Novel method of reducing ketones using sodium hydroxide in isopropanol

Article abstract of DOI:10.1080/00397910903061043

Ketones are readily reduced to secondary alcohols with sodium hydroxide in refluxing isopropanol.

Full text of DOI:10.1080/00397910903061043

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Novel Method of Reducing Ketones Using
Sodium Hydroxide in Isopropanol
Daniel R. Zuidema a , Katherine J. Wert a , Sarah L. Williams a
,
Samuel T. Chill b , Kimberly L. Holte b , Nathanael K. Kokes b
Robert C. Mebane b
&
a Department of Chemistry, Covenant College, Lookout Mountain,
Georgia, USA
b Department of Chemistry, University of Tennessee at Chattanooga,
Chattanooga, Tennessee, USA
Version of record first published: 12 Mar 2010
To cite this article: Daniel R. Zuidema, Katherine J. Wert, Sarah L. Williams, Samuel T. Chill,
Kimberly L. Holte, Nathanael K. Kokes & Robert C. Mebane (2010): Novel Method of Reducing Ketones
Using Sodium Hydroxide in Isopropanol, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:8, 1187-1191
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Synthetic Communications1, 40: 1187–1191, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903061043
NOVEL METHOD OF REDUCING KETONES USING
SODIUM HYDROXIDE IN ISOPROPANOL
Daniel R. Zuidema,1 Katherine J. Wert,1 Sarah L. Williams,1
Samuel T. Chill,2 Kimberly L. Holte,2 Nathanael K. Kokes,2
and Robert C. Mebane2
1Department of Chemistry, Covenant College, Lookout Mountain,
Georgia, USA
2Department of Chemistry, University of Tennessee at Chattanooga,
Chattanooga, Tennessee, USA
Ketones are readily reduced to secondary alcohols with sodium hydroxide in refluxing
isopropanol.
Keywords: Hydrogen transfer; ketone reduction; preparation of secondary alcohols; sodium hydroxide
The process of reducing a ketone to a secondary alcohol is a widely used and thor-
oughly studied synthetic technique.[1–4] Conventional methods commonly used for
the reduction of a ketone to a secondary alcohol include catalytic hydrogenation
and metal hydride reduction. Another common method employed is the Meerwein–
Ponndorf–Verley (MPV) reduction, which typically uses aluminum isopropoxide in
isopropanol.[5–7] Disadvantages to these methods include the flammability of hydro-
gen gas and metal hydride reagents and the expense of many of the catalysts. In the
MPV reduction, removal of the aluminum salts can be tedious.
In this report, we describe an attractive alternative to the aforementioned
methods that uses a solution of sodium hydroxide in isopropanol. The experimental
procedure for this method of reduction is simple and straightforward and affords
secondary alcohols in good yields. The overall reaction is described in Fig. 1, and
a summary of our results is presented in Table 1. As seen in Table 1, isolated yields
for the less volatile secondary alcohols were very good (entries 1, 3, 5, 9) but less so
for the more volatile alcohols because of product loss while removing the isopro-
panol solvent by rotary evaporation. Surprisingly, no evidence of aldol condensation
was observed for any of the ketones studied. In a typical run, the ketone was refluxed
(container open to the atmosphere) in a magnetically stirred solution of sodium
hydroxide in isopropanol. The solution was 0.25 M with respect to both the ketone
and the sodium hydroxide. The progress of the reaction was conveniently monitored
Received February 11, 2009.
Address correspondence to Daniel R. Zuidema, Department of Chemistry, Covenant College,
14049 Scenic Highway, Lookout Mountain, GA 30750, USA. E-mail: zuidema@covenant.edu
1187

