols in water

Article abstract of DOI:10.1055/s-2007-991070

Oil-in-water nanoemulsions, consisting of TEMPO, amphiphilic alcohols, and water, offer unique reaction environments for electrooxidation of the alcohols to give the corresponding carboxylic acids in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-991070

LETTER
2691
Electroorganic Synthesis in Oil-in-Water Nanoemulsion: TEMPO-Mediated
Electrooxidation of Amphiphilic Alcohols in Water
E
lectrooxidatio
o
of Amphip
m
hilic Alcohols in
W
oater nori Yoshida, Manabu Kuroboshi, Jun Oshitani, Kuniaki Gotoh, Hideo Tanaka*
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Tsushima-naka 3-1-1, Okayama, 700-8530, Japan
E-mail: tanaka95@cc.okayama-u.ac.jp
Received 2 August 2007
oxyl 3 with OBr– would give N-oxoammonium 4, which
Abstract: Oil-in-water nanoemulsions, consisting of TEMPO, am-
would oxidize alcohol 1 to the corresponding carbonyl
phiphilic alcohols, and water, offer unique reaction environments
compound 2. N-Hydroxylamine 5, generated in this step,
for electrooxidation of the alcohols to give the corresponding
would subsequently react with another molecule of 4 to
form 2 mol of 3. This electrooxidation can be performed
conveniently in an undivided cell under constant current
conditions. This system always requires the second water-
soluble mediator such as Br– even in the microemulsion
system,13 and the electrooxidation of alcohols scarcely oc-
curred in the absence of NaBr. The Br– sometimes causes
undesirable side reactions such as bromination of the sub-
strate. Although the electrooxidation in the single-phase
organic system proceeded without Br–, it proceeded only
in a divided cell under constant potential conditions, and
was not satisfactory in terms of operational simplicity,
manufacturing cost, and environmental stress.
carboxylic acids in good to excellent yields.
Key words: electrooxidation, alcohols, nanostructure, TEMPO,
aqueous environment
A nanoemulsion is a type of thermodynamically stable
liquid isotropic dispersion composed of water, oil, and
surfactants, and the particle sizes of the dispersed phase
are defined as less than 1000 nm.1 Nanoemulsions have
unique physical and chemical properties, and have been
used widely in many different fields, such as pharma-
ceuticals,2 cosmetics,3 lubricants,4 surfactants,5 and deter-
gents,6 in the last decade. For example, oil-in-water
nanoemulsions transport hydrophobic compounds (drugs)
in water and have been used as drug delivery materials.7
However, these nanoemulsions have scarcely been used in
organic synthesis, especially in electroorganic synthesis.8
This paper describes the first application of nanoemulsion
to a potent electrolysis medium.
OH
R1
R2
1
O
2
N
N
O
anode
2 e–
Br–
R1
R2
2 OH–
2
4
Electroorganic synthesis is one of the most promising en-
vironmentally benign processes because passage of elec-
tricity promotes the desired oxidation and/or reduction
without oxidants or reductants and, therefore, wastes aris-
ing from these reagents are not produced. Electrolyses
have been carried out in several reaction media such as or-
ganic solvents (DMF, MeCN, CH2Cl2, EtOAc, and so on),
water, and their mixed systems. Water is an ideal medium
for electrolysis: indeed, it is cheap, nonflammable, and
nontoxic, and its dielectric constant is high enough to pass
the required electricity. Solubility of the organic sub-
strates in water is, however, generally poor, and a unique
design and special care of the aqueous medium are re-
quired. We have reported N-oxyl-mediated electrooxida-
tion of alcohols9 in several aqueous electrolysis systems,
such as organic/aqueous two-phase system (CH2Cl2–
water),10 solid/water disperse systems (silica gel11 and
polymer particles12/water), and oil-in-water microemul-
sion systems.13 A representative mediatory system in the
heterogeneous environment is illustrated in Scheme 1.
