Water-soluble N-oxyl compounds-mediated electrooxidation of alcohols in water: A prominent access to a totally closed system

Article abstract of DOI:10.1016/j.tetlet.2005.10.114

Electrooxidation of alcohols in water involving water-soluble N-oxyl compounds (WS-TEMPOs) proceeded smoothly to afford the corresponding ketones and aldehydes in good yields. Notably, most of WS-TEMPOs in water remained intact after the electrolysis. The aqueous solution containing WS-TEMPOs was recovered easily and repeatedly used for the electrooxidation of alcohols, offering a totally closed system.

Full text of DOI:10.1016/j.tetlet.2005.10.114

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8975–8979
Water-soluble N-oxyl compounds-mediated electrooxidation
of alcohols in water: a prominent access to a totally closed system
Jun Kubota, Yusuke Shimizu, Koichi Mitsudo and Hideo Tanaka*
Department of Applied Chemistry, Faculty of Engineering, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan
Received 27 September 2005; revised 20 October 2005; accepted 24 October 2005
Available online 11 November 2005
Abstract—Electrooxidation of alcohols in water involving water-soluble N-oxyl compounds (WS-TEMPOs) proceeded smoothly to
afford the corresponding ketones and aldehydes in good yields. Notably, most of WS-TEMPOs in water remained intact after the
electrolysis. The aqueous solution containing WS-TEMPOs was recovered easily and repeatedly used for the electrooxidation of
alcohols, offering a totally closed system.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Water is an ideal solvent for organic synthesis since
water is a safe, cheap, and environmentally friendly sol-
vent; thus, organic reactions in water have received sig-
nificant attention of organic chemists.1 Electroorganic
reaction is one of the most promising tools for environ-
mentally benign protocol because only passage of
required electricity can promote the reaction without
consumption of any oxidants or reductants. Therefore,
electroorganic reaction in water must be one of the most
challenging subjects in green organic synthesis.2 Along
this line, we have developed the electrooxidation of alco-
hols in a disperse system with an N-oxyl-immobilized sil-
ica gel3 or polymer particles4,5 as the disperse phase and
aqueous saturated NaHCO3 containing 20 wt % NaBr
as the disperse media.5 Both the disperse phase and
the disperse media could be recovered by simple opera-
tions and used for the subsequent electrolysis, thereby
offering a totally closed system for the electrooxidation
of alcohols. In our continuing studies on electrooxida-
tion of alcohols 2 in water, we found that the electrooxi-
dation of alcohols could be achieved in water containing
water-soluble N-oxyl compounds6 (WS-TEMPOs,
Scheme 1) 1a–d in which WS-TEMPOs would work as
an emulsifier as well as a mediator (electron transfer cat-
alyst). Extractive work-up afforded the corresponding
ketones and aldehydes 3 in good to moderate yields. It
H
N
Y
Br
O
N
O
WS-TEMPOs 1
1
1a
Et
1b
1c
1d
Me
dodecyl
N
N
Et
N
Me
N
N
Y
Me
Et
Scheme 1. Water-soluble N-oxyl compounds (WS-TEMPOs).
is worthy to note that most of the WS-TEMPOs dis-
solved in water remained intact after extractive workup
process. The recovered aqueous solution containing
WS-TEMPOs could be used repeatedly for the electro-
oxidation of alcohols, thereby offering a novel totally
closed electrolysis system as illustrated in Figure 1.
Herein, we report the electrooxidation of alcohols 2 in
water containing WS-TEMPOs.
Water-soluble N-oxyl compounds (WS-TEMPOs) 1a–d
were prepared in the manner as illustrated in Scheme 2.
6-Bromohexanoic acid (4) was treated with 4-amino-
2,2,6,6-tetramethylpiperidine-N-oxyl
(4-amino-TEM-
PO) in CH2Cl2 in the presence of DCC and a catalytic
amount of DMAP at room temperature for 18 h to
afford 4-(6-bromohexanoylamino)-2,2,6,6-tetramethyl-
piperidine-N-oxyl (5) in 93% yield. Treatment of 5
with triethylamine in refluxing ethanol for 24 h afforded
WS-TEMPO 1a in 98% yield. WS-TEMPO 1a was
Keywords: Electrooxidation; Alcohols; Water-soluble mediators;
N-Oxyl compounds; Aqueous solution.
*
Corresponding author. Tel.: +81 86 251 8072; fax: +81 86 251
8079; e-mail: tanaka95@cc.okayama-u.ac.jp
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.114