1188
D. R. ZUIDEMA ET AL.
Figure 1. Conversion of ketones to secondary alcohols by treatment with sodium hydroxide in refluxing
isopropanol.
by gas chromatography–mass spectrometry (GC-MS). All of the secondary alcohols
prepared in this study are known. Therefore, product identities were confirmed by
comparison of NMR and mass spectral data with authentic samples or literature
spectra.
To demonstrate that the presence of sodium hydroxide was indeed required, a
control experiment was run in which acetophenone (12.5 mmol) was refluxed in
isopropanol (50 mL) for 18.5 h (no sodium hydroxide added). No conversion to
1-phenylethanol was observed. By comparison, in the presence of sodium hydroxide
(0.25 M), after 18.5 h of heating, well more than 50% conversion to 1-phenylethanol
had been realized. This established that the presence of sodium hydroxide is neces-
sary for the reduction to occur.
To verify that isopropanol was being converted to acetone in this redox reac-
tion, an experiment was run in which benzophenone (1.2 mmol) was refluxed for 2 h
in isopropanol (50 mL) that contained dissolved sodium hydroxide (1.2 mmol). A
Dean–Stark trap was used to collect distillate over the course of the reaction. The
distillate was tested for the presence of acetone by mixing several drops of a 3% sol-
ution of 2,4-dinitrophenylhydrazine with a few drops of distillate. The formation of a
yellow precipitate suggested a positive test for the presence of acetone. Examination
of the melting point of the precipitate revealed a melting point identical to that of
acetone 2,4-dinitrophenylhydrazone (124.7–126.4 ꢀC).[8] One source has reported
that this test easily detects 1 part of acetone in 500–1,000 parts of isopropanol.[9]
Because we knew that the rate of a chemical reaction is often accelerated by
microwave irradiation, due to superheating of the solvent,[10,11] we decided to
Table 1. Conversion of ketones to secondary alcohols by treatment with sodium hydroxide in refluxing
isopropanol
Entry
Ketone
Secondary alcohol
Benzhydrol
Cyclohexanol
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
Benzophenone
Cyclohexanone
27
90
71a
95
0
22.5
22.5
20
4-t-Butylcyclohexanone
2-t-Butylcyclohexanone
2-Octanone
4-t-Butylcyclohexanol
2-t-Butylcyclohexanol
2-Octanol
22.5
26
97
71
70a
65b
85
3-Octanone
Acetophenone
40-Fluoroacetophenone
40-Methoxyacetophenone
3-Octanol
1-Phenylethanol
22.5
26
1-(4-Fluorophenyl)ethanol
1-(4-Methoxyphenyl)ethanol
26
aIsolated yield was lowered because of the volatility of the alcohol.
bNucleophilic aromatic substitution side products were observed in the product mixture.