Electrooxidation of Br– would give OBr–. Oxidation of N-
N
OH
OBr-
H2O
O
2
5
3
aqueous
phase
organic phase
solid disperse phase
Scheme 1 N-Oxyl-mediated electrooxidation of alcohols in hetero-
geneous environments
In 1999, Schäfer et al. reported 2,2,6,6-tetramethylpipe-
ridine-1-oxyl (TEMPO)-mediated electrooxidation of
sugar derivatives in water.14 To our surprise, the elec-
trooxidation proceeded smoothly without use of bromide
salt. This prompted us to reinvestigate the electrooxida-
tion of various alcohols in water by dynamic light scatter-
ing (DLS) and cyclic voltammetry (CV) analyses, and we
found that this electrooxidation proceeded smoothly only
when a nanoemulsion was formed in the electrolysis
medium (Equation 1). Only amphiphilic alcohols such as
sugars and polyethylene glycols formed the nanoemulsion
with TEMPO in water, while water-soluble and water-in-
soluble alcohols did not form nanoemulsions and were not
efficiently oxidized.
SYNLETT 2007, No. 17, pp 2691–2694
1
6
.1
0
.
2
0
0
7
Advanced online publication: 25.09.2007
DOI: 10.1055/s-2007-991070; Art ID: U07207ST
© Georg Thieme Verlag Stuttgart · New York

2692
T. Yoshida et al.
LETTER
change resin (Amberlite IR 120, 30 min) and filtered. The
filtrate was concentrated in vacuo to give the correspond-
ing carboxylic acid 6a in 96% yield.
TEMPO (0.1 mmol)
buffer solution
nanoemulsion
O
O
R
OH
R
OH
R
H
undivided cell
(Pt)–(Pt), 30 mA
r.t.
1
Results of the electrooxidation using various alcohols are
summarized in Table 1. Electrooxidation of polyethylene
glycol monomethyl ethers 1b–c was performed in a simi-
lar manner to afford the corresponding carboxylic acids
6b–c in good yields (entries 2 and 3). Diols 1d and 1e gave
the corresponding dicarboxylic acids 6d and 6e quantita-
tively after passage of 9 F/mol15 of electricity (entries 4
and 5). Although water-soluble alcohols 1f–i gave a simi-
lar clean aqueous solution, the electrooxidation did not ef-
ficiently give the corresponding carboxylic acid 6f and
ketones 8g–i (entries 6–9). In cases of water-insoluble al-
cohols 1j–l (entries 10–12), oil droplets were observed in
the aqueous electrolysis medium, and the electrooxidation
did not smoothly proceed to give the corresponding alde-
hydes 7j and 7k in low yields and no ketone 8l.
6
7
(0.5 mmol)
Equation 1
A typical procedure is as follows (Table 1, entry 1): A
mixture of diethylene glycol monomethyl ether (1a, 0.5
mmol) and TEMPO (0.1 mmol) in a carbonate buffer
[Na2CO3 (0.4 M) and NaHCO3 (0.3 M), 10 mL] was elec-
trolyzed in a simple beaker-type undivided cell fitted with
two Pt electrodes (1.5 × 1.0 cm2) under constant current
density conditions (20 mA/cm2) at room temperature. The
mixture of 1a and TEMPO in the buffer solution gave a
clear solution. After passage of 4.5 F/mol15 of electricity
(2.5 h), the reaction mixture was treated with an ion-ex-
Table 1 Electrooxidation of Various Alcohols
Entry
F/mol
Substrate
Product
Yield (recov., %)a
Amphilic
O
O
MeO
OH
O
n
MeO
OH
n
1
2
3
4.5
4.5
4.5
1a (n = 1)
1b (n = 2)
1c (n = 6)
6a (n = 1)
6b (n = 2)
6c (n = 6)
96 (–)
99 (–)
90 (–)
O
O
O
HO
OH
O
n
HO
OH
n
4
9.0
9.0
1d (n = 2)
1e (n = 8)
6d (n = 2)
6e (n = 8)
94 (–)
99 (–)
5
Water-soluble
6
4.5
2.5
2.5
2.5
PhCH2CH(OH)CH2OH
1f
PhCH2CH(OH)CO2H
6f
16 (64)
– (77)
– (76)
– (98)
7
8
9
PhCH(OH)CO2H
1g
PhC(O)CO2H
8g
MeCH(OH)CO2H
1h
MeC(O)CO2H
8h
MeCH(OH)CH2CO2H
MeC(O)CH2CO2H
1i
8i
Water-insoluble
10
2.5
5.5
2.5
4-ClC6H4CH2OH
1j
4-ClC6H4CHO
7j
27 (40)b
14 (59)b
– (86)
11
Ph(CH2)2CH2OH
1k
Ph(CH2)2CHO
7k
12
Ph(CH2)2CH(OH)Me
Ph(CH2)2C(O)Me
1l
8l
a Isolated yields.
b The corresponding carboxylic acids were not obtained.
