Reduction of acetophenone using supercritical 2-propanol: The substituent effect and the deuterium kinetic isotope effect

Article abstract of DOI:10.1016/S0040-4039(03)00975-4

The reductions of several substituted acetophenones using supercritical 2-propanol were carried out to estimate the Hammett's reaction constant (ρ=0.33). Also, the reduction of acetophenone using supercritical deuteriated 2-propanol was carried out to determine the rate-determining step. The kinetic isotope effects were observed in the reduction using 2-deuterio-2-propanol (k_H/k_D=1.6) and O-deuterio-2-propanol (k_H/k_D=2.0). These findings suggest that the reaction proceeds via a cyclic transition state between acetophenone and 2-propanol similar to that of the Meerwein-Ponndorf-Verley reduction.

Full text of DOI:10.1016/S0040-4039(03)00975-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4551–4553
Reduction of acetophenone using supercritical 2-propanol:
the substituent effect and the deuterium kinetic isotope effect
Takashi Kamitanaka, Tomoko Matsuda and Tadao Harada*
Department of Materials Chemistry, Faculty of Science and Technology, Ryukoku University, Otsu, Shiga 520-2194, Japan
Received 28 February 2003; revised 4 April 2003; accepted 17 April 2003
Abstract—The reductions of several substituted acetophenones using supercritical 2-propanol were carried out to estimate the
Hammett’s reaction constant (z=0.33). Also, the reduction of acetophenone using supercritical deuteriated 2-propanol was
carried out to determine the rate-determining step. The kinetic isotope effects were observed in the reduction using 2-deuterio-2-
propanol (kH/kD=1.6) and O-deuterio-2-propanol (kH/kD=2.0). These findings suggest that the reaction proceeds via a cyclic
transition state between acetophenone and 2-propanol similar to that of the Meerwein–Ponndorf–Verley reduction. © 2003
Elsevier Science Ltd. All rights reserved.
The representative experimental procedures are as fol-
lows. All reactions were carried out in sealed Pyrex
tubes (ca. 2 mm inner diameter and ca. 70 mm length)
to eliminate the effect of the metal vessel. A portion of
the 2-propanol solution containing the substrate (0.25
mol dm−3, 140 ml) was placed in a Pyrex tube with one
closed end. The air in the tube was replaced by argon
gas and the other end of the tube was fused shut under
reduced pressure. After sealing, the tube was placed in
an autoclave (SUS316) with methanol, which prevents
the tube from breaking during the reaction. The auto-
clave was heated to 300°C and the temperature was
maintained for 1–15 h. After a specific time, the auto-
clave was cooled using an air stream to quench the
reaction. After the removal of the 2-propanol and the
acetone in vacuo at 30°C, the products in the tube were
subjected to the identification by GC, 1H NMR and IR.
Conversions were determined by GC analysis using the
internal standard method.
Supercritical fluids have been of significant interest to
organic chemists due to their unique properties. The
physicochemical properties of supercritical fluids, such
as diffusivities and polarities, can be continuously tuned
by adjusting their pressure and temperature. These
tunabilities make it possible to use them as unique
organic reaction media.1 Recently, organic reactions
using supercritical fluids not only as media but also as
reagents have been reported.2 Gubin reported that ben-
zaldehyde was reduced to benzyl alcohol using super-
critical 2-propanol (Tc=235°C) without catalysts or
reagents other than 2-propanol: during the reduction of
benzaldehyde, the 2-propanol was found to be oxidized
to acetone.3 Generally, the traditional procedures to
reduce the carbonyl group, such as the reduction with
hydride reagents4 and with hydrogenation catalysts,5
require complicated after-treatments. In contrast,
supercritical 2-propanol reduction requires no reagents
except for 2-propanol. Therefore, the after-treatment is
extremely easy; that is, only to remove the 2-propanol
and the produced acetone by evaporation. Although
this reaction is useful for synthetic chemistry, the reac-
tion mechanism has not yet been clarified. In this
communication, we report the results of studies on the
substituent effects and the deuterium kinetic isotope
effects for the reduction of acetophenone using super-
critical 2-propanol.
The reaction rates of the reduction of acetophenone
using supercritical 2-propanol may depend on both the
concentrations of acetophenone and 2-propanol. How-
ever, there is large excess of 2-propanol to the ace-
tophenone in the reaction system. Thus, this reaction
can be regarded as a pseudo-first order reaction with
respect to the concentration of acetophenone. Table 1
summarizes the rate constants of the reduction of the
substituted acetophenones using supercritical 2-
propanol. The rate constants depend on the type and
the position of the substituents. Obviously, the intro-
duction of the electron-withdrawing CF3 or Cl group to
the benzene ring enhances the reduction rate of the
Keywords: supercritical 2-propanol; reduction; Meerwein–Ponndorf–
Verley reduction; Hammett equation; kinetic isotope effect; acetophe-
none.
* Corresponding author. Tel.: +81-77-543-7461; fax: +81-77-543-7483;
e-mail: harada@rins.ryukoku.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00975-4