REDUCING KETONES USING SODIUM HYDROXIDE IN ISOPROPANOL
1189
explore the effect of microwave irradiation on the rate of this reduction reaction. In a
typical procedure, a 10-mL, round-bottom flask was charged with 4.0 mL of a sol-
ution that was 0.25 M with respect to both the ketone and sodium hydroxide in iso-
propanol. Decane was present in a concentration of 0.175 M to serve as an internal
standard for GC analysis. The flask was outfitted with a reflux condenser and irra-
diated in a modified 800-W Sharp household microwave oven. Isopropanol boils vig-
orously upon microwave irradiation. Thus, it was necessary to connect two reflux
condensers in series to the top of the reaction flask. To accommodate this, a small
hole was drilled in the top of the microwave oven. Simple tests revealed no leakage
of microwave radiation through this hole. Also, to guard against burnout of the
microwave oven, we placed a beaker of ice water on the microwave turntable and
irradiated in 2-min increments. The progress of the reaction was followed by
GC-MS. Because these reactions were run on a much smaller scale, isolated yields
were not determined. Instead, percent conversions as measured by GC were deter-
mined. As seen in Table 2, the rate of secondary alcohol formation was significantly
accelerated when the reaction was run in a household microwave oven. As was the
case in the thermal reduction procedure, no evidence of aldol condensation was
observed.
Again, we wished to demonstrate that sodium hydroxide was necessary for the
microwave reduction to proceed. Thus, we set up a control experiment in which a
10-mL, round-bottom flask was charged with cyclohexanone (98 mg, 1.0 mmol)
and 4.0 mL of isopropanol. Decane was present in a concentration of 0.175 M to
serve as an internal standard for GC analysis. The flask was outfitted with a reflux
condenser and irradiated in a modified 800-W Sharp household microwave oven.
After 6 min of irradiation, no conversion to cyclohexanol was observed by GC. By
comparison, in the presence of sodium hydroxide (0.25 M), after 6 min of irradiation,
more than 50% conversion to cyclohexanol had been recognized.
In conclusion, ketones are readily reduced to secondary alcohols when refluxed
in a solution of sodium hydroxide in isopropanol. This process is markedly acceler-
ated when run in a conventional household microwave oven. This affords an
attractive method of reducing ketones in that it offers cheap and readily available
reagents, operational simplicity, easy workup, and high, clean product yields. The
microwave procedure is easily adapted for laboratory use, and expensive commercial
Table 2. Conversion of ketones to secondary alcohols by treatment with sodium hydroxide in refluxing
isopropanol under microwave conditions
Entry
Ketone
Secondary alcohol
Time (min)
Conversion (%)
1
2
3
4
5
6
7
8
9
Benzophenone
Cyclohexanone
Benzhydrol
Cyclohexanol
30
20
20
30
30
30
30
30
30
67
99
99
0
4-t-Butylcyclohexanone
2-t-Butylcyclohexanone
2-Octanone
4-t-Butylcyclohexanol
2-t-Butylcyclohexanol
2-Octanol
24
11
79
86
28
3-Octanone
Acetophenone
40-Fluoroacetophenone
40-Methoxyacetophenone
3-Octanol
1-Phenylethanol
1-(4-Fluorophenyl)ethanol
1-(4-Methoxyphenyl)ethanol

1190
D. R. ZUIDEMA ET AL.
microwave reactors are not necessary. Future work will elaborate on the scope of the
reaction as to what other types of functional groups can be reduced by this method.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Jeol 400-MHz spectrometer
using tetramethylsilane as an internal reference. Mass spectra were recorded on a
ThermoElectron PolarisQ GC-MS. The NMR spectra and mass spectra of the alco-
hols prepared in this work were identical to authentic spectra.
As an illustrative example of the thermal reduction procedure, acetophenone
(6.000 g, 49.94 mmol) was refluxed in a magnetically stirred solution of sodium
hydroxide (1.989 g, 49.73 mmol) in isopropanol (200 mL) for 20.5 h with the con-
denser open to the atmosphere. After cooling to room temperature, the reaction mix-
ture was partitioned between diethyl ether (200 mL) and water (100 mL). The layers
were separated, and the organic layer was washed with water (3 ꢁ 100 mL) and brine
(1 ꢁ 100 mL). The organic layer was dried with anhydrous magnesium sulfate and
concentrated to yield an oil that was purified by vacuum distillation (4.294 g,
35.15 mmol, 70.38%) and whose spectral data (NMR, MS) were identical to those
of authentic 1-phenylethanol. As an illustrative example of the microwave reduction
procedure, cyclohexanone (98 mg, 1.0 mmol) and 4.0 mL of a solution of NaOH
(0.25 M) in 2-propanol was charged to a 10-mL, round-bottom flask. Decane was
present in a concentration of 0.175 M to serve as an internal standard for GC analy-
sis. The flask was outfitted with a reflux condenser and irradiated in a modified
800-W Sharp household microwave oven. Complete conversion to cyclohexanol
was observed by GC-MS after 20 min. The mass spectrum of the product was
identical to the mass spectrum of authentic cyclohexanol.
ACKNOWLEDGMENTS
The authors gratefully acknowledge financial support from the Covenant
College Kaleo Center, an NSF RSEC grant, Research Corporation, the University
of Chattanooga Foundation, and the Grote Chemistry Fund.
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REDUCING KETONES USING SODIUM HYDROXIDE IN ISOPROPANOL
1191
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