8976
J. Kubota et al. / Tetrahedron Letters 46 (2005) 8975–8979
OH
R'
Organic Solvent
R
O
Evaporation
Organic
2
Ultrasound
Irradiation
(Product)
Extraction
R
R'
3
Aqueous
WS-TEMPO
Aqueous
WS-TEMPO
Alcohol
WS-TEMPO
Electrolysis
Figure 1. A totally closed system for the electrooxidation of alcohols in water.
was supplied under vigorous stirring at 0 ꢁC. After pas-
sage of 2.5 F/mol of electricity, the aqueous solution
was extracted with EtOAc (5 · 5 mL) (Fig. 2C), the
combined extracts were dried (Na2SO4), and concen-
trated under reduced pressure. The residue was chro-
matographed by short-path column (SiO2) to afford
4-amino-TEMPO
DCC, DMAP
OH
Br
CH2Cl2, room temp.
18 h
O
4
H
N
" Y "
Br
1
O
N
EtOH, reflux, 24 h
O
5 (93%)
Table 1. Electrooxidation of alcohol 2a in WS-TEMPO 1a/Watera
Scheme 2.
H
Et
N
N
Et
Br
soluble (>1.0 g/mL) in water, methanol, ethanol, 2-pro-
panol, acetone, CH2Cl2, THF, acetonitrile, and DMF,
but hardly soluble (<4 mg/mL) in hexane, EtOAc,
Et2O, benzene, and toluene. In a similar manner, the
reaction of 5 with N,N-dimethyldodecylamine, pyridine,
and N-methylimidazole afforded the corresponding WS-
TEMPOs 1b–d in quantitative yields, respectively. WS-
TEMPOs 1b–d are also soluble in water (>1.0 g/mL).
Et
O
N
O
OH
O
1a
Water
Undivided Cell, (Pt)-(Pt)
30 mA, 2.5 F/mol, Ice Bath
R
R
2a
(R = 4-Me-C6H4)
3a
Entry
1
1a
(mol%)
Additives
Yield
3a (%)b
Recov.
2a (%)b
10
20 wt % NaBr,
Satd NaHCO3
20 wt % NaBr
Satd NaHCO3
—
20 wt % NaBr
aq Satd NaHCO3
4-PhCO2-TEMPO
(10 mol %),
Hexadecyl-Me3N+BrÀ
(10 mol %)
74
23
The high solubility of WS-TEMPOs 1 in water
prompted us to investigate electrooxidation of alcohols
2 in water containing 1. A typical electrolysis procedure
is as follows: in a test tube was placed a mixture of 1-(4-
methylphenyl)ethanol (2a, 0.70 mmol) and a catalytic
amount of WS-TEMPO 1a (10 mol %) in an aqueous
saturated NaHCO3 solution containing sodium bromide
(20 wt %) (Fig. 2A). The mixture was irradiated by
ultrasound for a few minutes to afford an emulsion
(Fig. 2B). Into the mixture were immersed two platinum
electrodes (1 · 1 cm2) and a regulated dc power (30 mA)
2
3
4
5
6
7
10
10
10
—
—
—
74
18
92
26
3
20
71
7
76
91
40
29
a Electrooxidation of 2a (0.70 mmol) using WS-TEMPO 1a (10 mol %)
in aqueous solution was carried out at a constant current (30 mA/
cm2, 2.5 F/mol) in an undivided cell under cooling with ice bath.
b Isolated yield.
100
80
Isolated
60
Yield (%)
40
20
0
1
2
3
4
5
Figure 2. A solution of (A) WS-TEMPO 1a in ion-free water, (B) a
mixture of WS-TEMPO 1a, 1-(4-methylphenyl)ethanol 2a in ion-free
water after ultrasonic irradiation, and (C) extraction of the aqueous
solution with EtOAc.
:
3a
Run
Figure 3. Recycle use of the solution containing WS-TEMPO 1a.