4552
T. Kamitanaka et al. / Tetrahedron Letters 44 (2003) 4551–4553
Table 1. The pseudo-first order rate constants of the reduction of various substituted acetophenones using supercritical
2-propanola
3%-Substituted
4%-Substituted
Substituent
H
CF3
6.4
Cl
CH3
4.6
CF3
7.3
Cl
CH3
3.9
Rate constant×105 (s−1
)
4.9
6.0
5.6
a Reaction conditions are described in the text. Mole ratio of substrate to 2-propanol is ca. 1:50.
acetophenone, whereas the electron-releasing CH3
group lowers the rate. These results indicate that the
reaction rates depend on the electron densities on the
carbonyl carbon of the acetophenones. The Hammett
equation6 has been well documented to evaluate the
effect of a substituent on the kinetics of many organic
reactions.7 Figure 1 shows the Hammett plots for the
reduction of acetophenones using supercritical 2-
propanol, where k0, k and | are the pseudo-first order
rate constants of acetophenone and substituted ace-
tophenones, and the Hammett’s substituent constants,
respectively. The Hammett plots give a straight line
Scheme 1.
with a positive slope (the Hammett’s reaction constant
z is 0.33). The small positive reaction constant suggests
reduction of acetophenone using supercritical 2-deu-
terio-2-propanol, the deuterium is exclusively trans-
ferred to the carbonyl carbon of acetophenone to give
1-deuterio-1-phenylethanol: mass spectrum of the
product reveals that no H/D exchange at the phenyl
and the methyl of acetophenone occurs during the
reaction.8 It is also showed that no H/D exchange in
the product occurred when it was treated with super-
critical 2-deuterio-2-propanol.
that this reaction involves a nucleophilic attack on the
carbonyl carbon by a slightly negative charged reagent.
It also suggests that this reaction contains no strongly
ionized intermediate or transition state.
Next, we examined the reduction of acetophenone
using supercritical 2-deuterio-2-propanol or O-deu-
terio-2-propanol. The kinetic isotope effect was
observed during both reductions using these deuteriated
2-propanols. The kH/kD values were 1.6 (2-deuterio-2-
propanol) and 2.0 (O-deuterio-2-propanol), respec-
tively. These results suggest that the eliminations of the
a- and O-hydrogens in 2-propanol are the rate deter-
mining step and simultaneously occur. During the
Based on the present results, we postulate that the
reduction of the carbonyl group using supercritical
2-propanol proceeds via a six-membered cyclic transi-
tion state similar to that of the Meerwein–Ponndorf–
Verley reduction,9 as shown in Scheme 1. During the
first step, 2-propanol coordinates to the carbonyl group
of acetophenone through the two hydrogens to form
the six-membered cyclic transition state. The donation
of the a- and O-hydrogens of 2-propanol to acetophe-
none then takes place. As a result, the acetophenone is
reduced to 1-phenylethanol and the 2-propanol is oxi-
dized to acetone.
References
1. (a) Jessop, P. G.; Leitner, W. Chemical Synthesis Using
Supercritical Fluids; Wiley-VCH: Weinheim, 1999; (b)
Baiker, A. Chem. Rev. 1999, 99, 453; (c) Bro¨ll, D.; Kaul,
C.; Kra¨mer, A.; Krammer, P.; Richter, T.; Jung, M.;
Vogel, H.; Zehner, P. Angew. Chem., Int. Ed. 1999, 38,
2999–3014; (d) Ikushima, Y.; Hatakeda, K.; Sato, O.;
Yokoyama, T.; Arai, M. J. Am. Chem. Soc. 2000, 122,
Figure 1. Hammett plots of the reduction of substituted
acetophenones using supercritical 2-propanol.