Synlett 2007, No. 17, 2691–2694 © Thieme Stuttgart · New York

LETTER
Electrooxidation of Amphiphilic Alcohols in Water
2693
The electrolysis media were analyzed by dynamic light was observed when 1b and methyl a-D-glucopyranoside14
scattering (DLS, Otsuka Denshi Corp., FPAR 1000R). were added to the solution, indicating that 1) direct oxida-
Triethylene glycol monomethyl ether (MTEG, 1b) dis- tion of 3 at the anode occurs to give 4, and 2) 3 seems to
solved in water to give a clear solution, in which broad interact lipophilically with 1b and methyl a-D-glucopyra-
distribution of the particle size (100–1000 nm) was ob- noside so closely in water that the electrogenerated 4
served (Figure 1, a). When TEMPO (3) was added to the would react with these alcohols immediately. On the other
solution, nanoparticles in narrow distribution of size (ca. hand, only a small catalytic current was observed with wa-
220 nm) were formed (Figure 1, b). Similarly, diethylene ter-soluble mandelic acid (1g). Water-insoluble 4-phenyl-
glycol monomethyl ether (1a) formed particles (50 mM, 2-butanol (1l) gave no catalytic current and the redox-
∅ 500–1100 nm) in water, which turned into nanoparti- peak current became small. These results show that elec-
cles (95–210 nm) when 10 mM of 3 were added. From trogeneration of 4 and/or subsequent reaction with alco-
these results, hydrophobic interaction between 3 and am- hols would not efficiently occur with water-soluble and
phiphilic alcohols, 1a and 1b, would be strong enough to water-insoluble alcohols.
form stable nanoemulsions in buffer solution (Scheme 2),
and the nanoparticles would be finely dispersed in water
by hydrophilic interaction between alcohols, 1a and 1b,
and water. The balance of these two interactions is a key
factor for the efficient TEMPO-mediated electrooxidation
of alcohols in water.
Figure 2 Cyclic voltammograms of TEMPO in the presence of
alcohols
A plausible mechanism of the electrooxidation in water is
illustrated in Scheme 2. In an aqueous solution of alcohol
Figure 1 Particle-size distribution of an aqueous (a) triethylene
1b, 1b would interact lipophilically with TEMPO (3) and
glycol monomethyl ether (MTEG, 1b) and (b) 1b/TEMPO solution
hydrophilically with water to form the nanoemulsion. The
nanoemulsion would disperse in water and bring 3 to the
anode by diffusion. Electron transfer from 3 to the anode,
i.e., oxidation of 3, would occur efficiently in the na-
ca. 200 nm
anode
O
OH
O
O
O
noemulsion to afford N-oxoammonium ion 4, which
would oxidize the surrounding 1b immediately. In the
case of primary alcohols, oxidation occurred repeatedly,
and finally gave the corresponding carboxylic acid. N-Hy-
droxylamine (5) would react with another molecule of 4 in
the nanoemulsion to give 2 mol of 3. Water-soluble alco-
hols dissolved in water to give homogeneous solutions
and would not form the nanoemulsion. As the result, the
electrogenerated 4 would not efficiently oxidize the alco-
hols, and reduction of 4 on the cathode would occur pre-
dominantly. In cases of water-insoluble alcohols, 3 would
be included in oil droplets (much larger than a microemul-
sion), and be separated from the anode so that oxidation of
TEMPO did not occur efficiently.
O
O
HO
O
N
O
OH
O N
O
3
OH
O
O
O
O
O
O
O
smooth
electron transfer
O
HO
N
OH
HO
5 O
N
O
OH
O
O
O
O
e–
O
O
O
O
HO
O
N
OH
N
4O
smooth oxidation
of alcohols
O
O
O
In conclusion, TEMPO-mediated electrooxidation in
water proceeded smoothly in the case of amphiphilic
alcohols wherein nanoemulsion of TEMPO, alcohols, and
water was formed; while the electrooxidation of water-
soluble and water-insoluble alcohols did not proceed
efficiently. Formation of the nanoemulsion is a key factor
for the efficient electrooxidation.