J. Kubota et al. / Tetrahedron Letters 46 (2005) 8975–8979
8977
4-methylacetophenone (3a) in 74% yield together with
recovered 2a in 23% (Table 1, entry 1). No appreciable
amount of 1a was recovered from the extracts, suggest-
ing that most of 1a remained intact in the aqueous phase
after the extractive workup.
did not efficiently proceed in the presence of NaHCO3
alone (entry 3). In the previous paper, we have devel-
oped the electrooxidation of alcohols in an organic/
aqueous two phase system, for example, CH2Cl2/aq satd
NaHCO3 containing 20 wt % NaBr, in which two redox
couples (N-oxyl/N-oxoammonium and BrÀ/Br+) work
as mediators, and both bromide ion and NaHCO3
are indispensable for the efficient electrooxidation of
alcohols in two phase system.7 In sharp contrast, the
No significant change of the yield of 3a was observed
when the electrolysis was carried out in the absence of
NaHCO3 (entry 2). On the other hand, the oxidation
Table 2. Electrooxidation of alcohols 2 using WS-TEMPO 1aa
Entry
1
Alcohol
OH
Product (yield)b
O
2b
2c
2d
2e
3b (81%)
Ph
Ph
OH
Ph
O
2
3c (78%)
Ph
OH
O
3c
3d (81%)
4-Cl-C6H4
4-Cl-C6H4
OH
O
4d
3e (80%)
OH
O
5d
2f
3f (85%)
OH
O
6d
2g
2h
2i
3g (79%)
4- -Bu-C H
4-t-Bu-C6H4
t
6
4
OH
O
7
3h (49%)e
3i (80%)
4-MeO-C6H4
4-MeO-C6H4
8
4-t-Bu-C6H4-CHO
4-t-Bu-C6H4
OH
OH
O
9
2j
3j (3%)
3j (90%)
10f
Ph
Ph
Ph
CHO
Ph
11
2k
3k (trace)
3k (28%)h
3k (—)i
OH
12g
13g
CO2H
Ph
6 (—)
6 (19%)h
6 (78%)i
a Electrooxidation of 2 (0.70 mmol) using WS-TEMPO 1a (10 mol %) in aqueous solution was carried out under a constant current (30 mA,
2.5 F/mol) in an undivided cell under cooling with ice bath.
b Isolated yield.
c 3.0 F/mol of electricity was passed.
d 3.5 F/mol of electricity was passed.
e 4-Bromoanisole (4%), 1-(3-bromo-4-methoxyphenyl)ethanol (8%), and 3-bromo-4-methoxyacetophenone (6%) were obtained.
f In the absence of 20 wt % NaBr.
g In the presence of 30 wt % NaBr.
h 3-Phenylpropyl 3-phenylpropanoate (6%) and 1,1-bis(3-phenylpropoxy)-3-phenylpropane (10%) were also obtained.
i 5.0 F/mol of electricity was passed.