T. Kamitanaka et al. / Tetrahedron Letters 44 (2003) 4551–4553
4553
1908–1918; (e) Oka, H.; Yamago, S.; Yoshida, J.; Kaji-
moto, O. Angew. Chem., Int. Ed. 2002, 41, 623; (f) Mat-
suda, T.; Ohashi, Y.; Harada, T.; Yanagihara, R.;
Nagasawa, T.; Nakamura, K. Chem. Commun. 2001,
2194–2195; (g) Matsuda, T.; Kanamaru, R.; Watanabe,
K.; Harada, T.; Nakamura, K. Tetrahedron Lett. 2001, 42,
8319–8321.
1960, 82, 1773–1777; (b) Aramend´ıa, M. A.; Borau, V.;
Go´mez, J. F.; Herrera, A.; Jime´nez, C.; Marinas, J. M. J.
Catal. 1993, 140, 335–343; (c) Dolbier, W. R.; Rong, X. X.
Tetrahedron Lett. 1994, 35, 6225–6228; (d) Yamataka, H.;
Sasaki, D.; Kuwatani, Y.; Mishima, M.; Shimizu, M.;
Tsuno, Y. J. Org. Chem. 2001, 66, 2131–2135.
8. Transfer of the deuterium from 2-deutero-2-propanol to
acetophenone was confirmed by 1H NMR and GC–MS. In
the 1H NMR spectrum, the authentic 1-phenylethanol
exhibits a one-proton quartet signal of the benzyl proton
at l 4.84, whereas the signal was not observed for the
product. The spectrum of the product: (400 MHz, CDCl3)
l 1.48 (s, 3H), 1.85 (br, s, 1H), 7.26–7.39 (m, 5H); MS (EI)
m/z 123 (M+). For 1-phenylethanol: l 1.46 (d, J=6.5 Hz,
3H), 2.24 (br, s, 1H), 4.84 (q, J=6.4 Hz), 7.23–7.33 (m,
5H); MS (EI) m/z 122 (M+).
2. (a) Jessop, P. G.; Ikariya, T.; Noyori, R. Nature 1994, 368,
231–233; (b) Oku, T.; Ikariya, T. Angew. Chem., Int. Ed.
2002, 41, 3467–3479; (c) Horikawa, Y.; Uchino, Y.; Sako,
T. Chem. Lett. 2003, 32, 232–233.
3. Gubin, S. P. Doklad. Akad. Nauk. 1995, 345, 490–492.
4. (a) Hudlicky´, M. Reductions in Organic Chemistry; John
Wiley & Sons: New York, 1984; (b) Brown, H. C.; Krish-
namurthy, S. Tetrahedron 1979, 35, 567–607.
5. Nishimura, S. Handbook of Heterogeneous Catalytic
Hydrogenation for Organic Synthesis; John Wiley & Sons:
New York, 2001.
6. Jaffe´, H. H. Chem. Rev. 1953, 53, 191–261.
7. (a) Anderson, B. M.; Jencks, W. P. J. Am. Chem. Soc.
9. (a) de Graauw, C. F.; Peters, J. A.; van Bekkum, H.;
Huskens, J. Synthesis 1994, 1007–1017; (b) Ooi, T.; Miura,
T.; Itagaki, Y.; Ichikawa, H.; Maruoka, K. Synthesis 2002,
279–291.