Scheme 2 TEMPO/1b nanoemulsion
The close lipophilic interaction between the alcohols and
TEMPO (3) was also confirmed by cyclic voltammetry
(CV, Figure 2). An aqueous solution of 3 (2.5 mM)
showed a small reversible redox peak at ca. 0.5 V vs. Ag/
AgCl, indicating that 3 was oxidized on the anode to give
the N-oxoammonium (4). A significant catalytic current
Synlett 2007, No. 17, 2691–2694 © Thieme Stuttgart · New York

2694
T. Yoshida et al.
LETTER
(9) Semmelhack, M. F.; Chou, C. S.; Cortes, D. A. J. Am. Chem.
Soc. 1983, 105, 4492.
(10) Inokuchi, T.; Matsumoto, S.; Torii, S. J. Org. Chem. 1991,
56, 2416.
References and Notes
(1) Osborne, D. W.; Middleton, C. A.; Rogers, R. L. J. Disp. Sci.
Technol. 1988, 9, 415.
(2) (a) Tiwari, S. B.; Amiji, M. M. In Nanotechnology for
Cancer Therapy; Amiji, M. M., Ed.; CRC Press LLC: Boca
Raton, 2007, 723. (b) Chepurnov, A. A.; Bakulina, L. F.;
Dadaeva, A. A.; Ustinova, N.; Chepurnova, T. S.; Baker, J.
R. Acta Tropica 2003, 87, 315.
(3) Yilmaz, E.; Borchert, H.-H. Int. J. Pharm. 2006, 307, 232.
(4) Shi, X.; Wang, Y. Chinese Patent CN 1873093, 2006; Chem.
Abstr. 2006, 146, 83440.
(5) Guiramand, C. EP 1634567, 2006; Chem. Abstr. 2006, 144,
298822.
(6) Myc, A.; Vanhecke, T.; Landers, J. J.; Hamouda, T.; Baker,
J. R. Jr. Mycopathologia 2002, 155, 195.
(11) Tanaka, H.; Kawakami, Y.; Goto, K.; Kuroboshi, M.
Tetrahedron Lett. 2001, 41, 445.
(12) (a) Kubota, J.; Ido, T.; Kuroboshi, M.; Tanaka, H.; Uchida,
T.; Shimamura, K. Tetrahedron 2006, 62, 4769.
(b) Tanaka, H.; Kubota, J.; Itogawa, S.; Ido, T.; Kuroboshi,
M.; Shimamura, K.; Uchida, T. Synlett 2003, 951.
(13) Water-soluble N-oxyl compounds having hydrophilic ionic
parts such as quaternary ammonium moiety and lipophilic
alkyl chains work as a mediator as well as an emulsifier to
make an oil-in-water microemulsion. Kubota, J.; Shimizu,
Y.; Mitsudo, K.; Tanaka, H. Tetrahedron Lett. 2005, 46,
8975.
(7) Kesisoglou, F.; Panmai, S.; Wu, Y. Curr. Nanosci. 2007, 3,
183.
(14) Schnatbaum, K.; Schäfer, H. J. Synthesis 1999, 864.
(15) Theoretical amounts of the electricity are 4 F/mol and 8 F/
mol for mono-ols (1a–c) and diols (1d,e), respectively;
1 F = 96500 C.
(8) A few reports dealing with electrolysis in emulsion were
published: (a) Wadhawan, J. D.; Marken, F.; Compton, R.
G.; Bull, S. D.; Davies, S. G. Chem. Commun. 2001, 87.
(b) Atobe, M.; Chen, P.-C.; Nonaka, T. Electrochemistry
(Tokyo) 1998, 66, 556. (c) Chen, P.-C.; Nonaka, T.
Electrochemistry (Tokyo) 1995, 63, 395. (d) Burzyk, J.;
Zjawiony, I. Pol. J. Appl. Chem. 1993, 37, 99. (e) Chen, P.-
C.; Chang, P.-C.; Kunugi, Y.; Nonaka, T. Electrochemistry
(Tokyo) 1993, 61, 866. (f) Georges, J.; Desmettre, S.
Electrochim. Acta 1986, 31, 1519.
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