8978
J. Kubota et al. / Tetrahedron Letters 46 (2005) 8975–8979
electrooxidation of 2a in the present emulsion system
proceeded most efficiently in the absence of both NaH-
CO3 and NaBr, affording 3a in excellent yield (entry 4).
The presence of WS-TEMPO 1a is indispensable for the
efficient oxidation of alcohol 2a; thus the yield of 3a
decreased to 26% and 3%, respectively, when the
electrolysis was carried out without 1a (entries 5 and
6). These results indicate that 1a would play significant
roles in the electrooxidation, presumably as both emul-
sifier and mediator. Notably, the electrooxidation of 2a
was not efficiently achieved with a combination of
10 mol % of 4-benzyloxy-2,2,6,6-tetramethylpiperidine-
N-oxyl (mediator) and 10 mol % of hexadecyltrimethyl-
ammonium bromide (emulsifier), affording only 29%
yield of 3a (entry 7). In a similar manner, the electrooxi-
dation of 2a in water containing other WS-TEMPOs
1b–d was examined. The yield of 3a decreased in the
order: 92% (1a) > 72% (1c) > 71% (1d) > 54% (1b).
recovered alcohol 2k, respectively (entry 12). When an
excess amount of electricity (5.0 F/mol) was passed, 6
was obtained as an only isolated product (entry 13).
In conclusion, water-soluble N-oxyl compounds (WS-
TEMPOs) 1a–d were prepared and used for the media-
tor of the electrooxidation of alcohols in water. Electro-
oxidation of benzylic sec-alcohols 2a–g in water
containing 1a proceeded smoothly to afford the corre-
sponding ketones 3a–g in good yields. Electrooxidation
of aliphatic alcohols was similarly performed in the
presence of 20–30 wt % NaBr, affording the corres-
ponding ketone or carboxylic acid. After the extractive
workup, most of 1a remained intact in the aqueous
solution and the recovered aqueous solution of 1a
could be used repeatedly for the electrooxidation of
alcohols.
As mentioned above, most of the WS-TEMPO 1a
remained intact in the aqueous solution after the extrac-
tive workup process. This fact enabled us to
investigate the recycled use of the aqueous solution
(Fig. 3). After the first run, electrooxidation of 2a using
the recovered aqueous solution of 1a (second run) was
carried out in a similar manner to that described above
to afford the corresponding ketone 5a in 95% yield. The
same process was repeated for totally five times. The
yield of 3a varied in the range 84–95%, demonstrating
that the aqueous solution of WS-TEMPO 1a could be
used repeatedly.
Acknowledgements
We thank the SC-NMR Laboratory of Okayama
University for H and 13C NMR analysis.
1
References and notes
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The scope of the electrooxidation of alcohols in water
containing the recyclable mediator 1a was investigated
and the results are shown in Table 2. The electrooxida-
tion of benzylic sec-alcohols 2b and 2c give the corre-
sponding ketones 3b and 3c in good yields,
respectively (entries 1 and 2). The oxidation of alcohols
2d, 2e, 2f, and 2g was also performed successfully when
a slightly excess amount of electricity was passed (entries
3–6). However, the present electrolysis system could not
successfully be applied to the oxidation of 1-(4-methoxy-
phenyl)ethanol 2h since the electron-donating substitu-
ent facilitated the bromination on the aromatic ring,
affording significant amounts of brominated products,
for example, 4-bromoanisole, 1-(3-bromo-4-methoxy-
phenyl)ethanol, and 3-bromo-4-methoxyacetophenone
(entry 7). Electrooxidation of benzylic prim-alcohol 2i
proceeded smoothly to give the corresponding aldehyde
3i in 80% yield and no appreciable amount of over-oxi-
dation product was isolated (entry 8). In contrast, the
electrooxidation of aliphatic sec-alcohol 2j did not effi-
ciently proceed under similar conditions to those
described above, affording only 3% of the ketone 3j
(entry 9). The yield of ketone 3j was improved signifi-
cantly when the electrolysis was carried out in 20 wt %
NaBr solution (entry 10). On the other hand, electrooxi-
dation of aliphatic prim-alcohol 2k afforded only a trace
amount of the corresponding aldehyde 3k, and most of
the alcohol 2k was recovered (entry 11). Upon a similar
electrolysis in the presence of 30 wt % NaBr, the oxida-
tion took place but gave a mixture of aldehyde 3k,
carboxylic acid 6, acetal, and ester, together with the

J. Kubota et al. / Tetrahedron Letters 46 (2005) 8975–8979
8979
Micallef, A. S. Chem. Commun. 1998, 1907; (f) Huang, W.;
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